Pathogenetische Konzepte der chronischen Pankreatitis

Zusammenfassung

Das Verständnis der pathogenetischen Vorgänge bei chronischer Pankreatitis ist nach wie vor lückenhaft. Mehrere in der Vergangenheit favorisierte Theorien (z. B. Obstruktionshypothese) haben sich nicht verifizieren lassen. Als formale Beschreibung des Krankheitsablaufes erscheint das Nekrose-Fibrose-Konzept sehr attraktiv. Die grundlegenden Mechanismen der Pathogenese bei akuter und chronischer Pankreatitis sind ähnlich. Ein wesentlicher Fortschritt war die Entdeckung mehrerer Mutationen im Trypsinogen, dem Trypsininhibitor (SPINK 1) und dem zystischen-Fibrose-Protein (CFTR) bei einigen Patienten mit chronischer Pankreatitis. Es ist zu erwarten, dass die Untersuchung dieser Mutationen das Konzept der Pathogenese der Pankreatitis auf eine solidere Basis stellen wird.

Summary

The understanding of the pathogenesis of chronic pancreatitis is limited. Several theories (i. e. obstruction hypothesis) were suggested in the past but could not be confirmed by experimental data. As a formal description of the course of the disease, the necrosis-fibrosis concept seems to be very attractive. According to this theory, there is no significant difference in the pathogenesis of acute and chronic pancreatitis. A major step was the identification of mutations of the cationic trypsinogen, the secretory trypsin inhibitor (SPINK 1) and the cystic-fibrosis protein (CFTR) in some patients. Investigation of these mutations may significantly contribute to a better understanding of the pathogenesis of chronic pancreatitis.

Schlüsselwörter

Chronische Pankreatitis - Pathogenese - Nekrose-Fibrose-Sequenz - Trypsinogen - Trypsininhibitor - CFTR

Key words

Chronic pancreatitis - Pathogenesis - Necrose-fibrose-sequence - Trypsinogen - Trypsin inhibitor - CFTR

Literatur

• 1 Adler G, Rohr G, Kern H F. Alteration of membrane fusion as a cause of acute pancreatitis in the rat.  Dig Dis Sci. 1982;  27 993-1002
• 2 Cohn J A, Friedman K J, Noone P G, Knowles M R, Silverman L M, Jowell P S. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.  N Engl J Med. 1998;  339 653-658
• 3 Comfort M W, Steinberg A G. Pedigree of a family with hereditary chronic relapsing pancreatitis.  Gastroenterology. 1952;  21 54-63
• 4 Ferec C, Raguenes O, Salomon R, Roche C, Bernard J P, Guillot M, Quere I, Faure C, Mercier B, Audrezet M P, Guillausseau P J, Dupont C, Munnich A, Bignon J D, Le Bodic L. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.  J Med Genet. 1999;  36 228-232
• 5 Gorry M C, Gabbaizedeh D, Furey W, Gates L K, Preston R A, Aston C E, Zhang Y, Ulrich C, Ehrlich G D, Whitcomb D C. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.  Gastroenterology. 1997;  113 1063-1068
• 6 Iovanna J, Orelle B, Keim V, Dagorn J C. Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis.  J Biol Chem. 1991;  266 24664-24669
• 7 Keim V, Iovanna J L, Dagorn J C. The acute phase reaction of the exocrine pancreas. Gene expression and synthesis of pancreatitis-associated proteins.  Digestion. 1994;  55 65-72
• 8 Keim V, Iovanna J L, Rohr G, Usadel K H, Dagorn J C. Characterization of a rat pancreatic secretory protein associated with pancreatitis.  Gastroenterology. 1991;  100 775-782
• 9 Klöppel G, Maillet B. Chronic pancreatitis. Evolution of the disease.  Hepato-Gastroenterology. 1991;  38 408-412
• 10 Kushner I. The acute phase response: an overview.  Methods Enzymol. 1988;  163 373-383
• 11 Lowenfels A B, Maisonneuve P, DiMagno E P, Elitsur Y, Gates L K, Perrault J, Whitcomb D C,. International Hereditary Pancreatitis Study Group . Hereditary pancreatitis and the risk of pancreatic cancer.  J Natl Cancer Inst. 1997;  89 442-446
• 12 Malka D, Vasseur S, Bödeker H, Ortiz E M, Dusetti N J, Verrando P, Dagorn J C, Iovanna J L. Tumor necrosis factor alpha triggers antiapoptotic mechanisms in rat pancreatic cells through pancreatitis-associated protein I activation.  Gastroenterology. 2000;  119 816-828
• 13 Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dork T, Manns M P. Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.  Am J Gastroenterol. 2000;  95 2061-2067
• 14 Ortiz E M, Dusetti N J, Vasseur S, Malka D, Bödeker H, Dagorn J C, Iovanna J L. The pancreatitis-associated protein is induced by free radicals in AR4-2J cells and confers cell resistance to apoptosis.  Gastroenterology. 1998;  114 808-816
• 15 Pitchumoni C S. Chronic pancreatitis: a historical and clinical sketch of the pancreas and pancreatitis.  Gastroenterologist. 1998;  6 24-33
• 16 Sahin-Toth M, Graf L, Toth M. Trypsinogen stabilization by mutation Arg117 → His: a unifying pathomechanism for hereditary pancreatitis.  Biochem Biophys Res Commun. 1999;  264 505-508
• 17 Sahin-Toth M, Toth M. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen.  Biochem Biophys Res Commun. 2000;  278 286-289
• 18 Schäfer C, Williams J A. Stress kinases and heat shock proteins in the pancreas: possible roles in normal function and disease.  J Gastroenterol. 2000;  35 1-9
• 19 Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.  N Engl J Med. 1998;  339 645-652
• 20 Rossi L, Pfützer R H, Parvin S, Ali L, Sattar S, Azad Kahn A K, Gyr N, Whitcomb D. SPINK 1/PSTI mutations are associated with tropical pancreatitis in Bangladesh. Pancreatology 2001; 1: 242-245
• 21 Subjeck J R, Shyy T T. Stress protein systems of mammalian cells.  Am J Physiol. 1986;  250 C1-17
• 22 Teich N, Mössner J, Keim V. Screening for mutations in the cationic trypsinogen: are they of relevance in chronic alcoholic pancreatitis.  Gut. 1999;  44 413-416
• 23 Teich N, Ockenga J, Hoffmeister A, Manns M, Mössner J, Keim V. Chronic pancreatitis associated with an activation-peptide mutation that facilitates trypsin activation.  Gastroenterology. 2000;  119 461-465
• 24 Whitcomb D C, Gorry M C, Preston R A, Furey W, Sossenheimer M J, Ulrich C D, Martin S P, Gates L K, Amann S T, Toskes P P, Liddle R, McGrath K, Uomo G, Post J C, Ehrlich G D. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.  Nat Genet. 1996;  14 141-145
• 25 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 7-10
• 26 Witt H, Luck W, Hennies H C, Classen M, Kage A, Lass U, Landt O, Becker M. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.  Nat Genet. 2000;  25 213-216
• 27 Witt H, Luck W, Becker M, Böhmig M, Kage A. et al . Mutation in the SPINK 1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis.  JAMA. 2001;  285 2716-2717