Clinical Manifestation

  • Tajana Pavić
  • Dominik Kralj
  • Jelena Forgač
  • Davor HrabarEmail author
  • Doris Ogresta
  • Vedran Tomašić
  • Ivan Lerotić
Part of the Clinical Gastroenterology book series (CG)


Diabetes is one of the most common chronic diseases and one of the leading causes of morbidity and mortality worldwide. Little is known about the correlation between diabetes and the pancreatobiliary tract. Diabetes mellitus and pancreatitis have complex relationships, with each serving as both a cause and a consequence of the other. The presence of diabetes not only increases the severity and worsens outcomes in acute pancreatitis; it is considered a risk factor for developing it. Post-pancreatitis diabetes is a novel disease entity, being increasingly recognized, which occurs even after one episode of pancreatitis. The mechanism underlying the association between diabetes mellitus and pancreatic cancer is complex, and probably involves immunological, hormonal, and metabolic changes which cause insulin resistance on one side and tumorogenesis on the other side. New onset of diabetes mellitus, especially in individuals with no predisposition, can be a first symptom of pancreatic cancer. Exocrine pancreatic insufficiency (EPI) is a commonly unrecognized complication not only associated with chronic pancreatitis but with a wide variety of conditions which can harm the pancreas. EPI in type 1 and 2 diabetes mellitus is fairly unrecognized although it has high prevalence. Type 3c diabetes mellitus is a separate condition caused by chronic pancreatic pathology such as chronic pancreatitis.


Acute pancreatitis Pancreatic cancer Exocrine pancreatic insufficiency Diabetes mellitus type 2 Clinical manifestations 



Acute necrotic collections


Acute pancreatitis


Body mass index


Diabetes mellitus


Exocrine pancreatic insufficiency


Fecal elastase-1 concentration


Metabolic syndrome


Non-alcoholic fatty liver disease


Non-alcoholic fatty pancreas disease


Non-alcoholic steatohepatitis


Non-alcoholic steatopancreatitis


Pancreatic duct gland


Reactive oxygenation species


Systemic inflammatory response syndrome


Walled-off necrosis


  1. 1.
    Albai O, Roman D, Frandes M. Hypertriglyceridemia, an important and independent risk factor for acute pancreatitis in patients with type 2 diabetes mellitus. Ther Clin Risk Manag. 2017;13:515–22.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Peery AF, Crockett SD, Barritt AS, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology. 2015;149(7):1731–41.e1.Google Scholar
  3. 3.
    Spanier B, Bruno MJ, Dijkgraaf MG. Incidence and mortality of acute and chronic pancreatitis in the Netherlands: a nationwide record-linked cohort study for the years 1995–2005. World J Gastroenterol. 2013;19:3018–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lindkvist B, Appelros S, Manjer J, Borgström A. Trends in incidence of acute pancreatitis in a Swedish population: is there really an increase? Clin Gastroenterol Hepatol. 2004;2:831–7.23.Google Scholar
  5. 5.
    Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144:1252–61.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Pant C, Deshpande A, Olyaee M, et al. Epidemiology of acute pancreatitis in hospitalized children in the United States from 2000–2009. PLoS One. 2014;9(5):e95552.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Forsmark CE, Vege SS, Wilcox CM. Acute pancreatitis. N Engl J Med. 2016;375:1972–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Shafqet M, Sharzehi K. Diabetes and the pancreatobilliary diseases. Curr Treat Options Gastrol. 2017;15:508.CrossRefGoogle Scholar
  9. 9.
    Forsmark CE. Incretins, diabetes, pancreatitis and pancreatic cancer: what the GI specialist needs to know. Pancreatology. 2016;16(1):10–3.Google Scholar
  10. 10.
    Gorelick FS, Lerch MM. Do animal models of acute pancreatitis reproduce human disease? Cell Mol Gastroenterol Hepatol. 2017 Sep;4(2):251–62.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Habtezion A. Inflammation in acute and chronic pancreatitis. Curr Opin Gastroenterol. 2015;31(5):395–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Catanzaro R, Cuffari B, Italia A, Marotta F. Exploring the metabolic syndrome: nonalcoholic fatty pancreas disease. World J Gastroenterol. 2016 Sep 14;22(34):7660–75.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Schludi B, Moin ASM, Montemurro C, et al. Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes. JCI Insight. 2017;2(13):e92282.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis — 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11.CrossRefGoogle Scholar
  15. 15.
    Tenner S, Baillie J, DeWitt J, Vege SS. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108:1400–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13(Suppl 2):e1–15.Google Scholar
  17. 17.
    Yang CJ, Chen J, Phillips AR, Windsor JA, Petrov MS. Predictors of severe and critical acute pancreatitis: a systematic review. Dig Liver Dis. 2014;46:446–51.CrossRefPubMedGoogle Scholar
  18. 18.
    Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638–52.CrossRefGoogle Scholar
  19. 19.
    Perez A, Whang EE, Brooks DC, et al. Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis? Pancreas. 2002;25:229–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Umapathy C, Raina A, Saligram S, Tang G, Papachristou GI, Rabinovitz M, et al. Natural history after acute necrotizing pancreatitis: a large US tertiary care experience. J Gastrointest Surg. 2016;20:1844–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;139:813–20.CrossRefGoogle Scholar
  22. 22.
    Schmidt PN, Roug S, Hansen EF, Knudsen JD, Novovic S. Spectrum of microorganisms in infected walled-off pancreatic necrosis. Impact on organ failure and mortality. Pancreatology. 2014;14:444–9.CrossRefPubMedGoogle Scholar
  23. 23.
    van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 2011;141:1254–63.CrossRefPubMedGoogle Scholar
  24. 24.
    van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362:1491–502.CrossRefGoogle Scholar
  25. 25.
    Huh JH, Jeon H, Park SM, et al. Diabetes mellitus is associated with mortality in acute pancreatitis. J Clin Gastroenterol. 2018;52:178–83. Scholar
  26. 26.
    Das SL, Singh PP, Phillips AR, Murphy R, Windsor JA, Petrov MS. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut. 2014;63(5):818–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Nikkola J, Laukkarinen J, Lahtela J, et al. The long-term prospective follow-up of pancreatic function after the first episode of acute alcoholic pancreatitis: recurrence predisposes one to pancreatic dysfunction and pancreatogenic diabetes. J Clin Gastroenterol. 2017;51(2):183–90.CrossRefPubMedGoogle Scholar
  28. 28.
    Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016;22(44):9694–705.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85.CrossRefPubMedGoogle Scholar
  31. 31.
    Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP, Boffetta P. Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog. 2012;51:3–13.CrossRefPubMedGoogle Scholar
  32. 32.
    Ansari D, Tingstedt B, Andersson B, Holmquist F, Sturesson C, Williamsson C, et al. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016;12(16):1929–46.CrossRefPubMedGoogle Scholar
  33. 33.
    Kamarajah SK, Burns WR, Frankel TL, Cho CS, Nathan H. Validation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with pancreatic adenocarcinoma: a surveillance, epidemiology and end results (SEER) analysis. Ann Surg Oncol. 2017;24:2023.CrossRefPubMedGoogle Scholar
  34. 34.
    Vrieling A, Bueno-de-Mesquita HB, Boshuizen HC, Michaud DS, Severinsen MT, Overvad K, et al. Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European prospective investigation into cancer and nutrition. Int J Cancer. 2010;126:2394–403.PubMedGoogle Scholar
  35. 35.
    Fuchs CS, Colditz GA, Stampfer MJ, Giovannucci EL, Hunter DJ, Rimm EB, et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med. 1996;156:2255.CrossRefPubMedGoogle Scholar
  36. 36.
    Lucenteforte E, La Vecchia C, Silverman D, Petersen GM, Bracci PM, Ji BT a. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case–Control Consortium (PanC4). Ann Oncol. 2012;23(2):374–82.CrossRefPubMedGoogle Scholar
  37. 37.
    Kudo Y, Kamisawa T, Anjiki H, Takuma K, Egawa N. Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis. Hepato-Gastroenterology. 2011;58:609–11.PubMedGoogle Scholar
  38. 38.
    Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog. 2012;51(1):53–63.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancreatic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol. 2014;21:2453–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Makhoul I, Yacoub A, Siegel E. Type 2 diabetes mellitus is associated with increased risk of pancreatic cancer: a veteran administration registry study. SAGE Open Med. 2016;4:205031211668225.CrossRefGoogle Scholar
  41. 41.
    Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005;129:504–11.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lu Y, García Rodríguez LA, Malgerud L, González-Pérez A, Martín-Pérez M, Lagergren J. New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer. Br J Cancer. 2015;113(11):1607–14.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol. 2015;44:186–98.CrossRefPubMedGoogle Scholar
  44. 44.
    Huang J, Magnusson M, Törner A, Ye W, Duberg AS. Risk of pancreatic cancer among individuals with hepatitis C or hepatitis B virus infection: a nationwide study in Sweden. Br J Cancer. 2013;109:2917.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013 September;63(5):318–48.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mujica VR, Barkin JS, Go VL. Acute pancreatitis secondary to pancreatic carcinoma. Study group participants. Pancreas. 2000;21:329.CrossRefPubMedGoogle Scholar
  47. 47.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.CrossRefPubMedGoogle Scholar
  48. 48.
    Duvnjak M. Tumori gušterače. In: Vrhovac B, Jakšić B, Vucelić B, editors. Interna medicina. Zagreb: Naklada Lijevak; 2008. p. 896–8.Google Scholar
  49. 49.
    Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655.CrossRefPubMedGoogle Scholar
  50. 50.
    Chen L, Li Y, Gebre W, Myocardial LJH. Cerebral infarction due to nonbacterial thrombotic endocarditis as an initial presentation of pancreatic adenocarcinoma. Arch Patho Lab Med. 2004;128:1307.Google Scholar
  51. 51.
    Ostler LS, Branfoot AC, Staughton RC. Cicatricial pemphigoid and carcinoma of the pancreas. Clin Exp Dermatol. 1992;17:67.CrossRefGoogle Scholar
  52. 52.
    Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. 2005;54(Suppl 6):vi1–v28.Google Scholar
  53. 53.
    DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288(16):813.CrossRefPubMedGoogle Scholar
  54. 54.
    Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19:7258–66.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev. 2012;28:338–42.CrossRefPubMedGoogle Scholar
  56. 56.
    Lankisch PG, Schmidt I, Konig H, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency. Gut. 1998;42:551–5.53.Google Scholar
  57. 57.
    Shivaprasad C, Pulikkal AA, Kumar KM. Pancreatic exocrine insufficiency in type 1 and type 2 diabetics of Indian origin. Pancreatology. 2015;15:616–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Weitgasser R, Abrahamian H, Clodi M, Zlamal-Fortunat S, Hammer HF. Exocrine pancreatic insufficiency and diabetes mellitus. Wien Klin Wochenschr. 2016;128(Suppl 2):S163–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1021 diabetic patients. Pancreatology. 2003;3:395–402.CrossRefPubMedGoogle Scholar
  60. 60.
    Ewald N, Raspe A, Kaufmann C, Bretzel RG, Kloer HU, Hardt PD. Determinants of exocrine pancreatic function as measured by fecal Elastase-1 concentrations (FEC) in patients with diabetes mellitus. Eur J Med Res. 2009;14:118–22.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Henderson JR, Daniel PM, Fraser PA. The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut. 1981;22:158–67.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Di Gialleonardo V, de Vries EF, Di Girolamo M, Quintero AM, Dierckx RA, Signore A. Imaging of β-cell mass and insulitis in insulin-dependent (type 1) diabetes mellitus. Endocr Rev. 2012;33:892–919.CrossRefPubMedGoogle Scholar
  63. 63.
    Campbell-Thompson M, Rodriguez-Calvo T, Battaglia M. Abnormalities of the exocrine pancreas in type 1 diabetes. Curr Diab Rep. 2015;15:79.Google Scholar
  64. 64.
    Gullo L, Pezzilli R. Follow-up of patients with chronic pancreatitis: what to do and which complications can be expected. In: Dominguez-Munoz J, editor. Clinical pancreatology for practising gastroenterologists and surgeons. Blackwell Publishing; 2008. p. 267–73.Google Scholar
  65. 65.
    Bellin MD, Whitcomb DC, Abberbock J, Sherman S, Sandhu BS, Gardner TB, 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;112:1457–65.CrossRefPubMedGoogle Scholar
  66. 66.
    Banks S. Chronic pancreatitis: clinical features and medical management. Am J Gastroenterol. 1986;81:153–67.Google Scholar
  67. 67.
    Lankisch PG, Lohr-Hoppe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Digestion. 1993;54:148–55.CrossRefPubMedGoogle Scholar
  68. 68.
    Del Prati S, Tiengo A. Pancreatic diabetes. Diab Rev. 1993;1:260–85.Google Scholar
  69. 69.
    Beger HG, Poch B, Mayer B, Siech M. New onset of diabetes and pancreatic exocrine insufficiency after pancreaticoduodenectomy for benign and malignant tumors: a systematic review and meta-analysis of long-term results. Ann Surg. 2017;267:259. Scholar
  70. 70.
    González-Sánchez V, Amrani R, González V, Trigo C, Picó A, de-Madaria E. Diagnosis of exocrine pancreatic insufficiency in chronic pancreatitis: 13C-mixed triglyceride breath test versus fecal elastase. Pancreatology. 2017;17:580–5.CrossRefPubMedGoogle Scholar
  71. 71.
    Elliott IA, Epelboym I, Winner M, Allendorf JD, Haigh PI. Population-level incidence and predictors of surgically induced diabetes and exocrine insufficiency after partial pancreatic resection. Perm J. 2017;21:16–095.PubMedCentralGoogle Scholar
  72. 72.
    Diem P. Pathogenesis and treatment of diabetes secondary to chronic pancreatitis. In: Buchler MW, Friess H, Uhl W, Malfertheiner P, editors. Chronic pancreatitis. Novel concepts in biology and therapy. Blackwell Publishing; 2002. p. 355–8.Google Scholar
  73. 73.
    von der Ohe MR. Diarrhoea in patients with diabetes mellitus. Eur J GastroenterolHepatol. 1995;7:730–6.Google Scholar
  74. 74.
    Lohr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, Lerch MM, et al. United European gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J. 2017;5:153–99.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Tajana Pavić
    • 1
    • 2
  • Dominik Kralj
    • 1
    • 2
  • Jelena Forgač
    • 1
    • 2
  • Davor Hrabar
    • 1
    • 2
    Email author
  • Doris Ogresta
    • 1
    • 2
  • Vedran Tomašić
    • 1
    • 2
  • Ivan Lerotić
    • 1
    • 2
  1. 1.Department of Gastroenterology and HepatologySestre milosrdnice University Hospital CenterZagrebCroatia
  2. 2.University of Zagreb School of MedicineZagrebCroatia

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