Zusammenfassung
Langjähriger Alkoholkonsum und Genmutationen sind die wichtigsten Ursachen einer chronischen Pankreatitis. Neben Mutationen in azinären Genen wie Verdauungsenzymen und deren Inhibitoren sind in den letzten Jahren auch genetische Defekte beschrieben worden, die vornehmlich oder ausschließlich die Gangzellen betreffen. Genveränderungen finden sich nicht nur bei Patienten mit positiver Familienanamnese (hereditäre Pankreatitis), sondern auch bei sogenannter idiopathischer und – in geringerem Maße – bei alkoholischer chronischer Pankreatitis. In den nächsten Jahren wird sich wahrscheinlich zeigen, dass sehr komplexe Interaktionen zwischen Umwelteinflüssen und zahlreichen genetischen Faktoren bestehen.
Abstract
Long-term alcohol consumption and gene mutations are the most important causes of chronic pancreatitis. In addition to mutations in acinar genes, such as digestive enzymes and their inhibitors, defects in genes that primarily or exclusively affect the duct cells have also been described in recent years. Genetic changes are found not only in patients with a positive family history (hereditary pancreatitis) but also in so-called idiopathic and, to a lesser extent, in alcoholic chronic pancreatitis. The coming years will likely show that there are very complex interactions between environmental influences and numerous genetic factors.
Literatur
Andriulli A, Botteri E, Almasio PL et al (2010) Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas 39:1205–1210
Ammann RW (1997) A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. Pancreas 14:215–221
Bruce JI, Yang X, Ferguson CJ et al (1999) Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem 274:20561–20568
Chiari H (1896) Über Selbstverdauung des menschlichen Pankreas. Z Heilkd 17:69–96
Comfort MW, Steinberg AG (1952) Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 21:54–63
Durbec JP, Sarles H (1978) Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 18:337–350
Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, Durie P (2002) Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 123:1857–1864
Felderbauer P, Hoffmann P, Einwächter H et al (2003) A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterol 3:34
Fjeld K, Weiss FU, Lasher D et al (2015) A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet 47:518–522
Gui F, Zhang Y, Wan J et al (2020) Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1 R122H. J Clin Invest 130:189–202
Hegyi E, Sahin-Tóth M (2019) Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. Gut 68:301–312
Lasher D, Szabó A, Masamune A et al (2019) Protease-sensitive pancreatic lipase variants are associated with early onset chronic pancreatitis. Am J Gastroenterol 114:974–983
Lévy P, Mathurin P, Roqueplo A et al (1995) A multidimensional case-control study of dietary, alcohol, and tobacco habits in alcoholic men with chronic pancreatitis. Pancreas 10:231–238
Kereszturi É, Sahin-Tóth M (2017) Pancreatic cancer cell lines heterozygous for the SPINK1 p.N34S haplotype exhibit diminished expression of the variant allele. Pancreas 46:e54–e55
Maisonneuve P, Lowenfels AB, Müllhaupt B et al (2005) Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 54:510–514
Masamune A, Kotani H, Sörgel FL et al (2020) Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis. Gastroenterology 158:1626–1641
Rosendahl J, Witt H, Szmola R et al (2008) Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 40:78–82
Rosendahl J, Landt O, Bernadova J et al (2013) CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut 62:582–592
Rosendahl J, Kirsten H, Hegyi E et al (2018) Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. Gut 67:1855–1863
Sahin-Tóth M, Tóth M (2000) Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun 278:286–289
Sakata K, Araki K, Nakano H et al (2016) Novel method to rescue a lethal phenotype through integration of target gene onto the X‑chromosome. Sci Rep 6:37200
Seltsam K, Pentner C, Weigl F et al (2020) Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis. Pancreatology 20:1598–1603
Szmola R, Sahin-Tóth M (2007) Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht’s enzyme Y. Proc Natl Acad Sci U S A 104:11227–11232
Talamini G, Bassi C, Falconi M et al (1999) Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 44:1303–1311
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
Whitcomb DC, LaRusch J, Krasinskas AM et al (2012) Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet 44:1349–1354
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
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, Sahin-Tóth M, Landt O et al (2006) A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 38:668–673
Witt H, Beer S, Rosendahl J et al (2013) Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 45:1216–1220
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Interessenkonflikt
J. Rosendahl und H. Witt geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.
Additional information
Redaktion
Markus M. Lerch, München
Joachim Mössner, Leipzig
QR-Code scannen & Beitrag online lesen
Rights and permissions
About this article
Cite this article
Rosendahl, J., Witt, H. Pathogenese der chronischen Pankreatitis. Internist 62, 1007–1014 (2021). https://doi.org/10.1007/s00108-021-01150-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00108-021-01150-6