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Volker Keim

Publications and source records attributed to Volker Keim.

28 records · Page 2Linked to original sources
PubMed2003

Analysis of tumour necrosis factor alpha and interleukin 10 promotor variants in patients with chronic pancreatitis.

OBJECTIVE: Cationic trypsinogen gene mutations are strong risk factors of hereditary pancreatitis. However, 20% of subjects with a trypsinogen mutation never get pancreatitis and the cause of this incomplete penetrance is unknown. We investigated the influence of interleukin 10 (IL10) and tumour necrosis factor alpha (TNFalpha) promotor variants on the manifestation of chronic pancreatitis of different underlying causes and in pancreatic cancer. METHODS: A total of 335 German patients with chronic pancreatitis were investigated. In 157 patients the disease was related to alcohol abuse; the other cases were of non-alcoholic origin. In the latter group, the serine protease inhibitor, Kazal type 1 (SPINK1) mutation N34S was found in 72 patients and the trypsinogen mutations N29I or R122H were present in 60 patients; in the remaining 46 patients no mutation was found. In addition, we studied 208 patients with pancreatic cancer. As controls, 116 healthy blood donors and 25 healthy carriers of the trypsinogen mutations N29I or R122H were investigated. After DNA extraction from blood leucocytes, genotyping for the cytokine polymorphisms was performed by induced heteroduplex generators and/or direct DNA sequencing of the IL10 and TNFalpha promotor regions. RESULTS: The frequencies of the promotor polymorphisms of IL10-627A, IL10-1117A, TNF-238A and TNF-308A in patients with alcoholic chronic pancreatitis, idiopathic pancreatitis, SPINK1-N34S-associated chronic pancreatitis and pancreatic cancer did not differ significantly from the control group. The variant TNF-238A was two to four times more frequent in index patients with trypsinogen mutations than in all other groups. The analysis of the allelic frequencies of whole families with trypsinogen mutations revealed that all subjects with the TNF-238A variant suffered from chronic pancreatitis, whereas all intrafamilial controls with wild-type TNF were unaffected. CONCLUSIONS: TNFalpha and IL10 promotor variants are not associated with a manifestation of chronic pancreatitis or pancreatic cancer. The variant TNF-238A, however, might be a relevant risk factor for disease manifestation in families with hereditary pancreatitis.

Case-Control Studies↗
PubMed2003

N34S, a pancreatitis associated SPINK1 mutation, is not associated with sporadic pancreatic cancer.

BACKGROUND: The SPINK1 mutation N34S is associated to chronic pancreatitis of idiopathic, alcoholic and tropic origin. Our aim was to evaluate its prevalence in patients with sporadic pancreatic cancer. METHODS: The N34S allele of SPINK1 was analyzed by melting curve analysis using fluorescence resonance energy transfer (FRET) probes and the LightCycler in 159 German patients with sporadic pancreatic cancer (83 male, 76 female, median age of diagnosis 61 years, range 36-84 years) and 492 healthy controls. RESULTS: The N34S mutation was detected in 2 (1.3%) of the 159 patients with pancreatic cancer and in 8 (1.6%) of the 492 controls (not significant). CONCLUSION: The N34S mutation of SPINK1 appears not to be a distinct genetic risk factor in patients with sporadic pancreatic cancer.

Adult↗
PubMed2003

Identification of patients with genetic risk factors of pancreatitis: impact on treatment and cancer prevention.

Recent data suggest that genetic alterations are relevant risk factors for chronic pancreatitis. The highest risk is associated with autosomal-dominant mutations (N29I, R122H) of the cationic trypsinogen (PRSS1). Further mutations were identified in the genes of the pancreatic trypsin inhibitor (SPINK1) and in the cystic fibrosis transmembrane conductance regulator (CFTR). A remarkable finding was that both molecules were also mutated in patients suffering from alcoholic chronic pancreatitis. According to recent estimations, genetic alterations may be regarded as more severe risk factors than chronic alcohol consumption. To identify patients with mutations, a positive family history could be of help, but mutations were also found in a significant number of those with a negative family history. On the other hand, in approximately 40% of the patients with a positive family history no mutations were found up to now. The age at onset is lower in patients with genetic risk factors; however, no clear limit can be denominated above which a screening is not appropriate. Therefore, in our department genetic screening is offered to all patients with chronic pancreatitis of unclear origin. There is no specific treatment in patients with a genetically based disease. The patients with familial pancreatitis-increased rates of pancreas cancer were described but there is no agreement concerning the prophylactic strategy. Prevention of cancer by routine pancreatectomy, though performed recently, is not justified at the moment. Clinical criteria may be more appropriate to decide the timing and the extent of the operation.

Chronic Disease↗
PubMed2003

The course of genetically determined chronic pancreatitis.

CONTEXT: The clinical course of chronic pancreatitis in patients with mutations of cationic trypsinogen and the trypsin inhibitor SPINK1 has not yet been characterized. SETTING: Cationic trypsinogen (PRSS1) and the serine protease inhibitor, Kazal type 1 (SPINK1), were analyzed in patients with pancreatitis of unclear origin. PATIENTS: Eighty subjects with trypsinogen mutations (21x N29I, 59x R122H) and 59 patients with the SPINK1 N34S variant (11 homozygous, 48 heterozygous) were included in the study. MAIN OUTCOME MEASURES: In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded. DESIGN: Case control studies were performed to compare both mutational groups, and the follow-up time served as a matching criterion. The Kaplan-Meier analysis was used to estimate the time course of the symptoms. RESULTS: Ten years after the onset of the disease, the probability (+/-SE) of symptoms in patients with PRSS1 mutations was as follows: 1st hospital stay: 86+/-4%; calcification: 21+/-4%; duct dilatation: 26+/-9%; surgery: 19+/-5%; diabetes: 6+/-5%. After 25 years, we found the following data: 1st hospital stay: 96+/-3%; calcification: 38+/-8%; duct dilatation: 38+/-8%; surgery: 37+/-10%; diabetes: 28+/-8%. A case-control-study of 38 pairs of patients with either PRSS1 or SPINK1 mutations showed that the probability of duct dilatation, diabetes and calcification was slightly higher in patients having a SPINK1 mutation. There was no difference between those subjects with a homozygous or heterozygous SPINK1 mutation. In comparison to alcoholic chronic pancreatitis patients, the PRSS1 associated disease revealed a lower frequency of calcification and diabetes. CONCLUSIONS: The progression of chronic pancreatitis was slightly more rapid in patients with SPINK1 mutations than in patients with cationic trypsinogen mutations, but was much less than in those having alcoholic chronic pancreatitis.

Case-Control Studies↗
PubMed2003

Clinical value of a new fecal elastase test for detection of chronic pancreatitis.

INTRODUCTION: Several pancreatic function tests exist, but their role in the diagnosis of chronic pancreatitis is controversial. Here we analyzed the clinical value of a newly available fecal elastase assay. MATERIALS AND METHODS: Fecal samples from 212 patients treated in our hospital from January to September 2002 were taken. Chronic pancreatitis was assumed when ductal alterations were present in ERCP. The severity of disease was assessed according to the Cambridge classification. Elastase (test from ScheBo, Germany) and chymotrypsin (Roche Diagnostics) were measured. As a new parameter an elastase ELISA from BIOSERV (Rostock, Germany) was employed. Specificity, sensitivity, and accuracy of each test as well as the ROC curves were calculated. RESULTS: In 45 patients (21.2%) chronic pancreatitis was diagnosed. The sensitivities of elastase from ScheBo, elastase from BIOSERV and chymotrypsin were 68.9%, 77.8%, and 57.8%, respectively. The corresponding specificities were 77.2%, 76.0%, and 52.7%. When a cut-off for the elastase tests of 100 U/ml was used the sensitivities (57.8%) and the specificities (89.2%) for both elastase tests were similar. The areas under the ROC curves for the ScheBo elastase, BIOSERV elastase, and chymotrypsin were 0.805, 0.840, and 0.628, respectively. The higher AUC of the BIOSERV test was maintained when patients with mild-moderate chronic pancreatitis (Cambridge I-II) were analyzed separately. CONCLUSION: The new elastase assay could probably replace the older test and was also much better than chymotrypsin.

Area Under Curve↗
PubMed2002

Cathepsin B cleavage of the trypsinogen activation peptide.

BACKGROUND: Cathepsin B is thought to play a central role in intrapancreatic trypsinogen activation and the onset of pancreatitis. A recent investigation of the cathepsin B mediated activability of wildtype trypsinogen and their mutations N29I, N29T and R122H, which are associated to hereditary pancreatitis, revealed no differences. This action seems to be restricted to the K23-I24 peptide bond, which is the trypsinogen activation bond. Here we investigated the influence of the mutations D22G and K23R of the trypsinogen activation peptide on the cleavability by cathepsin B. METHODS: To investigate the functional impact of the TAP mutations on cathepsin B mediated cleavage of the trypsinogen activating K23-I24 bond, the corresponding peptides pWT, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; and pK23R, APFDDDDRIVGG were digested with cathepsin B for 30 min at pH 3.8 and 5.0, and the fragments were analysed by high-performance liquid chromatography. RESULTS: Without cathepsin B, less than 1 % of the peptides were hydrolysed. After a 30-minute digestion with cathepsin B at pH 5, 96% of pWT, 48% of pK23R, but only 2.4% of pD22G were hydrolysed. At pH 3.8, the cathepsin B cleavage of pWT and pK23R was less than at pH 5, whereas the cleavage of pD22G was completely inhibited. CONCLUSIONS: Cathepsin B mediated trypsinogen activation seems not to be a crucial pathogenic step in hereditary pancreatitis patients with the trypsinogen mutations D22G and K23R.

Cathepsin B↗
PubMed2002

[Genetic risk factors in pancreatic diseases--significance for general practice].

GENETIC RISK FACTORS: Recently, several genetic risk factors for chronic pancreatic diseases were found. In patients with chronic pancreatitis several mutations of the cationic trypsinogen were identified. In the majority of these subjects an autosomal dominant disease was observed. Mutations in the pancreatic secretory trypsin inhibitor (SPINK 1) were found in 20% of subjects with idiopathic, in 5% of those with alcoholic chronic and in 50% of those with tropical pancreatitis. Further variants were identified in CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), a chlorid transporter initially identified a disease-causing molecule in cystic fibrosis. In approximately 20-25% of the patients with chronic pancreatitis a mutation of one of these genes can be found. INDICATION FOR EXAMINATION: A genetic investigation is useful when there is evidence for a family history of chronic pancreatitis and, at absence of typical risk factors, in patients with onset of disease earlier than 35-40 years of age. RECOMMENDATIONS: In addition to alcohol abstinence the patients should be advised not to smoke. National and international registers as well as self-aid groups exist.

Chronic Disease↗
PubMed2002

Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants.

OBJECTIVES: Mutations of the cationic trypsinogen (CT) and the serine protease inhibitor, Kazal type 1 (SPINK 1) are associated with chronic pancreatitis. After mutational screening of a cohort of patients with nonalcoholic chronic pancreatitis, we report three novel variants of the trypsinogen molecule and the clinical characteristics of the carriers. METHODS: The coding region of the exon 2 and 3 of the CT gene of 523 patients with chronic nonalcoholic pancreatitis (108 patients with suspected hereditary pancreatitis (HP) and 415 patients with "idio pathic" pancreatitis [IP]) and 82 controls was analyzed after polymerase chain reaction amplification. Clinical characteristics were obtained by questioning the patients and their relatives and physicians. HP was suspected when two members of a family had chronic pancreatitis. A restriction digestion was used to analyze the N34S mutation SPINK1. RESULTS: The mutation R122H of the cationic trypsinogen was found in 21 index patients, N291 in six index patients, and A16V and D22G in one index patient, all from HP families. The N34S mutation of SPINK1 was found in two index patients with a family history of HP. In three patients, the novel point mutations L104P, R116C, and C139F of the cationic trypsinogen were found. A clear autosomally dominant inheritance of chronic pancreatitis was not present in these families. In 75 index patients from HP families (69.4%), no mutation could be found. The SPINK 1-mutation N34S was detected in only one patient carrying a CT mutation, and was found in 68 (16.4%) of patients with IP. CONCLUSIONS: The R122H and N291 mutations of CT are the most common disease-associated mutations in HP; the N34S mutation of SPINK I is the most frequent genetic risk factor associated with IP. The CT gene carries several variations that could be associated with chronic pancreatitis. To avoid overestimating the pathogenetic impact of novel trypsinogen variants, a detailed clinical characterization of all patients with early onset chronic pancreatitis is mandatory.

Adult↗
PubMedDate not supplied

Quality of life in chronic pancreatitis: a prospective trial comparing classical whipple procedure and duodenum-preserving pancreatic head resection.

Few data are available with respect to quality of life after pancreatic head resection in patients with chronic pancreatitis. The aim of this study was to compare the classical Whipple pancreatoduodenectomy (PD) with the Beger duodenum-preserving pancreatic head resection (DPPHR), in terms of quality of life, using standardized, valid, and reliable questionnaires. Sixty-five consecutive patients were included in this study. The PD procedure was chosen when pancreatic cancer could not be ruled out (n = 30); otherwise DPPHR was performed (n = 35). Quality of life was measured prospectively three times with the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) and the Gastrointestinal Quality-of-Life Index (GIQLI). Both procedures led to a significant improvement in quality of life, especially with regard to pain status. However, at the second follow-up examination (18 to 24 months postoperatively), all functional scales and the most important symptom scales of the EORTC QLQ-C30 revealed a better quality of life in the DPPHR group compared to the PD group. After classical PD, more patients seem to develop diabetes mellitus. The EORTC QLQ-C30 was found to be a better tool for quality-of-life assessment than the GIQLI in patients with chronic pancreatitis.

Chronic Disease↗