J.B.M.J. Jansen

Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis

BACKGROUND Although chronic pancreatitis is associated with risk factors such as alcoholism, hyperparathyroidism, and hypertriglyceridaemia, little is known of the actual aetiology of the disease. It is thought that inappropriate activation of trypsinogen causes pancreatitis, and indeed in cases of hereditary pancreatitis mutations of cationic trypsinogen (PRSS1) have been described. As serine protease inhibitor Kazal type 1 (SPINK1) is a potent natural inhibitor of pancreatic trypsin activity, we hypothesised that SPINK1 mutations would be more common than expected among an unselected cohort of adult chronic pancreatitis patients. AIMS To detect the prevalence of SPINK1 mutations in a cohort of chronic pancreatitis patients. METHODS DNA was isolated from a cohort of 115 adult patients with chronic pancreatitis of alcoholic (n=72), hereditary (n=10), idiopathic (n=24), and miscellaneous (n=9) origin. We performed mutational analysis for two PRSS1 mutations (R122H, N29I) and four specific SPINK1 gene mutations (M1T, L14P, N34S, P55S) and compared the results with a control group of 120 healthy Dutch subjects. RESULTS In six of the 10 patients that fulfilled the criteria for hereditary pancreatitis, but in none of the control subjects, mutations in the PRSS1 gene were found. In 14 patients we detected a SPINK1 mutation. Eleven patients were heterozygous for the N34S mutation and sequencing confirmed the homozygous state of N34S in a brother and sister. Two patients carried the P55S mutation, one as a compound heterozygote with N34S. The M1T and L14P SPINK1 mutations were not found in our cohort. The N34S mutation was detected in only two of 120 controls, while the P55S, M1T, and L14P mutations were absent in the same group. Patients with the N34S allele had a later onset of disease than those with PRSS1 gene mutations but earlier onset compared with the mutation negative group. CONCLUSION Identification of SPINK1 mutations in 12.2% of patients with adult alcoholic and idiopathic chronic pancreatitis suggests an important role for SPINK1 as a predisposing factor in adult chronic pancreatitis.

Review article: symptom improvement through eradication of Helicobacter pylori in patients with non‐ulcer dyspepsia

The aim of this article is to determine, by reviewing the literature, whether treatment of Helicobacter pylori infection in patients with non‐ulcer dyspepsia affects symptoms. Ten publications were identified through a computerized and manual literature search, and the percentage of patients with symptom improvement after successful or unsuccessful eradication therapy for H. pylori infection was calculated. In the 10 studies, symptom improvement after treatment was found in 73% of the patients that became H. pylori‐negative and 45% of the patients that remained H. pylori‐positive. Symptom improvement was modified by various clinical features and methodological aspects. If eradication of H. pylori failed, symptoms only improved over a short period. Symptom improvement was more pronounced in dyspeptic patients in whom H. pylori was eradicated than in those in whom H. pylori infection persisted.

Randomized controlled trial of omeprazole or endoscopy in patients with persistent dyspepsia: a cost‐effectiveness analysis

Cost‐effectiveness analysis, Helicobacter pylori research and the development of proton pump inhibitors are having an increasing impact on the management of dyspepsia. However, clinical trials have not always included both H. pylori diagnosis and proton pump inhibitors in their protocols.

FDG-PET scanning in the diagnosis of gastrointestinal cancers

This review deals with the current, well-established indications for two-([Formula: See Text]F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning in patients with gastrointestinal cancers. FDG-PET is a non-invasive, functional imaging technique. FDG exploits the native glucose transporter to enter the cell. Since many tumours have enhanced glucose uptake, FDG is readily accumulated in malignant cells and can be detected by a PET camera. FDG-PET has been established as an important diagnostic tool in clinical oncology. This review deals with the current, well-established indications for FDG-PET scanning in patients with gastrointestinal cancers. In the current practice, FDG-PET is most commonly used to stage oesophageal carcinoma, to detect and stage recurrence of colorectal carcinoma and to differentiate between benign and malignant pancreatic lesions. The benefit of FDG-PET scanning in patients with oesophagus carcinoma is best established in stage IV disease, as the diagnostic accuracy to detect metastatic disease is higher compared to the combination of computed tomography (CT) and endoscopic ultrasound (EUS). In patients with a history of colorectal carcinoma, FDG-PET scanning is particularly effective in diagnosing recurrent disease, especially in those with a rising carcinoembryonic antigen without a suspect lesion on conventional imaging. Large series have indicated that the sensitivity and specificity for detecting recurrent colorectal carcinoma are in the range of 87%-100% and 66%-100%, respectively. Equally, FDG-PET has a high sensitivity (68%-96%) and specificity (78%-100%) in detecting pancreatic carcinoma in patients with a suspicious-looking pancreatic mass on CT scan. Lastly, we focus on the use of FDG-PET as a modality for early monitoring of treatment response in patients with gastrointestinal stromal cell tumours. Without doubt, future developments will further establish the diagnostic role of the FDG-PET scan in the care of patients with gastrointestinal cancers.

Management in general practice of patients with persistent dyspepsia : A decision analysis

To determine whether an empirical drug treatment strategy (empirical group) instead of upper gastrointestinal endoscopy followed by treatment (conventional group) in patients with persistent dyspepsia increases appropriate use of endoscopy facilities, we did a decision analysis based on data found in the literature. We estimated the percentage of patients having an upper gastrointestinal endoscopy in 1 year, the percentage of patients with symptom relief, and the average medical costs per patient for both groups. In the empirical group, fewer patients (38%) had upper gastrointestinal endoscopies compared with the conventional group. Furthermore, an additional 5% of patients in the empirical group experienced symptom relief, and the average medical costs per patient were estimated to be 8% less in this group when compared with the patients in the conventional treatment group. The proposed empirical drug treatment strategy for patients with persistent dyspepsia results in the performance of fewer diagnostic upper gastrointestinal endoscopies per year with greater effectiveness compared with upper gastrointestinal endoscopy followed by treatment.

UGT1A7 polymorphisms in chronic pancreatitis: an example of genotyping pitfalls

UDP-glucuronosyltransferases (UGT) catalyze the glucuronidation of various compounds and thus inactivate toxic substrates. Genetic variations reducing the activity of UGT1A7 have been associated with various gastrointestinal cancers. Most recently, the UGT1A7*3 allele has been reported as a significant risk factor for pancreatic disorders, but we could not confirm these data. This study focused on the possible causes for the noted discrepancy. UGT1A7 genotypes were assessed in 37 samples, which were previously analyzed for UGT1A7 polymorphisms by others. We determined genotypes by melting curve analysis and by DNA sequencing. Additionally, we produced UGT1A7*1 and *3 constructs with or without a mutation at position − 57 of UGT1A7 and analyzed various combinations of these constructs. In 14/37 samples UGT1A7 genotyping results differed. The discrepancy could be explained by polymerase chain reaction bias owing to an unbalanced allelic amplification which was caused by a −57T>G variant located within the sequence of the chosen primer template in previous studies. Our findings indicate that most of the previously reported genetic associations between UGT1A7 and gastrointestinal cancers are based on primer-dependent genotyping errors.

Randomized controlled trial of omeprazole or endoscopy in patients with persistent dyspepsia: A cost-effectiveness analysis

BACKGROUND Cost-effectiveness analysis, Helicobacter pylori research and the development of proton pump inhibitors are having an increasing impact on the management of dyspepsia. However, clinical trials have not always included both H. pylori diagnosis and proton pump inhibitors in their protocols. METHODS Patients who were referred for upper gastrointestinal endoscopy by their general practitioner were randomized to either prompt endoscopy followed by directed medical treatment (conventional group, n=38), or to empirical treatment with omeprazole and, in the case of symptom relapse, serological screening for H. pylori infection followed by eradication therapy in seropositive patients (empirical group, n=42). The study lasted for up to 1 year. RESULTS In the empirical group, only 13 patients (31%) underwent endoscopy. The average number of days for which the patients kept records of their dyspeptic symptoms was 266 (95% CI: 226-307) in the empirical group, of which 166 (95% CI: 128-204) were symptom-free. In the conventional group, 159 (95% CI: 119-198) out of 255 days (95% CI: 209-302) were recorded as symptom-free. The average medical cost in the empirical group was

Mutational analysis of the gene encoding the zymogen granule membrane glycoprotein 2 (GP2) in patients with chronic pancreatitis.

284 (95% CI: 218-350) and in the conventional group

A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis

491 (95% CI: 383-600). In the empirical group, two malignancies were found, whereas in the conventional group one malignancy was found. CONCLUSIONS The empirical drug treatment strategy in patients with persistent dyspeptic symptoms resulted in 69% fewer diagnostic endoscopies with lower medical costs and equal effectiveness in the first year, compared to prompt endoscopy followed by directed medical treatment.

Short-Term Follow-Up by Serology of Patients Given Antibiotic Treatment for Helicobacter pylori Infection

Objectives: Premature activation of pancreatic digestive enzymes is considered as a major factor in the pathogenesis of pancreatitis. Genetic alterations of different pancreatic zymogens or their inhibitors have been associated with chronic pancreatitis (CP). Methods: We sequenced all 12 GP2 exons in 380 German CP patients and in 182 German control subjects. In addition, we analyzed exon 3 of GP2 in 803 further CP patients and 1780 controls originating from Germany, the Netherlands, and India by targeted DNA sequencing. Results: We detected 12 nonsynonymous and 6 synonymous exonic variants. All nonsynonymous changes with exception of c.220C>T (p.R74X) and c.502_503delG (p.G168fsX174) in exon 3 and c.541C>T (p.R181X) in exon 4 were missense mutations and predominantly located in exon 3. All nonsynonymous variants were found in single cases only, with exception of 2 alterations, c.355A>G (p.M119V) and c.409G>A (p. A137T), both located in exon 3. To elucidate the role of these 2 exon 3 variants, we investigated additional patients and controls. The frequency of these variants was similar between patients and controls regardless of ethnic background or cause of CP. Conclusions: Our data suggest that GP2 alterations do not alter the risk for the development of CP.