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Background & Aims Although serologic analysis is used in diagnosis of celiac disease, histopathology is considered most reliable. We performed a prospective study to determine the clinical, pathologic, and serologic spectrum of celiac disease in a general population (Kalixanda study). Methods A random sample of an adult general population (n = 1000) was analyzed by upper endoscopy, duodenal biopsy, and serologic analysis of tissue transglutaminase (tTg) levels; endomysial antibody (EMA) levels were analyzed in samples that were tTg+. The cut off values for diagnosis of celiac disease were villous atrophy with 40 intraepithelial lymphocytes (IELs)/100 enterocytes (ECs). Results Samples from 33 subjects were tTg+, and 16 were EMA+. Histologic analysis identified 7 of 1000 subjects (0.7%) with celiac disease; all were tTg+, and 6 of 7 were EMA+. Another 26 subjects were tTg+ (7/26 EMA+). This was addressed by a second quantitative pathology study (nested case control design) using a threshold of 25 IELS/100 ECs. In this analysis, all 13 samples that were tTg+ and EMA+ had ≥25 IELs/100 ECs. In total, 16 subjects (1.6%) had serologic and histologic evidence of gluten-sensitive enteropathy. IELs were quantified in duodenal biopsy samples from seronegative individuals (n = 500); 19 (3.8%) had >25 IELs and lymphocytic duodenosis. Conclusions Measurement of ≥25 IELs/100 ECs correlated with serologic indicators of celiac disease; a higher IEL threshold could miss 50% of cases. Quantification of tTg is a sensitive test for celiac disease; diagnosis can be confirmed by observation of ≥25 IELs/100ECs in duodenal biopsy specimens. Lymphocytic enteropathy (celiac disease and lymphocytic duodenosis) is common in the population (5.4%).

Background & Aims The Rome III criteria for functional dyspepsia have been changed to include 2 distinct syndromes: postprandial distress syndrome and epigastric pain syndrome. We investigated risk factors for functional dyspepsia among the functional dyspepsia subgroups defined by the Rome III criteria. Methods We performed a cross-sectional population-based study in a primary care setting (the Kalixanda study). A random sample (n = 2860) of the adult population from 2 northern Swedish municipalities (n = 21,610) was surveyed using a validated postal questionnaire to assess gastrointestinal symptoms (response rate, 74.2%; n=2122). A randomly selected subgroup (n = 1001) of responders was invited to undergo an esophagogastroduodenoscopy (participation rate, 73.3%) including biopsy specimen collection, Helicobacter pylori culture and serology, and symptom assessments. Results Of the 1001 subjects examined by endoscopy, 202 (20.2%; 95% confidence interval [CI], 17.7–22.7) were classified as having uninvestigated dyspepsia and 157 (15.7%; 95% CI, 13.4–18.0) as having functional dyspepsia. Major anxiety (Hospital Anxiety and Depression Scale score ≥11) was associated with uninvestigated dyspepsia (odds ratio [OR], 3.01; 95% CI, 1.39–6.54), as was obesity (body mass index ≥30 kg/m2) (OR, 1.86; 95% CI, 1.15–3.01). Major anxiety was associated with functional dyspepsia and postprandial distress syndrome (OR of 2.56 [95% CI, 1.06–6.19] and 4.35 [95% CI, 1.81–10.46], respectively), as was use of nonsteroidal anti-inflammatory drugs (OR, 2.49 [95% CI, 1.29–4.78] and 2.75 [95% CI, 1.38–5.50], respectively). Depression was not associated with any dyspepsia group. Conclusions Anxiety but not depression is linked to uninvestigated dyspepsia, functional dyspepsia, and postprandial distress syndrome but not to epigastric pain syndrome.

Background & Aims: Barrett's esophagus (BE) is associated with esophageal adenocarcinoma, the incidence of which has been increasing dramatically. The prevalence of BE in the general population is uncertain because upper endoscopy is required for diagnosis. This study aimed to determine the prevalence of BE and possible associated risk factors in an adult Swedish population. Methods: A random sample (n = 3000) of the adult population (n = 21,610) in 2 municipalities was surveyed using a validated gastrointestinal symptom questionnaire (response rate, 74%); a random subsample (n = 1000; mean age, 53.5 years; 51% female) underwent upper endoscopy. Endoscopic signs suggestive of columnar-lined esophagus (CLE) were defined as mucosal tongues or an upward shift of the squamocolumnar junction. BE was diagnosed when specialized intestinal metaplasia was detected histologically in suspected CLE. Results: BE was present in 16 subjects (1.6%; 95% confidence interval, 0.8–2.4): 5 with a long segment and 11 with a short segment. Overall, 40% reported reflux symptoms and 15.5% showed esophagitis; 103 (10%) had suspected CLE, and 12 (1.2%) had a visible segment ≥2 cm. The prevalence of BE in those with reflux symptoms was 2.3% and in those without reflux symptoms was 1.2% ( P = .18). In those with esophagitis, the prevalence was 2.6%; in those without, the prevalence was 1.4% ( P = .32). Alcohol ( P = .04) and smoking ( P = .047) were independent risk factors for BE. Conclusions: BE was found in 1.6% of the general Swedish population. Alcohol and smoking were significant risk factors.

Background & aims Functional dyspepsia (FD) is associated with anxiety but it is not clear if one causes the other. We investigated whether anxiety and depression precede the onset of FD (based on the modified Rome III criteria) and gastroesophageal reflux symptoms (GERS) in a population-based follow-up study. Methods Participants from the Kalixanda study (n = 3000), randomly selected from the national population register of Sweden, were given the validated Abdominal Symptom Questionnaire 1998-2001; 1000 of these participants then were selected randomly to undergo esophagogastroduodenoscopy and were given the Abdominal Symptom Questionnaire along with the Hospital Anxiety and Depression Scale questionnaire. All eligible subjects who underwent endoscopy (n = 887) were invited to participate in a follow-up study in June-August 2010 and were given the same questionnaires. Data were analyzed by logistic regression. Results Of the 703 subjects who completed the follow-up questionnaires (79.3%); 110 were found to have FD at baseline (15.6%) and 93 at the follow-up examination (13.3%); 48 of these were new cases of FD. GERS without organic disease was reported by 273 individuals (38.8%) at baseline and by 280 at follow-up examination (39.8%); 93 cases were new. Major anxiety was associated with FD at the follow-up evaluation (odds ratio [OR], 6.30; 99% confidence interval [CI], 1.64-24.16). Anxiety was associated with postprandial distress syndrome at baseline (OR, 4.83; 99% CI, 1.24-18.76) and at the follow-up examination (OR, 8.12; 99% CI, 2.13-30.85), but not with epigastric pain syndrome. Anxiety at baseline was associated with new-onset FD at the follow-up examination (OR, 7.61; 99% CI, 1.21-47.73), but not with GERS. Conclusions In a study of the Swedish population, anxiety at baseline, but not depression, increased the risk for development of FD by 7.6-fold in the next 10 years. Anxiety did not affect risk for GERS.

Background and aims: Gastroesophageal reflux disease (GERD) is common in the West and the increased incidence is associated with obesity. A third of those with symptoms of GERD have endoscopic signs of erosive esophagitis. Two thirds have non-erosive reflux disease; esophageal hypersensitivity may explain some but it is controversial whether an association of psychological distress exists with GERD. Epigastric pain and burning have been found to be associatedwith both hypersensitivity to gastric distension and the personality trait of neuroticism. It has also been shown that anxiety induction significantly increases the experienced acid-induced esophageal hyperalgesia. Visceral hypersensitivity has also been identified in a subset, although the relationship between specific gastric symptoms and physiological changes has been inconsistent. Our aim was to study whether nociceptive pressure pain threshold (PPT) or tolerance (PPTo) is decreased in GERD indicating pain hypersensitivity.Methods: The prospectively collected Northern Finland Birth Cohort 1966 (NFBC 1966) population (http://www.oulu.fi/nfbc/) is comprised of children from the two northernmost provinces of Finland, Oulu and Lapland with a date of birth Jan 1st Dec 31st, 1966 (12 231 children, 96.3% of all births during 1966 in that area). Between years 2013 and 2014, at the age of 46 years, a large health examination including both questionnaires (n=6868/10282, 67% response rate) and clinical examination (n=5851/10282, 57% response rate) was performed. For this study, 3810 subjects (n=1761, 46% male) were available. Uncomfortable pressure, i.e. PPT and intolerable pressure, i.e. PPTo were tested using an algometer (Somedic AB, Horby, Sweden) and the pressure was increased from 0 kPa at a constant rate of 50 kPa/s until the safety maximum of 1200 kPa. The measurements were done for four anatomical sites in the following order: 1) the upper trapezius muscle, 2) the tibialis anterior muscle, 3) the dorsal aspect of the wrist joint line, and 4) the L5/S1 interspinous space. GERD was defined according to the Montreal definition. Anxiety and depression were assessed with 25-items Hopkins Symptom Checklist with a cut off of 1.55. Smoking habits were recorded and body mass index (BMI) was calculated (kg/m). Data were analyzed by Tobit regression analysis adjusting for BMI, anxiety, depression and smoking and crude Kaplan-Meier curves were drawn. Results: 524 subjects (14%) had GERD (n=230, 44% male), 509 (13%) had anxiety (n=196, 39% male) and 852 (22%) had depression (n=340, 40% male). In the crude model, PPT and PPTo were decreased only in women with GERD (Fig.).The difference was explained by anxiety and depression based on the adjusted models. (Table) Conclusions: Psychological distress may explain pain hypersensitivity in women with GERD. Tobit regression analysis of pressure pain threshold and pain tolerance in females with GERD.

Background: Serotonin (5-HT) signaling in the small intestine is involved in motor, sensory and secretory pathways. Studies of neuroendocrine cell mapping in functional dyspepsia (FD), characterized by upper gastrointestinal motor and sensory disturbances, are scarce although it has been previously noted that there is no significant difference in numbers of 5HT cells in duodenum in post infectious FD vs. controls1. In patients with irritable bowel syndrome, another functional bowel disorder, a low density of duodenal neuroendocrine cells is also described2.Aim: To examine the content of neuroendocrine cells in the duodenum of subjects with FD, specifically the relative content of serotonin (5-HT) containing cells and to investigate a possible relationship between neuroendocrine cell numbers and FD subtypes. Methods: A random sample of an adult Swedish population (n = 1000) (the Kalixanda study) underwent upper endoscopy and biopsies taken from the duodenal bulb (D1) and the second part of duodenum (D2). From this study 23 subjects with FD were identified, 13 with postprandial distress syndrome (PDS), 10 with epigastric pain syndrome (EPS) and 12 healthy controls. Immunocytochemistry was performed for Chromogranin A (CGA) and 5-HT. Positive cells were quantified per mm2. Results: Cases and controls showed similar demographics. The number of CGA stained cells was significantly lower in FD patients both in D1 (p = 0.01) and D2 (p = 0.04) whereas there was no significant difference in 5-HT content. See figure. When EPS and PDS were studied separately, the number of CGA stained cells was significantly decreased in D1 in patients with EPS (p = 0.03). Conclusions: The number of duodenal neuroendocrine cells is decreased in FD compared with control subjects, but this is not due to a reduction in the number of 5-HT containing cells. It is possible that this reduction reflects reduced cellular densities of other hormones (e.g. somatostatin) which could result in a high secretion of gastric acid, with a change in motility or visceral sensitivity leading to dyspeptic symptoms in these cases. 1. Futagami S et al. Am J Gastroenterol. 2010 ;105:1835-42. 2. El-Salhy M et al. Scand J Gastroenterol. 2010 ;45:1435-9.

Objectives: Low-grade esophageal eosinophilia may be a manifestation of reflux disease but Eosinophilic Esophagitis (EoE) has previously been linked to Celiac disease (CD). However, population-based studies of the prevalence of EoE in patients with CD are lacking. Methods: A Population-based study of 1000 randomly selected adults in Northern Sweden. Study participants were invited to answer a questionnaire and undergo upper endoscopy. Three endoscopists performed all endoscopies during a 2.5-year period. Esophageal biopsies were obtained from 2 cm above, and at the Z-line. Any eosinophil infiltration of the epithelium was defined as esophageal eosinophilia and EoE was defined as having at least 15 eosinophils/ high power field (HPF, at magnification x40) in biopsies from the distal oesophagus. CD was defined on the basis of positive serology in parallel with mucosal abnormalities of the small intestine (increased number of intraepithelial lymphocytes and/or villous atrophy). We used Fisher's exact test to compare the prevalence of esophageal eosinophilia and EoE in patients with CD vs. controls who had also undergone upper endoscopy with biopsy. Results: Of the 1000 adults undergoing endoscopy, 48 (4.8%) had esophageal eosinophilia, 11 (1.1%) had EoE and 18 (1.8%) had CD. CD was diagnosed in 2/48 (4.2%) individuals with esophageal eosinophilia (controls: 16/952 (1.7%), p=0.21), but in none of the 11 individuals with EoE (controls: 18/989 (1.8%), p=1.0). Conclusion: This population-based study of 1000 individuals undergoing esophageal and duodenal biopsy found no increased risk of esophageal eosinophilia or EoE among individuals with CD.

Background and aims: Major changes were made in the Rome III criteria for functional dyspepsia where two distinct syndromes were postulated, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Our aim in a general population sample was to explore if quality of life, using the validated SF-36, is impaired in functional dyspepsia and among functional dyspepsia subgroups defined according to the Rome III definition. Method: A random sample (n=2,860) of the adult population of two northern Swedish municipalities (n=21,610) was surveyed using a validated questionnaire assessing gastrointestinal symptoms (ASQ) and the SF-36 for quality of life with the 8 standard domains Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Mental Health (MH), Vitality (VT), Social Functioning (SF) and Role Emotional (RE). A random sub-sample (n=1,001) of the responders was invited to undergo an esophagogastroduodenoscopy (participation rate 73.3%). The mean values of SF-36 domains in different dyspepsia categories were calculated. Multivariate logistic regression analysis, adjusting with age and sex, was used to analyze associations of different dyspepsia groups with dichotomized SF-36 domains. Results: SF-36 data were available in 999 of the 1,001 subjects endoscoped. 202 (20.2%) were classified as uninvestigated dyspepsia (UID) and 157 (15.7%) as functional dyspepsia (FD); 52 (5.2%) reported epigastric pain syndrome and 122 individuals (12.2%) had postprandial distress syndrome. FD was significantly associated with low scores in every SF-36 domain (all p≤0.01); EPS was associated only with worse Bodily Pain (p