Guest guest Posted December 9, 2002 Report Share Posted December 9, 2002 RESEARCH LETTER Mutation in the SPINK1 Trypsin Inhibitor Gene, Alcohol Use, and Chronic Pancreatitis To the Editor: In industrialized countries, chronic pancreatitis (CP) is caused by long-term alcohol abuse in about 70% of cases, whereas the cause is generally unknown in the other 30% of patients. Furthermore, it is unclear how alcohol use may lead to CP, and wide variation exists among individuals in their susceptibility to alcoholic CP (ACP). Only a minority of frequent drinkers develop ACP.1 However, genetic factors may also affect the pathogenesis of ACP. Recently, an N34S mutation in the pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1) gene was found in 18 of 96 patients with idiopathic or hereditary CP.2 Therefore, in such patients with ACP, a prominent pathogenic role of trypsin activity in the pancreatic acinar cell may be suspected. Methods We investigated the frequency of the N34S mutation of SPINK1 in 274 patients with ACP who were admitted to 1 of our 6 institutions between 1998 and 2000, as well as 98 patients with chronic alcoholism who presented with liver disease or for treatment of alcohol addiction but were without clinical evidence of pancreatitis, and 540 healthy controls (ie, 143 cord blood samples taken following a normal obstetric delivery and blood samples from 397 medical students and staff). Diagnosis of ACP was based on a typical history and at least 1 of the following criteria: pancreatic calcifications, characteristic histologic findings, ductal alterations, or persistent exocrine insufficiency. Patients with a family history of CP were excluded. Alcoholism was defined as an ethanol intake of more than 80 g/d in men and more than 60 g/d in women for at least 2 years.1 Forty-seven patients and 210 controls were from the United Kingdom, 173 patients and 428 controls were from Germany, and 54 patients were from Switzerland. Written or oral informed consent was obtained. The N34S mutation was analyzed as described previously.2 Statistical analysis was performed using cross-tabulation with the Fisher exact test (SPSS version 9.0; SPSS Inc, Chicago, Ill). Results The N34S mutation was detected in 16 (5.8%) of 274 patients with ACP. All these patients were heterozygous for the mutation. A heterozygous N34S mutation was found in only 1 (1.0%) of 98 patients with alcoholism without ACP and in 4 (0.8%) of 540 controls. The mutation was significantly more prevalent in patients with ACP vs patients with alcoholism but without CP (P = .004) and vs controls (P<.001). There were no significant differences in the frequency of N34S between controls and patients with alcoholism without CP or among the different ethnicities. Comment The SPINK1 N34S mutation appears to be a genetic risk factor for ACP. Studies investigating the cationic trypsinogen,3 1-antitrypsin, alcohol dehydrogenase, and HLA antigen have yielded negative or conflicting results,4 and a previously demonstrated association between cystic fibrosis mutations and CP was not confirmed in patients with ACP.5 Our results suggest that the pancreatic protease–protease inhibitor system plays a role in pathogenesis of ACP. Patients with chronic alcoholism have been found to have a significantly higher ratio of trypsinogen to trypsin inhibitor in their pancreatic fluids compared with controls without alcholism.6 This may indicate a weakening of the defense mechanism provided by trypsin inhibitor against premature zymogen activation. Because the majority of patients with alcoholism do not develop CP, our findings support the hypothesis that a combination of both exogenous and genetic factors may predispose to CP. Heiko Witt, MD Werner Luck, MD Becker, MD Department of Pediatrics Böhmig, MD Department of Medicine s Kage, MD Institute of Laboratory Medicine and Pathobiochemistry Humboldt University Berlin, Germany Kaspar Truninger, MD Rudolf W. Ammann, MD Department of Medicine Division of Gastroenterology University Hospital Zürich, Switzerland O'Reilly, MRCS Kingsnorth, FRCS, FACS Department of Surgery Derriford Hospital Plymouth, England Hans-Ulrich Schulz, MD Walter Halangk, PhD Department of Surgery Otto-von-Guericke University Magdeburg Volker Kielstein, MD Outpatient Clinic for Addiction Diseases Magdeburg, Germany Wolfram T. Knoefel, MD Department of Surgery Universitätsklinikum Eppendorf Hamburg, Germany Niels Teich, MD Volker Keim, MD Department of Medicine University of Leipzig Leipzig, Germany 1. Ammann RW. A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. Pancreas. 1997;14:215-221. MEDLINE 2. 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;25:213-216. MEDLINE 3. Teich N, Mössner J, Keim V. Screening for mutations of the cationic trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut. 1999;44:413-416. MEDLINE 4. Haber P, J, Apte M, Korsten M, Pirola A. Individual susceptibility to alcoholic pancreatitis: still an enigma. J Lab Clin Med. 1995;125:305-312. MEDLINE 5. Norton ID, Apte MV, Dixson H, et al. Cystic fibrosis genotypes and alcoholic pancreatitis. J Gastroenterol Hepatol. 1998;13:496-499. MEDLINE 6. Rinderknecht H, Stace NH, Renner IG. Effects of alcohol abuse on exocrine pancreatic secretion in man. Dig Dis Sci. 1985;50:65-71. Funding/Support: This work was supported by a grant from Sonnenfeld-Stiftung, Berlin, Germany. Letters Information Guidelines for Letters Letters Section Editors: J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor. Mark E. Armstrong www.top5plus5.com NW Chapter Rep Pancreatitis Association, International Mark E. Armstrong www.top5plus5.com NW Chapter Rep Pancreatitis Association, International Quote Link to comment Share on other sites More sharing options...
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