Functional dyspepsia patients have lower mucosal cholecystokinin concentrations in response to duodenal lipid.

BACKGROUND: Dyspeptic symptoms are frequently induced, or exacerbated, by fatty food ingestion. Excessive release of, and/or hypersensitivity to, cholecystokinin (CCK) may explain the exaggerated response to lipid in patients with functional dyspepsia (FD). Thus far, plasma CCK response has been evaluated. However, stimulation of CCK1 receptors on duodenal vagal afferents occurs in a paracrine manner, suggesting that mucosal CCK concentrations are relevant to quantify. Apolipoprotein A-IV stimulates mucosal CCK release. AIM: To investigate the hypothesis that fat-induced release of CCK and apolipoprotein A-IV (apoA-IV) is enhanced in the duodenum of FD patients. PATIENTS AND METHODS: Sixteen symptomatic FD patients and 10 healthy volunteers (HV) underwent duodenal perfusion with intralipid 20%, 2 kcal/min, for 60 min. Symptoms were scored and blood samples were collected every 15 min during lipid perfusion and 15 min after discontinuation when duodenal biopsies were taken. Plasma and mucosal concentrations of CCK and apoA-IV were quantified. RESULTS: Abdominal discomfort (P=0.001), nausea (P=0.05), and fullness (P=0.005) in response to duodenal lipid increased significantly only in FD patients. Following lipid infusion, the mean mucosal CCK concentration was lower in FD patients compared with HV (P<0.0001). Fasting concentrations and plasma response of CCK were comparable in FD patients and HV. Plasma apoA-IV response appeared to differ between patients and HV, whereas mucosal apoA-IV concentrations were similar. CONCLUSION: Our results suggest excessive local release of CCK in response to duodenal lipid in FD. This likely causes exaggerated stimulation of duodenal vagal afferents, explaining dyspeptic symptom generation. The mechanisms underlying elevated mucosal CCK release warrant further investigation.

In gastroesophageal reflux disease, differential gene expression in the duodenum points towards enhanced chylomicron production and secretion.

BACKGROUND: Duodenal signaling affects esophageal motility and perception, both pathophysiological factors in gastroesophageal reflux disease (GERD). Duodenal gene expression abnormalities, contributing to altered esophageal sensorimotor function, have not been reported to date. AIM: To identify differentially expressed genes in GERD patients' duodenum. METHODS: Twenty GERD patients (total 24-h acid exposure 6-12%, SAP ≥95%) and ten healthy controls (HC) were included. Two weeks prior to duodenal biopsy collection, ten patients discontinued proton pump inhibitor (PPI) treatment and ten took maximum dose PPI. RNA was profiled on an Affymetrix Human Genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA, USA). Genes exhibiting a fold change ≥ 1.4 (t test p value <1E-4) were considered differentially expressed. A subset of 21 differentially expressed genes was selected for confirmatory TaqMan low-density array RT-PCR. Mucosal apolipoprotein A-IV (apoA-IV) and cholecystokinin (CCK) concentrations were determined by ELISA and RIA, respectively. RESULTS: In GERD patients off PPI, 23 up- and 23 down-regulated genes relative to HC were found. In GERD patients on PPI, 33 and five genes were higher, respectively, lower expressed. The majority of up-regulated genes were associated with lipid absorption, particularly triglyceride resynthesis and intracellular vesicular transport, rate-limiting processes for chylomicron production and secretion. Differential expression of 11 genes was confirmed by RT-PCR. Mucosal apoA-IV and CCK concentrations (signaling proteins released upon chylomicron secretion) were similar in GERD patients and HC. CONCLUSIONS: The identified mRNA expression differences suggest that in GERD patients' duodenum, the chylomicron production and secretion potential is elevated, and may underlie a mechanism by which postprandial duodenal signaling contributes to GERD symptom generation.

Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study.

OBJECTIVES: Recent studies have raised concerns on the clinical effectiveness of clopidogrel when taken in combination with proton pump inhibitors (PPIs), demonstrating an increase in the occurrence of cardiovascular events. In this study, the association between the co-administration of a PPI and clopidogrel and the occurrence of cardiovascular and gastrointestinal (GI) events in a large cohort in the Netherlands was investigated. METHODS: A retrospective study was conducted using data from 4 million individuals. New clopidogrel users were identified between January 2006 and December 2007 and followed over time. The Kaplan-Meier method and Cox proportional hazard regression [corrected]analysis were used to calculate the risk of cardiovascular and GI outcomes in clopidogrel patients with or without PPI use. RESULTS: A total of 18,139 new clopidogrel users were identified; 5,734 subjects (32%) used PPIs concurrently. Patients on PPIs were significantly older, used more co-medications and suffered from more comorbidities. Use of clopidogrel and PPIs was associated with an increased risk of myocardial infarction (hazard ratio (HR) 1.93, 95% confidence interval (CI) 1.40-2.65), unstable angina pectoris (HR 1.79, 95% CI 1.60-2.03), and the composite endpoint (HR 1.75, 95% CI 1.58-1.94) compared with clopidogrel users without PPIs. PPI users also had an increased risk of GI events compared with non-PPI users (HR 4.76, 95% CI 1.18-19.17). CONCLUSIONS: New clopidogrel users on PPIs are at an increased risk of cardiovascular and GI complications compared with those who are not using a PPI. The inferior cardiovascular profile of clopidogrel users on PPIs and the occurrence of channeling bias may be important factors underlying this observation.

Sociodemographic factors influence use of proton pump inhibitors among users of nonsteroidal anti-inflammatory drugs.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs. Although adequate gastroprotection is indicated in individuals at high risk for upper gastrointestinal complications, underutilization of preventive strategies has been demonstrated. We investigated the utilization of proton pump inhibitors (PPIs) in high risk, short term users of NSAIDs and assessed the association between sociodemographic factors and the rates at which PPIs are prescribed. METHODS: A retrospective study was conducted using data from 2.8 million individuals. Short term use was defined as an isolated period of NSAID use between 7 to 30 days. Logistic regression was performed to determine sociodemographic factors associated with PPI inhibitor use. RESULTS: A total of 155,825 short term users of NSAID were identified. Of these, 52,842 subjects (33.9%) had 1 or more risk factors; 56.1% of these subjects did not receive PPIs. Utilization was associated with sociodemographic factors of patients (such as older age [odds ratio (OR), 1.80; 95% confidence interval (CI), 1.64-1.99], female gender [OR, 1.14; 95% CI, 1.10-1.18], risk factors for upper gastrointestinal complications [OR, 3.72; 95% CI, 3.45-4.00]) and physicians (such as female gender [OR, 1.09; 95% CI, 1.03-1.14], practice in a deprived area [OR, 0.57; 95% CI, 0.53-0.61], or an urban area [OR, 0.86; 95% CI, 0.82-0.90]). CONCLUSIONS: Adequate gastroprotection is not provided to more than 50% of short term users of NSAIDs who are at an increased risk for upper gastrointestinal complications. Utilization is associated with sociodemographic factors of patients and physicians.