Zusammenfassung
Der Schlüssel zum Verständnis der genetischen Ursachen der chronischen Pankreatitis war die Identifikation einer spezifischen Mutation des kationischen Trypsinogens bei mehreren großen Familien mit hereditärer chronischer Pankreatitis. In rascher Folge wurden weitere genetische Variationen dieses Gens auch bei kleineren Familien mit nur wenigen Betroffenen nachgewiesen. Wenig später wurden Mutationen des wichtigsten intrapankreatischen Trypsininhibitors SPINK1 in hoher Prävalenz sowohl bei Patienten mit idiopathischer, tropischer und alkoholischer chronischer Pankreatitis gefunden. Wir fassen hier interessante genetische und biochemische Befunde zusammen, stellen klinische Charakteristika der betroffenen Patienten vor und summieren die bisherigen Empfehlungen zur genetischen Analyse, zum klinischen Follow-up und zur Karzinomprävention.
Abstract
The identification of a specific mutation in the human cationic trypsinogen gene in large kindreds with hereditary pancreatitis was the key to understand the genetic background of chronic pancreatitis. Rapidly, other variants within the same gene were identified—even in small families with a minority of patients. Later, mutations of the most important intrapancreatic trypsin inhibitor SPINK1 were found with high prevalence in patients with idiopathic, tropical and alcoholic chronic pancreatitis. We summarize interesting genetic and biochemical findings, point to clinical features and review recommendations for genetic analysis, follow-up and cancer prevention.
This is a preview of subscription content, log in via an institution to check access.
Literatur
Beranek H, Teich N, Witt H et al. (2003) Analysis of tumour necrosis factor alpha and interleukin 10 promotor variants in patients with chronic pancreatitis. Eur J Gastroenterol Hepatol 15: 1223–1227
Chandak GR, Idris MM, Reddy DN et al. (2002) Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis. J Med Genet 39: 347–351
Chen JM, Raguenes O, Ferec C et al. (2000) A CGC>CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. J Med Genet 37: E36
Cohn JA, Friedman KJ, Noone PG et al. (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 339: 653–658
Comfort MW, Steinberg AG (1952) Pedigree of a family with hereditary pancreatitis. Gastroenterology 21: 54–63
Ellis I, Lerch MM, Whitcomb DC et al. (2001) Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 1: 405–415
Ferec C, Raguenes O, Salomon R et al. (1999) Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J Med Genet 36: 228–232
Freedman SD, Blanco P, Shea JC, Alvarez JG (2000) Mechanisms to explain pancreatic dysfunction in cystic fibrosis. Gastroenterol Clin North Am 84: 657–664
Gelrud A, Sheth S, Banerjee S 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
Gorry MC, Gabbaizedeh D, Furey W et al. (1997) Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113: 1063–1068
Howes N, Lerch MM, Greenhalf W et al. (2004) Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2: 252–261
Imoto M, DiMagno EP (2000) Cigarette smoking increases the risk of pancreatic calcification in late-onset but not early-onset idiopathic chronic pancreatitis. Pancreas 21: 115–119
Keim V, Bauer N, Teich N et al. (2001) Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am J Med 111: 622–626
Keim V, Witt H, Bauer N et al. (2003) The course of genetically determined chronic pancreatitis. JOP 4: 146–154
Kukor Z, Toth M, Pal G, Sahin-Toth M (2002) Human cationic trypsinogen. Arg(117) is the reactive site of an inhibitory surface loop that controls spontaneous zymogen activation. J Biol Chem 277: 6111–61117
Lowenfels AB, Maisonneuve P, Cavallini G et al. (1993) Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 328: 1433–1437
Lowenfels AB, Maisonneuve P, DiMagno EP et al. (1997) Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 89: 442–446
Lowenfels AB, Maisonneuve P, Whitcomb DC (2000) Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group. Med Clin North Am 84: 565–573
Malka D, Hammel P, Maire F et al. (2002) Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 51: 849–852
Miller AR, Nagorney DM, Sarr MG (1992). The surgical spectrum of hereditary pancreatitis in adults. Ann Surg 215: 39–43
Moir CR, Konzen KM, Perrault J (1992) Surgical therapy and long-term follow-up of childhood hereditary pancreatitis. J Pediatr Surg 27: 282–286
Rommens JM, Iannuzzi MC, Kerem B et al. (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245: 1059–1065
Sahin-Toth M (2000) Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis. J Biol Chem 275: 22750–22755
Sahin-Toth M, Toth M (2000) Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun 278: 286–289
Sharer N, Schwarz M, Malone G et al. (1998) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 339: 645–652
Simon P, Weiss FU, Sahin-Toth M et al. (2002) Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122→Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J Biol Chem 277: 5404–5410
Teich N, Le Marechal C, Kukor Z et al. (2004) Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79 K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). Hum Mutat 23: 22–31
Teich N, Mössner J, Keim V (1998) Mutations of the cationic trypsinogen in hereditary pancreatitis. Hum Mutat 12: 39–43
Teich N, Nemoda Z, Köhler H et al. (2005) Gene conversion between functional trypsinogen genes associated with chronic pancreatitis in a six-year-old girl. Hum Mutat 24: (in press)
Teich N, Ockenga J, Hoffmeister A et al. (2000) Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation. Gastroenterology 119: 461–465
Ulrich CD (2001) Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment. Pancreatology 1: 416–422
Whitcomb DC, Gorry MC, Preston RA et al. (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14: 141–145
Witt H (2003) Chronic pancreatitis and cystic fibrosis. Gut 52 [Suppl 2]: 31–41
Witt H, Luck W, Becker M (1999) A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 117: 7–10
Witt H, Luck W, Becker M et al. (2001) Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. JAMA 285: 2716–2717
Witt H, Luck W, Hennies HC 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
Interessenkonflikt:
Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Teich, N., Keim, V. & Mössner, J. Chronische Pankreatitis. Internist 46, 123–130 (2005). https://doi.org/10.1007/s00108-004-1320-6
Issue Date:
DOI: https://doi.org/10.1007/s00108-004-1320-6