Etiopathogenesis of chronic pancreatitis

Czech version

Authors: Mačinga; J. Špičák; T. Hucl
Authors‘ workplace: Klinika hepatogastroenterologie, IKEM, Praha
Published in: Gastroent Hepatol 2013; 67(4): 275-288
Category: Clinical and Experimental Gastroenterology: Review Article

Overview

Chronic pancreatitis is a progressive inflammatory disease, which leads to destruction of pancreatic parenchyma and its replacement with fibrotic tissue. Subsequently it is associated with exogenous and later endogenous alteration of pancreatic function. The most prevalent cause of chronic pancreatitis in western countries is alcohol overconsumption. However, etiology of the disease of most patients is multi-factorial and the disease is a result of combined actions of genetic, metabolical factors and also of the influence of external environment. Former theories explaining mechanisms of genesis of chronic pancreatitis as an effect of toxins, metabolites, oxidative stress, obstruction or necrosis, are supported by many observations, but they are also partially inconsistent. Recently, there has been a major advance in the understanding of the genetic predisposition of chronic pancreatitis. Mutations causing alteration in regulation of trypsin activity or secretion of ductal cells contributes to the origin of chronic pancreatitis and modify the course of the disease. Newer SAPE hypothesis links knowledge of previous theories into a step-wise model of chronic pancreatitis origin. Pathogenesis, similarly to etiology, is probably complex with involvement of various pathogenetic mechanisms, depending on the cause. A key moment in understanding the disease pathogenesis was the characterization of pancreatic stellate cells as effector elements of fibrogenesis. They represent central cells, which activate themselves and create fibrotic tissue as a response to different pathological events. Better understanding of pathogenetic mechanisms of chronic pancreatitis gives hope for new causal modalities for treatment.

Key words:
chronic pancreatitis – etiology – pathogenesis – pancreatic stellate cell – SAPE hypothesis

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
26. 7. 2013

Accepted:
12. 8. 2013

Sources

1. Lin Y, Tamakoshi A, Matsuno S et al. Nationwide epidemiological survey of chronic pancreatitis in Japan. J Gastroenterol 2000; 35(2): 136–141.

2. Tinto A, Lloyd DA, Kang JY et al. Acute and chronic pancreatitis – diseases on the rise: a study of hospital admissions in England 1989/90-1999/2000. Aliment Pharmacol Ther 2002; 16(12): 2097–2105.

3. Díte P, Starý K, Novotný I et al. Incidence of chronic pancreatitis in the Czech Republic. Eur J Gastroenterol Hepatol 2001; 13(6): 749–750.

4. Rinderknecht H, Stace NH, Renner IG. Effects of chronic alcohol abuse on exocrine pancreatic secretion in man. Dig Dis Sci 1985; 30(1): 65–71.

5. Liu JH, Wang ZX. Kinetic analysis of ligand-induced autocatalytic reactions. Biochem J 2004; 379(3): 697–702.

6. Bennett WS, Huber R. Structural and functional aspects of domain motions in proteins. CRC Crit Rev Biochem 1984; 15(4): 291–384.

7. Nemoda Z, Sahin-Tóth M. The tetra-aspartate motif in the activation peptide of human cationic trypsinogen is essential for autoactivation control but not for enteropeptidase recognition. J Biol Chem 2005; 280(33): 29645–29652.

8. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000; 95(10): 2795–2800.

9. Lerch MM, Gorelick FS. Early trypsinogen activation in acute pancreatitis. Med Clin North Am 2000; 84(3): 549–563.

10. Szmola R, Sahin-Tóth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht's enzyme Y. Proc Natl Acad Sci USA 2007; 104(27): 11227–11232.

11. Beer S, Zhou J, Szabó A et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut 2012.

12. Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci 2007; 52(1): 1–17.

13. Laskowski M, Wu FC. Temporary inhibition of trypsin. J Biol Chem 1953; 204(2): 797–805.

14. Steward MC, Ishiguro H. Molecular and cellular regulation of pancreatic duct cell function. Curr Opin Gastroenterol 2009; 25(5): 447–453.

15. Schneider A, Löhr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol 2007; 42(2): 101–119.

16. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984; 25(7): 756–759.

17. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120(3): 682–707.

18. Frulloni L, Gabbrielli A, Pezzilli R et al. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis 2009; 41(4): 311–317.

19. Whitcomb DC, Yadav D, Adam S et al. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 2008; 8(4–5): 520–531.

20. 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(11): 1035–1045.

21. Kristiansen L, Grønbaek M, Becker U et al. Risk of pancreatitis according to alcohol drinking habits: a population-based cohort study. Am J Epidemiol 2008; 168(8): 932–937.

22. Irving HM, Samokhvalov AV, Rehm J. Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. JOP 2009; 10(4): 387–392.

23. Corrao G, Bagnardi V, Zambon A et al. Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction 1999; 94(10): 1551–1573.

24. Lankisch PG, Lowenfels AB, Maisonneuve P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 2002; 25(4): 411–412.

25. Yadav D, Eigenbrodt ML, Briggs MJ et al. Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas 2007; 34(4): 390–398.

26. Deng X, Wang L, Elm MS et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005; 166(1): 93–106.

27. Singh M, LaSure MM, Bockman DE. Pancreatic acinar cell function and morphology in rats chronically fed an ethanol diet. Gastroenterology 1982; 82(3): 425–434.

28. Witt H, Luck W, Becker M et al. Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. JAMA 2001; 285(21): 2716–2717.

29. Rosendahl J, Witt H, Szmola R et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 2008; 40(1): 78–82.

30. Apte MV, Wilson JS, McCaughan GW et al. Ethanol-induced alterations in messenger RNA levels correlate with glandular content of pancreatic enzymes. J Lab Clin Med 1995; 125(5): 634–640.

31. Haber PS, Wilson JS, Apte MV et al. Chronic ethanol consumption increases the fragility of rat pancreatic zymogen granules. Gut 1994; 35(10): 1474–1478.

32. Apte MV, Phillips PA, Fahmy RG et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000; 118(4): 780–794.

33. Pandol SJ, Raraty M. Pathobiology of alcoholic pancreatitis. Pancreatology 2007; 7(2–3): 105–114.

34. Talamini G, Bassi C, Falconi M et al. Cigarette smoking: an independent risk factor in alcoholic pancreatitis. Pancreas 1996; 12(2): 131–137.

35. Chowdhury P, Bone RC, Louria DB et al. Effect of cigarette smoke on human serum trypsin inhibitory capacity and antitrypsin concentration. Am Rev Respir Dis 1982; 126(1): 177–179.

36. Bynum TE, Solomon TE, Johnson LR et al. Inhibition of pancreatic secretion in man by cigarette smoking. Gut 1972; 13(5): 361–365.

37. Crowley-Weber CL, Dvorakova K, Crowley C et al. Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact 2003; 145(1): 53–66.

38. 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(1): 42–46.

39. Tolstrup JS, Kristiansen L, Becker U et al. Smoking and risk of acute and chronic pancreatitis among women and men: a population-based cohort study. Arch Intern Med 2009; 169(6): 603–609.

40. Lindkvist B, Appelros S, Manjer J et al. A prospective cohort study of smoking in acute pancreatitis. Pancreatology 2008; 8(1): 63–70.

41. Castineira-Alvarino M, Luaces-Regueira M, Domínguez-Munoz JE. Tobacco has a synergistic effect with alcohol in pancreatic fibrogenesis: An in-vitro study in early and primary culture of pancreatic steallate cells. Pancreatology; 13 (3 Suppl): 53–54.

42. Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol 2004; 99(11): 2256–2270.

43. Howes N, Lerch MM, Greenhalf W et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2(3): 252–261.

44. Rebours V, Boutron-Ruault MC, Schnee M et al. The natural history of hereditary pancreatitis: a national series. Gut 2009; 58(1): 97–103.

45. Joergensen MT, Brusgaard K, Crüger DG et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol 2010; 105(8): 1876–1883.

46. Sahin-Tóth M, Tóth M. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun 2000; 278(2): 286–289.

47. Teich N, Rosendahl J, Tóth M et al. Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum Mutat 2006; 27(8): 721–730.

48. Teich N, Le Maréchal C, Kukor Z et al. Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). Hum Mutat 2004; 23(1): 22–31.

49. Kereszturi E, Szmola R, Kukor Z et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat 2009; 30(4): 575–582.

50. Nemoda Z, Sahin-Tóth M. Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen. J Biol Chem 2006; 281(17): 11879–11886.

51. Whitcomb DC. Genetic predisposition to alcoholic chronic pancreatitis. Pancreas 2003; 27(4): 321–326.

52. Witt H, Luck W, Becker M. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 1999; 117(1): 7–10.

53. Masson E, Le Maréchal C, Chandak GR et al. Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis. Clin Gastroenterol Hepatol 2008; 6(1): 82–88.

54. Le Maréchal C, Masson E, Chen JM et al. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet 2006; 38(12): 1372–1374.

55. Lowenfels AB, Maisonneuve P, DiMagno EP et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997; 89(6): 442–446.

56. Malka D, Hammel P, Maire F et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002; 51(6): 849–852.

57. Witt H, Sahin-Tóth M, Landt O et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 2006; 38(6): 668–673.

58. Rinderknecht H. Pancreatic secretory enzymes. In: Vay Liang WG, DiMagno EP, Gardner JD et al (eds). The Pankreas, Biology, Pathobiology, and Disease. New York: Raven Press 1993: 219–251.

59. Witt H, Luck W, Hennies HC et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25(2): 213–216.

60. Ohmuraya M, Hirota M, Araki M et al. Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice. Gastroenterology 2005; 129(2): 696–705.

61. Yadav D, Timmons L, Benson JT et al. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011; 106(12): 2192–2199.

62. Threadgold J, Greenhalf W, Ellis I et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 2002; 50(5): 675–681.

63. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144(6): 1292–1302.

64. Kuwata K, Hirota M, Shimizu H et al. Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. J Gastroenterol 2002; 37(11): 928–934.

65. Witt H, Luck W, Hennies HC et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25(2): 213–216.

66. Cohn JA, Friedman KJ, Noone PG et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339(10): 653–658.

67. Sharer N, Schwarz M, Malone G et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339(10): 645–652.

68. Noone PG, Zhou Z, Silverman LM et al. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001; 121(6): 1310–1319.

69. Chen JM, Férec C. Genetics and pathogenesis of chronic pancreatitis: the 2012 update. Clin Res Hepatol Gastroenterol 2012; 36(4): 334–340.

70. LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol 2011; 27(5): 467–474.

71. Felderbauer P, Klein W, Bulut K et al. Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis? Scand J Gastroenterol 2006; 41(3): 343–348.

72. Muddana V, Lamb J, Greer JB et al. Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1 type and alcohol. World J Gastroenterol 2008; 14(28): 4486–4491.

73. Chen JM, Férec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet 2009; 10: 63–87.

74. Spicak J, Pulkertova A, Kralova-Lesna I et al. Alcoholic chronic pancreatitis and liver cirrhosis: coincidence and differences in lifestyle. Pancreatology 2012; 12(4): 311–316.

75. Carey MC, Díte P, Gabryelewicz A et al. Future Perspectives in Gastroenterology. Dordrecht, The Netherlands: Springer 2008.

76. Pezzilli R. Etiology of chronic pancreatitis: has it changed in the last decade? World J Gastroenterol 2009; 15(38): 4737–4740.

77. Boerma D, Straatsburg IH, Offerhaus GJ et al. Experimental model of obstructive, chronic pancreatitis in pigs. Dig Surg 2003; 20(6): 520–526.

78. Reber HA, Karanjia ND, Alvarez C et al. Pancreatic blood flow in cats with chronic pancreatitis. Gastroenterology 1992; 103(2): 652–659.

79. Spicak J, Poulova P, Plucnarova J et al. Pancreas divisum does not modify the natural course of chronic pancreatitis. J Gastroenterol 2007; 42(2): 135–139.

80. Bertin C, Pelletier AL, Vullierme MP et al. Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. Am J Gastroenterol 2012; 107(2): 311–317.

81. Sahel J, Sarles H. Modifications of pure human pancreatic juice induced by chronic alcohol consumption. Dig Dis Sci 1979; 24(12): 897–905.

82. Bockman DE, Kennedy RH, Multigner L et al. Fine structure of the organic matrix of human pancreatic stones. Pancreas 1986; 1(3): 204–210.

83. Multigner L, De Caro A, Lombardo D et al. Pancreatic stone protein, a phosphoprotein which inhibits calcium carbonate precipitation from human pancreatic juice. Biochem Biophys Res Commun 1983; 110(1): 69–74.

84. Multigner L, Sarles H, Lombardo D et al. Pancreatic stone protein. II. Implication in stone formation during the course of chronic calcifying pancreatitis. Gastroenterology 1985; 89(2): 387–391.

85. Bimmler D, Graf R, Scheele GA et al. Pancreatic stone protein (lithostathine), a physiologically relevant pancreatic calcium carbonate crystal inhibitor? J Biol Chem 1997; 272(5): 3073–3082.

86. Mahurkar S, Bhaskar S, Reddy DN et al. Comprehensive screening for reg1alpha gene rules out association with tropical calcific pancreatitis. World J Gastroenterol 2007; 13(44): 5938–5943.

87. Hawrami K, Mohan V, Bone A et al. Analysis of islet regenerating (reg) gene polymorphisms in fibrocalculous pancreatic diabetes. Pancreas 1997; 14(2): 122–125.

88. Klöppel G, Maillet B. The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 1992; 420(1): 1–4.

89. DiMagno EP, Layer P, Clain JE. Chronic pancreatitis. In: Vay Liang WG, DiMagno EP, Gardner JD et al (eds). The Pankreas, Biology, Pathobiology, and Disease. New York: Raven Press 1993: 665–706.

90. Bordalo O, Goncalves D, Noronha M et al. Newer concept for the pathogenesis of chronic alcoholic pancreatitis. Am J Gastroenterol 1977; 68(3): 278–285.

91. Braganza JM. Pancreatic disease: a casualty of hepatic “detoxification”? Lancet 1983; 2(8357): 1000–1003.

92. Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002; 16(3): 347–363.

93. Watari N, Hotta Y, Mabuchi Y. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn 1982; 58(4–6): 837–858.

94. Ikejiri N. The vitamin A-storing cells in the human and rat pancreas. Kurume Med J 1990; 37(2): 67–81.

95. Bachem MG, Schneider E, Gross H et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115(2): 421–432.

96. Apte MV, Haber PS, Applegate TL et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998; 43(1): 128–133.

97. Apte MV, Phillips PA, Fahmy RG et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000; 118(4): 780–794.

98. Apte MV, Pirola RC, Wilson JS. Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J Gastroenterol Hepatol 2006; 21 (Suppl 3): 97–101.

99. Norman J, Franz M, Riker A et al. Rapid elevation of pro-inflammatory cytokines during acute pancreatitis and their origination within the pancreas. Surg Forum 1994; 45: 148–160.

100. Yokota T, Denham W, Murayama K et al. Pancreatic stellate cell activation and MMP production in experimental pancreatic fibrosis. J Surg Res 2002; 104(2): 106–111.

101. Menke A, Yamaguchi H, Gress TM et al. Extracellular matrix is reduced by inhibition of transforming growth factor beta1 in pancreatitis in the rat. Gastroenterology 1997; 113(1): 295–303.

102. Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroentol Hepatol 2010; 7(3): 131–45.

103. Woessner JF Jr. The family of matrix metalloproteinases. Ann N Y Acad Sci 1994; 732: 11–21.

104. Ishihara T, Hayasaka A, Yamaguchi T et al. Immunohistochemical study of transforming growth factor-beta 1, matrix metalloproteinase-2,9, tissue inhibitors of metalloproteinase-1,2, and basement membrane components at pancreatic ducts in chronic pancreatitis. Pancreas 1998; 17(4): 412–418.

105. Phillips PA, McCarroll JA, Park S et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut 2003; 52(2): 275–282.