Journal of Gastroenterology

, Volume 42, Supplement 17, pp 60–65

Is genetic analysis helpful for diagnosing chronic pancreatitis in its early stage?

  • Satoru Naruse
  • Kotoyo Fujiki
  • Hiroshi Ishiguro
Article
  • 76 Downloads

Abstract

Diagnosis of chronic pancreatitis in its early stage is an extremely difficult task. If the genetic predispositions are identified, it may help make possible the earlier diagnosis of chronic pancreatitis or the detection of patients at risk. There are two major hypotheses about the pathogenesis of chronic pancreatitis known as the “necrosis–fibrosis” and “pancreatic stone protein” hypotheses. Recent molecular and genetic evidence suggests that both pathways contribute to the pathogenesis of chronic pancreatitis. Chronic pancreatitis may be caused by either increased proteolytic activity [the cationic trypsinogen (PRSS1) gene] or decreased protease inhibition (the pancreatic secretory trypsin inhibitor (PSTI) gene]. The impaired pancreatic duct function [cystic fibrosis transmembrane conductance regulator (CFTR) gene] may also be involved in the pathogenesis of the disease. Except for PRSS1 mutations, the known genetic risk for chronic pancreatitis is not high. The high individual variability and low incidence of chronic pancreatitis suggest that yet unidentified genetic and environmental factors are important. Further genetic analysis is necessary for understanding the pathogenesis of chronic pancreatitis, which may be helpful for the earlier diagnosis of the juvenile- or young-onset disease.

Key words

chronic pancreatitis necrosis–fibrosis hypothesis pancreatic stone protein hypothesis PRSS1 gene PSTI gene CFTR gene 

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References

  1. 1.
    Kondo, T, Hayakawa, T, Noda, A, Ito, K, Yamazaki, Y, Iinuma, Y,  et al. 1981Follow-up study of chronic pancreatitisGastroenterol Jpn164653PubMedGoogle Scholar
  2. 2.
    Ammann, RW, Akovbiantz, A, Largiader, F, Schueler, G 1984Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patientsGastroenterology868208PubMedGoogle Scholar
  3. 3.
    Hayakawa, T, Kondo, T, Shibata, T, Sugimoto, Y, Kitagawa, M 1989Chronic alcoholism and evolution of pain and prognosis in chronic pancreatitisDig Dis Sci34338PubMedCrossRefGoogle Scholar
  4. 4.
    Layer, P, Yamamoto, H, Kalthoff, L, Clain, JE, Bakken, LJ, DiMagno, EP 1994The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitisGastroenterology10714817PubMedGoogle Scholar
  5. 5.
    Lankisch, PG, Lowenfels, AB, Maisonneuve, P 2002What is the risk of alcoholic pancreatitis in heavy drinkers?Pancreas254112PubMedCrossRefGoogle Scholar
  6. 6.
    Klöppel, G, Maillet, B 1993Pathology of acute and chronic pancreatitisPancreas865970PubMedCrossRefGoogle Scholar
  7. 7.
    Sarles, H, Bernard, JP, Gullo, L 1990Pathogenesis of chronic pancreatitisGut3162932PubMedGoogle Scholar
  8. 8.
    Guy, O, Robles-Diaz, G, Adrich, Z, Sahel, J, Sarles, H 1983Protein content of precipitates present in pancreatic juice of alcoholic subjects and patients with chronic calcifying pancreatitisGastroenterology841027PubMedGoogle Scholar
  9. 9.
    Whitcomb, DC, Gorry, MC, Preston, RA, Furey, W, Sossenheimer, MJ, Ulrich, CD,  et al. 1996Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen geneNat Genet141415PubMedCrossRefGoogle Scholar
  10. 10.
    Witt, H, Luck, W, Hennies, HC, Classen, M, Kage, A, Lass, U,  et al. 2000Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitisNat Genet252136PubMedCrossRefGoogle Scholar
  11. 11.
    Pfützer, RH, Barmada, MM, Brunskill, AP, Finch, R, Hart, PS, Neoptolemos, J,  et al. 2000PINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitisGastroenterology11961523PubMedCrossRefGoogle Scholar
  12. 12.
    Witt, H, Sahin-Toth, M, Landt, O, Chen, JM, Kahne, T, Drenth, JP,  et al. 2006A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitisNat Genet3866873PubMedCrossRefGoogle Scholar
  13. 13.
    Sharer, N, Schwarz, M, Malone, G, Howarth, A, Painter, J, Super, M,  et al. 1998Mutations of the cystic fibrosis gene in patients with chronic pancreatitisN Engl J Med33964552PubMedCrossRefGoogle Scholar
  14. 14.
    Cohn, JA, Friedman, KJ, Noone, PG, Knowles, MR, Silverman, LM, Jowell, PS 1998Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitisN Engl J Med3396538PubMedCrossRefGoogle Scholar
  15. 15.
    Steward, MC, Ishiguro, H, Case, RM 2005Mechanisms of bicarbonate secretion in the pancreatic ductAnnu Rev Physiol67377409PubMedCrossRefGoogle Scholar
  16. 16.
    Ko, SB, Naruse, S, Kitagawa, M, Ishiguro, H, Furuya, S, Mizuno, N,  et al. 2002Aquaporins in rat pancreatic interlobular ductsAm J Physiol Gastrointest Liver Physiol282G32431PubMedGoogle Scholar
  17. 17.
    Graf, R, Schiesser, M, Reding, T, Appenzeller, P, Sun, LK, Fortunato, F,  et al. 2006Exocrine meets endocrine: pancreatic stone protein and regenerating protein—two sides of the same coinJ Surg Res13311320PubMedCrossRefGoogle Scholar
  18. 18.
    Jin, CX, Naruse, S, Kitagawa, M, Ishiguro, H, Kondo, T, Hayakawa, S,  et al. 2002Pancreatic stone protein of pancreatic calculi in chronic calcified pancreatitis in manJOP35461PubMedGoogle Scholar
  19. 19.
    Sarles, H, Dagorn, JC, Giorgi, D, Bernard, JP 1990Renaming pancreatic stone protein as ‘lithostathineGastroenterology999001PubMedGoogle Scholar
  20. 20.
    Gross, J, Carlson, RI, Brauer, AW, Margolies, MN, Warshaw, AL, Wands, JR 1985Isolation, characterization, and distribution of an unusual pancreatic human secretory proteinJ Clin Invest76211526PubMedGoogle Scholar
  21. 21.
    Graf, R, Schiesser, M, Scheele, GA, Marquardt, K, Frick, TW, Ammann, RW,  et al. 2001A family of 16-kDa pancreatic secretory stress proteins form highly organized fibrillar structures upon tryptic activationJ Biol Chem2762102838PubMedCrossRefGoogle Scholar
  22. 22.
    Harada, H, Takeda, M, Yabe, H, Hanafusa, E, Hayashi, T, Kunichika, K,  et al. 1980The calcium concentration in human pure pancreatic juice in chronic pancreatitisGastroenterol Jpn1535561PubMedGoogle Scholar
  23. 23.
    Harada, H, Takeda, M, Yabe, H, Hanafusa, E, Hayashi, T, Kunichika, K,  et al. 1980The hexosamine concentration and output in human pure pancreatic juice in chronic pancreatitisGastroenterol Jpn155206PubMedGoogle Scholar
  24. 24.
    Nishimori, I, Kamakura, M, Fujikawa-Adachi, K, Morita, M, Onishi, S, Yokoyama, K,  et al. 1999Mutations in exons 2 and 3 of the cationic trypsinogen gene in Japanese families with hereditary pancreatitisGut4425963PubMedCrossRefGoogle Scholar
  25. 25.
    Otsuki, M, Nishimori, I, Hayakawa, T, Hirota, M, Ogawa, M, Shimosegawa, T 2004Research Committee on Intractable Disease of the Pancreas. Hereditary pancreatitis: clinical characteristics and diagnostic criteria in JapanPancreas282006PubMedCrossRefGoogle Scholar
  26. 26.
    Kaneko, K, Nagasaki, Y, Furukawa, T, Mizutamari, H, Sato, A, Masamune, A,  et al. 2001Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitisJ Hum Genet462937PubMedCrossRefGoogle Scholar
  27. 27.
    Kuwata, K, Hirota, M, Nishimori, I, Otsuki, M, Ogawa, M 2003Mutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in JapanJ Gastroenterol3836570PubMedCrossRefGoogle Scholar
  28. 28.
    Fujiki, K, Ishiguro, H, Ko, SB, Mizuno, N, Suzuki, Y, Takemura, T,  et al. 2004Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitisJ Med Genet41e55PubMedCrossRefGoogle Scholar
  29. 29.
    Cuppens, H, Lin, W, Jaspers, M, Costes, B, Teng, H, Vankeerberghen, A,  et al. 1998Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutationJ Clin Invest10148796PubMedCrossRefGoogle Scholar
  30. 30.
    Lee, JH, Choi, JH, Namkung, W, Hanrahan, JW, Chang, J, Song, SY,  et al. 2003A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseasesHum Mol Genet12232132PubMedCrossRefGoogle Scholar
  31. 31.
    Noda, A, Hamano, H, Shibata, T, Hayakawa, T, Tsuchie, K, Nimura, Y,  et al. 1987Chronic pancreatitis at early age of onset presenting interesting findings through endoscopic retrograde pancreatography and chemical analysis of nonopaque pancreatic concretionDig Dis Sci3243340PubMedCrossRefGoogle Scholar
  32. 32.
    Suda, K, Takase, M, Fukumura, Y, Suzuki, F, Jim, A, Kakinuma, C,  et al. 2004Histopathologic difference between chronic pancreatitis animal models and human chronic pancreatitisPancreas28e869PubMedCrossRefGoogle Scholar
  33. 33.
    Sakakibara, A, Okumura, N, Hayakawa, T, Kanzaki, M 1982Ultrastructural changes in the exocrine pancreas of experimental pancreatolithiasis in dogsAm J Gastroenterol77498503PubMedGoogle Scholar
  34. 34.
    Okumura, N, Sakakibara, A, Hayakawa, T, Noda, A 1982Pancreatic endocrine function in experimental pancreatolithiasis in dogsAm J Gastroenterol773926PubMedGoogle Scholar
  35. 35.
    Khalid, A, Finkelstein, S, Thompson, B, Kelly, L, Hanck, C,  et al. 2006A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetranceGut5572831PubMedCrossRefGoogle Scholar
  36. 36.
    Noone, PG, Zhou, Z, Silverman, LM, Jowell, PS, Knowles, MR, Cohn, JA 2001Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutationsGastroenterology12113109PubMedCrossRefGoogle Scholar
  37. 37.
    Threadgold, J, Greenhalf, W, Ellis, I, Howes, N, Lerch, MM, Simon, P,  et al. 2002The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the diseaseGut5067581PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Satoru Naruse
    • 1
  • Kotoyo Fujiki
    • 2
  • Hiroshi Ishiguro
    • 1
    • 2
  1. 1.Department of GastroenterologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of Human NutritionNagoya University Graduate School of MedicineNagoyaJapan

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