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Mechanisms of Disease: advances in understanding the mechanisms leading to chronic pancreatitis

Nature Clinical Practice Gastroenterology & Hepatology volume 1, pages 46–52 (2004)Cite this article

Abstract

Chronic pancreatitis remains a challenging and frustrating clinical problem. In the past few years, however, advances in genetic and immunologic research have spawned new insights and approaches to chronic pancreatitis. Genetic and environmental risk assessment may help identify individuals who are likely to develop severe chronic pancreatitis early in the disease course, and allow targeted attention to reduce confounding risks and slow or prevent this problem in the future.

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Figure 1: Organization of the exocrine pancreas.
Figure 2: Research models of chronic pancreatitis.

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References

  1. Kloppel G and Maillet B (1991) A morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 6: 266–274

    CAS  PubMed  Google Scholar 

  2. Whitcomb DC et al. (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14: 141–145

    CAS  PubMed  Google Scholar 

  3. Gorry MC et al. (1997) Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113: 1063–1068

    CAS  PubMed  Google Scholar 

  4. Somogyi L et al. (2001) Recurrent acute pancreatitis: an algorithmic approach to identification and elimination of inciting factors. Gastroenterology 120: 708–717

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  7. Van Laethem J et al. (1996) Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology 110: 576–582

    CAS  PubMed  Google Scholar 

  8. Muller-Pillasch F et al. (1999) TGFbeta and the extracellular matrix in pancreatitis. Hepatogastroenterology 46: 2751–2756

    CAS  PubMed  Google Scholar 

  9. Bachem MG et al. (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115: 421–432

    CAS  PubMed  Google Scholar 

  10. Apte MV and Wilson JS (2003) Stellate cell activation in alcoholic pancreatitis. Pancreas 27: 316–320

    CAS  PubMed  Google Scholar 

  11. Whitcomb DC (2000) Genetic predispositions to acute and chronic pancreatitis. Med Clin North Am 84: 531–547

    CAS  PubMed  Google Scholar 

  12. Howes N et al. (2004) Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2: 252–261

    CAS  PubMed  Google Scholar 

  13. Teich N et al. (2000) Mutations of the activation peptide of cationic trypsinogen may lead to chronic pancreatitis by facilitated activation of trypsinogen to trypsin. Gastroenterology 118: a195

    Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Frick TW et al. (1997). Elevated calcium and activation of trypsinogen in rat pancreatic acini. Gut 41: 339–343

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sutton R et al. (2003) Signal transduction, calcium and acute pancreatitis. Pancreatology 3: 497–505

    CAS  PubMed  Google Scholar 

  18. Whitcomb DC : Value of genetic testing in management of pancreatitis. Gut (in press)

  19. Ward JB et al. (1996) Progressive disruption of acinar cell calcium signaling is an early feature of cerulein-induced pancreatitis in mice. Gastroenterology 111: 481–491

    CAS  PubMed  Google Scholar 

  20. Kruger B et al. (2000) The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis. Am J Pathol 157: 43–50

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Voronina S et al. (2002) Bile acids induce calcium signals in mouse pancreatic acinar cells: implications for bile-induced pancreatic pathology. J Physiol 540: 49–55

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pandol SJ et al. (1999) Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. Gastroenterology 117: 706–716

    CAS  PubMed  Google Scholar 

  23. Li H.S. et al. (2001) Rat mitochondrial ATP synthase ATP5G3: cloning and upregulation in pancreas after chronic ethanol feeding. Physiol Genomics 6: 91–98

    CAS  PubMed  Google Scholar 

  24. Teich N et al. (2002) Cathepsin B cleavage of the trypsinogen activation peptide. BMC Gastroenterol 2: 27

    Google Scholar 

  25. Kukor Z et al. (2002) Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. J Biol Chem 277: 21389–21396

    CAS  PubMed  Google Scholar 

  26. Witt H et al. (2000) Mutations in the gene encoding the serine protease inhibitor, kazal type 1 are associated with chronic pancreatitis. Nat Genet 25: 213–216

    CAS  PubMed  Google Scholar 

  27. Pfützer RH et al. (2000) SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 119: 615–623

    PubMed  Google Scholar 

  28. Rossi L et al. (2001) SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh: a preliminary report. Pancreatology 1: 242–245

    CAS  PubMed  Google Scholar 

  29. Sharer N et al. (1998) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Eng J Med 339: 645–652

    CAS  Google Scholar 

  30. Cohn JA et al. (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 339: 653–658

    CAS  PubMed  Google Scholar 

  31. Stern RC (1997) The diagnosis of cystic fibrosis. N Engl J Med 336, 487–491

    CAS  PubMed  Google Scholar 

  32. Whitcomb DC and Ermentrout DB (2004) A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice. Pancreas 29: E30–E40

    PubMed  Google Scholar 

  33. Reddy MM and Quinton PM (2003) Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells. Nature 423: 756–760

    CAS  PubMed  Google Scholar 

  34. Choi JY et al. (2001) Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature 410: 94–97

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Durno C et al. (2002) Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 123: 1857–1864

    PubMed  Google Scholar 

  36. Nguyen TD et al. (1999) Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2. J Clin Invest 103: 261–269

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Namkung W et al. (2004) Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis. Gastroenterology 126: 1844–1859

    PubMed  Google Scholar 

  38. Gelrud A et al. (2004) Analysis of cystic fibrosis gene product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis. Am J Gastroenterol 99: 1557–1562

    PubMed  Google Scholar 

  39. Ito T et al. (1997) Autoimmune pancreatitis as a new clinical entity. Three cases of autoimmune pancreatitis with effective steroid therapy. Dig Dis Sci 42: 1458–1468

    CAS  PubMed  Google Scholar 

  40. Okazaki K et al. (2000) Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology 118: 573–581

    CAS  PubMed  Google Scholar 

  41. Hamano H et al. (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: 732–738

    CAS  PubMed  Google Scholar 

  42. Sarles H (1965) Proposal adopted unanimously by the participants of the Symposium, Marseilles 1963. Bibl Gastroenterol 7: 7–8

    Google Scholar 

  43. Sarles H (1965) Pancreatitis: Symposium of Marseille, 1963. Basel: Karger

    Google Scholar 

  44. Shrikhande SV et al. (2003) Comparison of histological features and inflammatory cell reaction in alcoholic, idiopathic and tropical chronic pancreatitis. Br J Surg 90: 1565–1572

    CAS  PubMed  Google Scholar 

  45. Sarner M and Cotton PB (1984) Classification of pancreatitis. Gut 25: 756–759

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Homma T et al. (1997) Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 15: 14–15

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Chief, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA

    David C Whitcomb

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  1. David C Whitcomb
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Corresponding author

Correspondence to David C Whitcomb.

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Competing interests

The author declares that he owns the patent for testing for PRSS1 mutations, and has just licensed the patent to Ambry Genetics, Irvine, CA. He also serves as a consultant for Ambry Genetics and for Solvay Pharmaceuticals Inc., Marietta, GA, who make a pancreatic digestive enzyme product.

Glossary

HEREDITARY PANCREATITIS

An autosomal dominant disorder. Recurrent attacks of acute pancreatitis begin in childhood, chronic pancreatitis in adolescence and pancreatic cancer later in life

TRANSFORMING GROWTH FACTOR-β

This anti-inflammatory cytokine reduces the severity of acute pancreatitis, but stimulates the secretion of proteins involved in fibrosis

FAMILIAL PANCREATITIS

Pancreatitis in an individual in whose family pancreatitis occurs more frequently than expected by chance alone. Genetic defects might not be present

TROPICAL PANCREATITIS

An idiopathic form of recurrent acute pancreatitis and chronic pancreatitis that usually occurs in children in tropical latitudes

COMPLEX TRAIT

A trait with a non-Mendelian genetic component. Its expression may require the effects of two or more genes or gene–environment interactions

CHLORIDE-BICARBONATE ANTIPORTER

A membrane-bound ion-exchange molecule that transports chloride and bicarbonate across cell membranes in opposite directions

SPHINCTEROTOMY

A technique used to decrease resistance to the flow of bile or pancreatic juice and to facilitate the passage of material from the pancreatic ducts

MENDELIAN INHERITANCE

Conditions in which genetic traits are passed from parents to offspring following autosomal dominant, autosomal recessive or sex linked patterns

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Whitcomb, D. Mechanisms of Disease: advances in understanding the mechanisms leading to chronic pancreatitis. Nat Rev Gastroenterol Hepatol 1, 46–52 (2004). https://doi.org/10.1038/ncpgasthep0025

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