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
Prof. Dr. med. V. Keim
Universität Leipzig
Medizinische Klinik und Poliklinik II
Philipp-Rosenthal-Straße 27
04103 Leipzig
