Prevalence of Histological Gastritis in a Community Population and Association with Epigastric Pain.

BACKGROUND AND AIMS: Gastritis is a common histological diagnosis, although the prevalence is decreasing in developed populations, alongside decreasing prevalence of H. pylori infection. We sought to determine the prevalence of the etiology of gastritis in a Swedish population sample and to analyze any associations with symptoms, an area of clinical uncertainty. METHODS: Longitudinal population-based study based in Östhammar, Sweden. A randomly sampled adult population completed a validated gastrointestinal symptom questionnaire (Abdominal Symptom Questionnaire, ASQ) in 2011 (N = 1175). Participants < 80 years of age and who were eligible were invited to undergo esophagogastroduodenoscopy (EGD) (N = 947); 402 accepted and 368 underwent EGD with antral and body biopsies (average 54.1 years, range 20-79 years; 47.8% male) with H. pylori serology. RESULTS: Gastritis was found in 40.2% (148/368; 95% CI 35.2-45.2%). By rank, the most common histological subtype was reactive (68/148; 45.9%), then H. pylori (44/148; 29.7%), chronic non-H. pylori (29/148; 19.6%), and autoimmune (4/148; 2.7%). Gastritis was significantly associated with older age and H. pylori status (p < 0.01). Gastritis subjects were divided into three histological categories: chronic inactive inflammation, autoimmune gastritis, and active inflammation; there was no difference in the presence of upper gastrointestinal symptoms when categories were compared to cases with no pathological changes. Functional dyspepsia or gastroesophageal reflux were reported in 25.7% (38/148) of those with gastritis (any type or location) versus 34.1% (75/220) with no pathological changes (p = 0.32). Epigastric pain was more common in chronic H. pylori negative gastritis in the gastric body (OR = 3.22, 95% CI 1.08-9.62). CONCLUSION: Gastritis is common in the population with a prevalence of 40% and is usually asymptomatic. Chronic body gastritis may be associated with epigastric pain, but independent validation is required to confirm these findings. Clinicians should not generally ascribe symptoms to histological gastritis.

Food and functional dyspepsia: a systematic review.

BACKGROUND: Functional dyspepsia (FD) is a debilitating functional gastrointestinal disorder characterised by early satiety, post-prandial fullness or epigastric pain related to meals, which affects up to 20% of western populations. A high dietary fat intake has been linked to FD and duodenal eosinophilia has been noted in FD. We hypothesised that an allergen such as wheat is a risk factor for FD and that withdrawal will improve symptoms of FD. We aimed to investigate the relationship between food and functional dyspepsia. METHODS: Sixteen out of 6451 studies identified in a database search of six databases met the inclusion criteria of studies examining the effect of nutrients, foods and food components in adults with FD or FD symptoms. RESULTS: Wheat-containing foods were implicated in FD symptom induction in six studies, four of which were not specifically investigating gluten and two that were gluten-specific, with the implementation of a gluten-free diet demonstrating a reduction in symptoms. Dietary fat was associated with FD in all three studies that specifically measured this association. Specific foods reported as inducing symptoms were high in either natural food chemicals, high in fermentable carbohydrates or high in wheat/gluten. Caffeine was associated with FD in four studies, although any association with alcohol was uncertain. CONCLUSIONS: Wheat and dietary fats may play key roles in the generation of FD symptoms and reduction or withdrawal eased symptoms. Randomised trials investigating the roles of gluten, FODMAPs (fermentable oligosaccharide, disaccharide, monosaccharide and polyols) and high fat ingestion and naturally occurring food chemicals in the generation of functional dyspepsia symptoms are warranted and further investigation of the mechanisms is now required.

Functional dyspepsia is associated with duodenal eosinophilia in an Australian paediatric cohort.

BACKGROUND: The pathophysiology of functional dyspepsia (FD) remains unknown. Duodenal eosinophil infiltration has been reported. AIM: To assess the association between dyspeptic symptoms and duodenal eosinophilia in children undergoing upper gastrointestinal endoscopy. METHODS: In this retrospective cohort study, children with normal upper endoscopy and routine histology at a single tertiary paediatric centre between 2010 and 2014 were included. FD was defined as epigastric pain or discomfort >2 months without response to acid suppression. Controls presented with nonerosive reflux disease, dysphagia or rumination syndrome. Intramucosal eosinophil counts were compared between the groups using uni- and multivariate regression analyses. RESULTS: Thirty-six cases and 36 nonmatched controls were identified. Atopic history (39% vs. 25%) and psychological comorbidity (53% vs. 39%; both P = 0.2) were frequent in cases and controls. Self-reported nausea (64% vs. 17%; P < 0.0001), lethargy (19% vs. 0%; P = 0.005) and family functional gastrointestinal disorder(FGID) (28% vs. 3%; P = 0.003) were more common in cases than controls. Duodenal eosinophil counts [median (IQR): 151 (118-207) vs. 76 (60-106) per mm2 ; P < 0.001] were significantly higher in cases than controls with >112 eosinophils per mm2 predictive for FD (OR: 33.6, 95% CI: 7.1-159.0; P < 0.001). Duodenal eosinophilia was associated with weight loss (OR: 7.1, 95% CI: 1.1-45.5; P = 0.04). CONCLUSIONS: Functional dyspepsia in children is strongly associated with duodenal eosinophilia, in the absence of endoscopic or routine histological findings. Frequent atopic and psychological comorbidity illustrate likely multifactorial mechanisms.

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

Identification of early environmental risk factors for irritable bowel syndrome and dyspepsia.

BACKGROUND: The role of childhood environment including exposure to infection via siblings and pets in irritable bowel syndrome (IBS) and dyspepsia is relatively unknown. We assessed proxy measures of microbial exposure in early childhood to assess if these are associated with IBS and functional dyspepsia in later life. METHODS: Participants (n = 767, response rate = 53%) were a random population sample from Sydney, Australia who previously responded to a validated survey. IBS and functional dyspepsia were defined using Rome III criteria. Early environmental risk factors assessed included type of birth delivery, premature birth, breastfeeding, bedroom sharing, and pet exposure (the latter two then combined as early hygiene factors) up to 5 years of age. Post infectious IBS (PI-IBS) was assessed by development of IBS following gastroenteritis. KEY RESULTS: In this sample, in adult life 17% developed IBS (of which 20% had PI-IBS) and 12% functional dyspepsia. Development of IBS was associated with childhood factors-a shorter duration of breastfeeding (odds ratios [OR] = 0.87, 95% CI: 0.78-0.97, p = 0.01), sharing a bedroom (OR = 1.89, 95% CI: 1.73-3.08, p = 0.01), exposure to a herbivore pet (OR = 1.65 (1.10, 2.48), p = 0.02), and hygiene factors (OR = 4.39; 95% CI: 1.89-10.21, p = 0.001). The sole factor associated with functional dyspepsia was exposure to a herbivore pet (1.79; 95% CI: 1.19-2.87, p = 0.02). CONCLUSIONS & INFERENCES: Childhood environment factors, particularly bedroom sharing and pet exposure, combined with subsequent risk of microbial exposure are a risk factor for IBS in later life. These associations however need confirmation to rule out any risk of a type I error.

Increased prevalence of autoimmune diseases in functional gastrointestinal disorders: case-control study of 23471 primary care patients.

BACKGROUND: There is increasing evidence that impaired mucosal defence mechanisms are implicated in the pathogenesis of the functional gastrointestinal disorders (FGIDs), allowing inappropriate immune activation. AIM: To test the hypothesis that an excess of autoimmune disorders among sufferers, using a large primary care database to examine this. METHODS: Cases were diagnosed with FGIDs - irritable bowel syndrome (IBS), functional dyspepsia (FD), chronic idiopathic constipation (CIC), and multiple FGIDs. Controls were those without FGIDs. Prevalence of autoimmune disorders was compared between cases and controls using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 23,471 patients (mean age 51.4 years, 66.1% female). Prevalence of autoimmune disorders was greater among all FGIDs, compared with controls without. In those with FD (OR 1.35; 95% CI 1.12-1.63), CIC (OR 1.75; 95% CI 1.11-2.75), or multiple FGIDs (OR 1.49; 95% CI 1.25-1.77) this was statistically significant after controlling for age and gender. Rheumatological autoimmune disorders were significantly more frequent in those with FD (OR 1.44; 95% CI 1.15-1.80), CIC (OR 1.84; 95% CI 1.08-3.13), or multiple FGIDs (OR 1.53; 95% CI 1.24-1.88), after controlling for age and gender. However, endocrine autoimmune disorders were no more frequent in those with FGIDs, after controlling for age and gender. CONCLUSIONS: In a large sample of primary care patients, there was a significantly higher prevalence of autoimmune disorders among those with FD, CIC, or multiple FGIDs not explained by differences in age or gender. We were unable to control for concomitant drug use, which may partly explain this association.

The overlap of atopy and functional gastrointestinal disorders among 23,471 patients in primary care.

BACKGROUND: Activation of the immune system has been demonstrated in atopy and functional gastrointestinal disorders (FGIDs). Previous data from our group have suggested a connection between immune dysregulation, FGIDs and mood disorders. AIM: To investigate if these data translate to clinical practice and examine connections from the perspective of FGIDs to determine whether atopy and FGIDs are connected via mood disorders. METHODS: Evidence of irritable bowel syndrome (IBS), functional dyspepsia (FD) and constipation was sought from the medical records of 30,000 primary care records over a minimum 5 year period. The same records yielded diagnoses of four atopic conditions (asthma, eczema, allergic rhinitis/hay fever and conjunctivitis). RESULTS: Atopic conditions were found in excess among all FGID groups considered when compared with controls. In the groups with IBS alone (OR = 1.43, 1.29-1.58), FD alone (OR = 1.41, 1.26-1.58) and those with multiple FGIDs (OR = 1.92, 1.75-2.12) there was elevated prevalence of asthma compared with controls without a FGID. Across disorders the excess was generally highest among patients diagnosed with multiple FGIDs (rhinitis/hay fever OR = 3.74, 3.32-4.20; conjunctivitis OR = 3.00, 2.49-3.62) and was only partly explained by a common association between both FGIDs and atopic conditions with mood disorders, although not for every atopic/FGID combination (rhinitis/hay fever OR = 2.60, 2.29-2.96, conjunctivitis OR = 2.34, 1.90-2.87). CONCLUSIONS: Irritable bowel syndrome, functional dyspepsia and constipation share an association with atopy that is only partly explained via a common connection with mood disorders. These data have important implications for understanding both the pathophysiology of functional gastrointestinal disorders and development of new treatments.

Review article: bacteria and pathogenesis of disease in the upper gastrointestinal tract--beyond the era of Helicobacter pylori.

BACKGROUND: Study of the upper gastrointestinal microbiome has shown that other bacteria besides Helicobacter pylori flourish despite the hostile environment. Whilst H. pylori is the most studied bacteria in this region with a defined role in inflammation and neoplasia, it is apparent that other bacteria may contribute to UGI disease. AIM: To review current knowledge of bacteria inhabiting the oesophagus, stomach and duodenum. METHODS: Published studies on the upper gastrointestinal microbiome (extracted from PubMed during the last 20 years). RESULTS: The stomach is a hostile environment for bacteria; however, recent studies categorising the microbiota have shown surprising results. Helicobacter pylori has been intensively studied since 1984 and recent sequencing analysis of other gastric microbiota shows that H. pylori is not alone. Composition can be influenced by acid suppression, gastritis and abundance of H. pylori. Eradication of H. pylori, whilst decreasing gastric cancer is associated with an increase in asthma, reflux and obesity. A future approach may be to selectively eradicate bacteria which predispose to inflammation and cancer as opposed to a comprehensive knockout policy. In the oesophagus, viridans streptococci are the most common bacteria influenced by both oral and gastric bacteria. Oesophagitis and Barrett's oesophagus are characterised by a significant decrease in Gram-positive bacteria and an increase in Gram-negative bacteria. An inverse association of H. pylori and oesophageal adenocarcinoma is described. The duodenal microbiome has been shown to influence small intestinal bacterial overgrowth, irritable bowel syndrome and coeliac disease. The numbers of bacteria recoverable by culture are variable in the stomach mucosa and gastric juice, typically 10(2) -10(4) colony-forming units (CFU)/g or mL and in the oesophagus, up to 10(4) bacteria per mm(2) mucosal surface. In the small bowel, in health, 10(3) CFU/mL are normal. CONCLUSION: This review highlights current knowledge of upper gastrointestinal bacteria and associations with disease.

Comparing virtual with conventional microscopy for the consensus diagnosis of Barrett's neoplasia in the AspECT Barrett's chemoprevention trial pathology audit.

AIMS: To compare the diagnostic accuracy of conventional versus virtual microscopy for the diagnosis of Barrett's neoplasia. METHODS AND RESULTS: Sixty-one biopsies from 35 ASPirin Esomeprazole ChemopreventionTrial (AspECT) trial patients were given a Barrett's neoplasia score (1-5) by a panel of five pathologists using conventional microscopy. Thirty-three biopsies positive for neoplasia were digitized and rescored blindly by virtual microscopy. Diagnostic reliability was compared between conventional and virtual microscopy using Fleiss' kappa. There was substantial reliability of diagnostic agreement (κ = 0.712) scoring the 61 biopsies and moderate agreement scoring the subgroup of 33 'positive' biopsies with both conventional microscopy (κ = 0.598) and virtual microscopy (κ = 0.436). Inter-observer diagnostic agreement between two pathologists by virtual microscopy was substantial (κ = 0.76). Comparison of panel consensus neoplasia scores between conventional and virtual microscopy was almost perfect (κ = 0.8769). However, with virtual microscopy there was lowering of the consensus neoplasia score in nine biopsies. CONCLUSIONS: Diagnostic agreement with virtual microscopy compares favourably with conventional microscopy in what is recognized to be a challenging area of diagnostic practice. However, this study highlights possible limitations for this method in the primary diagnostic setting.

Implications of eosinophilia in the normal duodenal biopsy - an association with allergy and functional dyspepsia.

BACKGROUND: Allergy and functional gastrointestinal disorders have been associated with eosinophilia in duodenal mucosa. AIM: To assess the prevalence of eosinophilia in duodenal biopsies of patients attending for oesophogastroduodenoscopy and delineate associated clinical conditions. METHODS: A total of 155 patients (mean age 55 years, 59% women) with normal duodenal biopsies were randomly selected for audit from histopathology files. Eosinophil counts in five high power fields (HPFs) were assessed. Records were analysed for symptoms, diagnosis and medications; patients were divided into five groups based on upper gastrointestinal (UGI) symptom profiles, including a control group of those without predominant UGI symptoms. The prevalence of duodenal eosinophilia (defined as >22/5HPFs a priori) was calculated. RESULTS: In the control group, the mean duodenal eosinophil count was 15/5HPFs; prevalence of duodenal eosinophilia was 22.5%. In postprandial distress syndrome (PDS), both mean eosinophil counts (20.2/5HPF, P < 0.04) and prevalence of duodenal eosinophilia (47.3%, P < 0.04) were significantly higher. Duodenal eosinophilia was significantly associated with allergy (OR 5.04, 95% CI 2.12-11.95, P < 0.001). There was no association with irritable bowel syndrome or medications. CONCLUSIONS: Subtle duodenal eosinophilia is relatively common in routine oesophogastroduodenoscopy and previously overlooked; it is associated with allergy and may indicate a hypersensitivity mechanism in some patients with PDS including early satiety.

Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia.

BACKGROUND: Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common functional disorders without defined pathology. Mast cells and eosinophils interact with T lymphocytes and may alter enteric nerve and smooth muscle function. AIM: To examine mast cell, eosinophil and intraepithelial lymphocyte populations in duodenal biopsies of subjects with IBS and FD. METHODS: A random sample of an adult Swedish population (n = 1001; mean age 54 years; 51% female) underwent upper endoscopy and biopsy; 51 cases with FD and 41 cases with IBS were compared with 48 randomly selected controls. Eosinophils were identified by light microscopy; mast cells by immunocytochemistry (CD117). Intraepithelial lymphocytes were counted per 100 enterocytes. Cell counts were quantified by counting the number per high power field (HPF) in 5HPFs in the bulb (D1) and second part of duodenum (D2), summed over 5HPFs at each site. RESULTS: Cases and controls showed similar demographics. Compared to controls, IELs in IBS-constipation were significantly increased (P = 0.005). Mast cells were significantly increased in IBS in D2 (P < 0.001), while eosinophils were significantly increased in FD in D1 and D2 (P < 0.001). CONCLUSION: Duodenal mast cell hyperplasia is linked to IBS and eosinophilia to FD, and duodenal biopsy may identify subsets of these disorders.

Beta-subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression.

We previously identified high levels of Na(v)1.7 voltage-gated sodium channel alpha-subunit (VGSCalpha) mRNA and protein in human prostate cancer cells and tissues. Here, we investigated auxillary beta-subunit (VGSCbetas) expression. In vitro, the combined expression of all four VGSCbetas was significantly (approximately 4.5-fold) higher in strongly compared to weakly metastatic cells. This was mainly due to increased beta1-expression, which was under androgenic control. In vivo, beta1-beta4 mRNAs were detectable and their expression in CaP vs non-CaP tissues generally reflected the in vitro levels in relation to metastatic potential. The possible role(s) of VGSCbetas (VGSCalpha-associated and VGSCalpha-independent) in prostate cancer are discussed.

Regulation of prostate cell growth and morphogenesis by Dickkopf-3.

Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dickkopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNA-mediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression.

Brn-3a neuronal transcription factor functional expression in human prostate cancer.

Neuroendocrine differentiation has been associated with prostate cancer (CaP). Brn-3a (short isoform) and Brn-3c, transcriptional controllers of neuronal differentiation, were readily detectable in human CaP both in vitro and in vivo. Brn-3a expression, but not Brn-3c, was significantly upregulated in >50% of tumours. Furthermore, overexpression of this transcription factor in vitro (i) potentiated CaP cell growth and (ii) regulated the expression of a neuronal gene, the Nav1.7 sodium channel, concomitantly upregulated in human CaP, in an isoform-specific manner. It is concluded that targeting Brn-3a could be a useful strategy for controlling the expression of multiple genes that promote CaP.

A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo.

Functional expression of voltage-gated sodium channel alpha-subunits (VGSCalphas), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro. Furthermore, VGSC activity in vitro directly potentiates processes integral to metastasis. To investigate VGSCalpha expression in CaP in vivo, immunohistochemistry and real-time PCR were performed on human prostate biopsies (n>20). VGSCalpha immunostaining was evident in prostatic tissues and markedly stronger in CaP vs non-CaP patients. Importantly, RT-PCRs identified Nav1.7 as the VGSCalpha most strikingly upregulated (approximately 20-fold) in CaP, and the resultant receiver-operating characteristics curve demonstrated high diagnostic efficacy for the disease. It is concluded that VGSCalpha expression increases significantly in CaP in vivo and that Nav1.7 is a potential functional diagnostic marker.