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Hereditary pancreatitis

Author
David C Whitcomb, MD, PhD
Section Editor
Melvin B Heyman, MD, MPH
Deputy Editor
Alison G Hoppin, MD

INTRODUCTION

Chronic or recurrent acute pancreatitis that occurs with an autosomal dominant pattern of inheritance has been termed hereditary pancreatitis. In some cases, hereditary pancreatitis may follow an autosomal recessive pattern of inheritance. When caused by mutations in the PRSS1 gene, this disorder has high penetrance and causes chronic or recurrent acute pancreatitis in both children and adults.  

Familial pancreatitis refers to pancreatitis from any cause that occurs in a family with an incidence that is greater than would be expected by chance alone, given the size of the family and the standardized incidence of pancreatitis within a defined population. Familial pancreatitis may or may not be caused by a genetic defect.

Issues related to hereditary pancreatitis will be reviewed here. The etiology, clinical manifestations, complications, and treatment of chronic pancreatitis in children and adults are discussed separately. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents" and "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children" and "Etiology and pathogenesis of chronic pancreatitis in adults" and "Clinical manifestations and diagnosis of chronic pancreatitis in adults" and "Overview of the complications of chronic pancreatitis" and "Treatment of chronic pancreatitis".)

GENETICS

There are at least three different inheritance patterns for chronic pancreatitis (see "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Genetic'). In addition, cases of pancreatitis without a family history may have a genetic basis (simplex case).

Autosomal dominant hereditary pancreatitis — This is most often associated with mutations in the serine protease 1 gene (PRSS1) on chromosome 7q35, which encodes trypsin-1 (cationic trypsinogen) [1-3]. Rarely, autosomal-dominant-appearing hereditary pancreatitis is identified in a kindred that does not have an identifiable PRSS1 mutation [4-6]. (See 'PRSS1' below.)

                    

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Literature review current through: Nov 2016. | This topic last updated: Fri May 06 00:00:00 GMT 2016.
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References
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  1. Whitcomb DC, Preston RA, Aston CE, et al. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996; 110:1975.
  2. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14:141.
  3. Gorry MC, Gabbaizedeh D, Furey W, et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997; 113:1063.
  4. Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2:252.
  5. LaFemina J, Roberts PA, Hung YP, et al. Identification of a novel kindred with familial pancreatitis and pancreatic cancer. Pancreatology 2009; 9:273.
  6. LaRusch J, Barmada MM, Solomon S, Whitcomb DC. Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. JOP 2012; 13:258.
  7. Schneider A, Larusch J, Sun X, et al. Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology 2011; 140:162.
  8. Rosendahl J, Landt O, Bernadova J, et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut 2013; 62:582.
  9. Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut 2009; 58:97.
  10. DiMagno MJ, DiMagno EP. Chronic pancreatitis. Curr Opin Gastroenterol 2005; 21:544.
  11. Applebaum-Shapiro SE, Finch R, Pfützer RH, et al. Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology 2001; 1:439.
  12. Howes N, Greenhalf W, Stocken DD, Neoptolemos JP. Cationic trypsinogen mutations and pancreatitis. Gastroenterol Clin North Am 2004; 33:767.
  13. Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut 2004; 53:1710.
  14. Schwarzenberg SJ, Bellin M, Husain SZ, et al. Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden. J Pediatr 2015; 166:890.
  15. 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; 117:7.
  16. Creighton J, Lyall R, Wilson DI, et al. Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis. Lancet 1999; 354:42.
  17. Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med 2010; 61:413.
  18. Genetic risk factors in chronic pancreatitis database. Available at: www.pancreasgenetics.org/ (Accessed on November 16, 2015).
  19. Sossenheimer MJ, Aston CE, Preston RA, et al. Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG). Am J Gastroenterol 1997; 92:1113.
  20. Witt H, Sahin-Tóth M, Landt O, et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 2006; 38:668.
  21. 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; 30:575.
  22. Sahin-Tóth M. Hereditary pancreatitis-associated mutation asn(21) --> ile stabilizes rat trypsinogen in vitro. J Biol Chem 1999; 274:29699.
  23. Teich N, Ockenga J, Hoffmeister A, et al. Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation. Gastroenterology 2000; 119:461.
  24. Teich N, Bauer N, Mössner J, Keim V. Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants. Am J Gastroenterol 2002; 97:341.
  25. Grocock CJ, Rebours V, Delhaye MN, et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut 2010; 59:357.
  26. Le Maréchal C, Masson E, Chen JM, et al. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet 2006; 38:1372.
  27. Whitcomb DC, LaRusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet 2012; 44:1349.
  28. Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am 2007; 36:325.
  29. Pfützer RH, Barmada MM, Brunskill AP, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000; 119:615.
  30. 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; 25:213.
  31. Schneider A, Barmada MM, Slivka A, et al. Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 Mutations. Scand J Gastroenterol 2004; 39:903.
  32. Shimosegawa T, Kume K, Masamune A. SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan. J Gastroenterol Hepatol 2008; 23 Suppl 1:S82.
  33. Aoun E, Chang CC, Greer JB, et al. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One 2008; 3:e2003.
  34. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 2003; 67:471.
  35. Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653.
  36. Ooi CY, Dorfman R, Cipolli M, et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 2011; 140:153.
  37. Cohn JA, Mitchell RM, Jowell PS. The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis. Clin Lab Med 2005; 25:79.
  38. LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol 2011; 27:467.
  39. LaRusch J, Jung J, General IJ, et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet 2014; 10:e1004376.
  40. Weiss FU, Simon P, Bogdanova N, et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut 2005; 54:1456.
  41. Cohn JA, Neoptolemos JP, Feng J, et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat 2005; 26:303.
  42. 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; 107:311.
  43. Gelrud A, Sheth S, Banerjee S, et al. Analysis of cystic fibrosis gener product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis. Am J Gastroenterol 2004; 99:1557.
  44. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339:645.
  45. Lowenfels A, Maisonneuve P, Palys B. Re: Ockenga et al.--mutations of cystic fibrosis gene in patients with pancreatitis. Am J Gastroenterol 2001; 96:614.
  46. 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; 40:78.
  47. Masson E, Chen JM, Scotet V, et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 2008; 123:83.
  48. LaRusch J, Lozano-Leon A, Stello K, et al. The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol 2015; 6:e68.
  49. 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 2013; 62:1616.
  50. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144:1292.
  51. Derikx MH, Kovacs P, Scholz M, et al. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut 2015; 64:1426.
  52. Masamune A, Nakano E, Hamada S, et al. Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan. Gut 2015; 64:1345.
  53. Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013; 45:1216.
  54. Santhosh S, Witt H, te Morsche RH, et al. A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis. Pancreas 2008; 36:317.
  55. Keim V, Bauer N, Teich N, et al. Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am J Med 2001; 111:622.
  56. Cui Y, Andersen DK. Pancreatogenic diabetes: special considerations for management. Pancreatology 2011; 11:279.
  57. Whitcomb DC. Genetic predispositions to acute and chronic pancreatitis. Med Clin North Am 2000; 84:531.
  58. Sibert JR. Hereditary pancreatitis in England and Wales. J Med Genet 1978; 15:189.
  59. 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; 89:442.
  60. Whitcomb DC, Applebaum S, Martin SP. Hereditary pancreatitis and pancreatic carcinoma. Ann N Y Acad Sci 1999; 880:201.
  61. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA 2001; 286:169.
  62. Ulrich CD, Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment. Pancreatology 2001; 1:416.
  63. Brand RE, Lerch MM, Rubinstein WS, et al. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut 2007; 56:1460.
  64. Kumar A, Ajilore O, Zhang A, et al. Cortical thinning in patients with late-life minor depression. Am J Geriatr Psychiatry 2014; 22:459.
  65. Ellis I, Lerch MM, Whitcomb DC, Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 2001; 1:405.
  66. Solomon S, Whitcomb DC. Genetics of pancreatitis: an update for clinicians and genetic counselors. Curr Gastroenterol Rep 2012; 14:112.
  67. Felderbauer P, Hoffmann P, Einwächter H, et al. A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterol 2003; 3:34.
  68. Whitcomb DC. Hereditary disease of the pancreas. In: Textbook of gastroenterology, 4 Ed, Yamada T, Alpers DH, Laine L (Eds), Lippincott, Williams and Wilkins, Philadelphia 2002. p.2147-65.
  69. Ellis, JH, Greenhalf, W, Howes, N, et al. Clinical and molecular findings of cationic trypsinogen mutations in 60 families with hereditary pancreatitis on the EUROPAC Register (abstract). Digestion 2000; 61:266.
  70. Uomo G, Talamini G, Rabitti PG. Antioxidant treatment in hereditary pancreatitis. A pilot study on three young patients. Dig Liver Dis 2001; 33:58.
  71. Burton F, Alkaade S, Collins D, et al. Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States. Aliment Pharmacol Ther 2011; 33:149.
  72. Kargl S, Kienbauer M, Duba HC, et al. Therapeutic step-up strategy for management of hereditary pancreatitis in children. J Pediatr Surg 2015; 50:511.
  73. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. Total pancreatectomy with islet autotransplantation: summary of a National Institute of Diabetes and Digestive and Kidney diseases workshop. Pancreas 2014; 43:1163.
  74. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2014; 14:27.
  75. Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg 2014; 218:530.
  76. Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation Lessons Learned From Over 500 Cases. Ann Surg 2015; 262:610.
  77. Chinnakotla S, Bellin MD, Schwarzenberg SJ, et al. Total pancreatectomy and islet autotransplantation in children for chronic pancreatitis: indication, surgical techniques, postoperative management, and long-term outcomes. Ann Surg 2014; 260:56.
  78. Rebours V, Lévy P, Mosnier JF, et al. Pathology analysis reveals that dysplastic pancreatic ductal lesions are frequent in patients with hereditary pancreatitis. Clin Gastroenterol Hepatol 2010; 8:206.
  79. Blondet JJ, Carlson AM, Kobayashi T, et al. The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Surg Clin North Am 2007; 87:1477.
  80. Rebours V, Boutron-Ruault MC, Jooste V, et al. Mortality rate and risk factors in patients with hereditary pancreatitis: uni- and multidimensional analyses. Am J Gastroenterol 2009; 104:2312.