"True" Helicobacter pylori infection and non-cardia gastric cancer: A pooled analysis within the Stomach Cancer Pooling (StoP) Project.

BACKGROUND: Helicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status. METHODS: A pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted. RESULTS: The OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology. CONCLUSION: The NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

Worldwide and Regional Efficacy Estimates of First-line Helicobacter pylori Treatments: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Eradication of Helicobacter pylori infection is challenging. We aimed to determine the optimal first-line H. pylori treatments at global and regional levels. METHODS: We searched Embase, PubMed, Cochrane CENTRAL, Web of Science, Scopus, WHO ICTRP, ClinicalTrials.gov, and ISRCTN registry, for randomized controlled trials published during 2011-2020. Utilizing a network meta-analysis in a Bayesian framework, success rates of 23 regimens were compared. The effect size was standardized risk ratio (RR) with 95% credible interval (CrI). Pooled eradication rate (ER) with 95% CrI was also reported for top combinations. The reference regimen was 7-day clarithromycin-based triple therapy. RESULTS: This review identified 121 trials comprising 34,759 participants. Globally, 14-day levofloxacin-based sequential therapy was the most efficient (RR: 1.43; 95% CrI, 1.26-1.59) with low certainty of evidence, followed by modified bismuth-containing quadruple therapy (proton pump inhibitor+bismuth compounds+clarithromycin+amoxicillin) for 10 days (RR: 1.35; 95% CrI, 1.22-1.48) and 14 days (RR: 1.27; 95% CrI, 1.12-1.42), and 14-day hybrid therapy (RR: 1.27; 95% CrI, 1.19-1.36). The corresponding ERs were 98.7% (95% CrI, 86.9-100.0), 93.2% (95% CrI, 84.2-100.0), 87.6% (95% CrI, 82.1-93.8), and 87.6% (95% CrI, 77.3-98.0), respectively. Continentally, the most effective combinations were: 10-day clarithromycin-based sequential therapy [(RR: 1.21; 95% CrI, 1.02-1.42), (ER: 89.5%, 95% CrI, 75.5-100.0)] for Africa, 14-day levofloxacin-based sequential therapy [(RR: 1.41; 95%CrI, 1.27-1.58), (ER: 98.7%, 95% CrI, 88.9-100.0)] for Asia, and 14-day clarithromycin-based triple therapy [(RR: 1.58; 95% CrI, 1.25-2.04), (ER: 94.8%; 95% CrI, 75.0-100.0)] for Europe. For Northern America, no sufficient data were found for network meta-analysis. In South America, none of the combinations were superior to the reference regimen. CONCLUSION: Although results of this network meta-analysis revealed optimal combinations for empiric therapy, the treatment preference would be based on the local pattern of antibacterial resistance, when the necessary information exists.

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

OBJECTIVE: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.

Abdominal Compression by Waist Belt Aggravates Gastroesophageal Reflux, Primarily by Impairing Esophageal Clearance.

BACKGROUND & AIMS: Central obesity promotes gastroesophageal reflux, which may be related to increased intra-abdominal pressure. We investigated the effect of increasing abdominal pressure by waist belt on reflux in patients with reflux disease. METHODS: We performed a prospective study of patients with esophagitis (n = 8) or Barrett's esophagus (n = 6); median age was 56 years and median body mass index was 26.8. Proton pump inhibitors were stopped at least 7 days before the study and H2 receptor antagonists were stopped for at least 24 hours before. The severity of upper GI symptoms was assessed and measurements of height, weight, and waist and hip circumference taken. Combined high-resolution pH measurement and manometry were performed in fasted state for 20 minutes and for 90 minutes following a standardized meal. The squamocolumnar junction was marked by endoscopically placed radiopaque clips. The procedures were performed with and without a waist belt (a weight-lifter belt applied tightly and inflated to a constant cuff pressure of 50 mmHg). We compared variables between groups using the Wilcoxon Signed Rank test and tested for correlations using Spearman Rho bivariate analysis. RESULTS: Without the belt, intragastric pressure correlated with waist circumference (r = 0.682; P = .008), with the range in pressure between smallest and largest waist circumference being 15 mmHg. The belt increased intragastric pressure by a median of 6.9 mmHg during fasting (P = .002) and by 9.0 mmHg after the meal (P = .001). Gastroesophageal acid reflux at each of the pH sensors extending 5.5 cm proximal to the peak lower esophageal sphincter pressure point was increased by approximately 8-fold by the belt (all P < .05). Following the meal, the mean number of reflux events with the belt was 4, vs 2 without (P = .008). Transient lower esophageal sphincter relaxations were not increased by the belt, but those associated with reflux were increased (2 vs 3.5; P = .04). The most marked effect of the belt was impaired esophageal clearance of refluxed acid (median values of 23.0 seconds without belt vs 81.1 seconds with belt) (P = .008). The pattern of impaired clearance was that of rapid re-reflux after peristaltic clearance. CONCLUSIONS: In a prospective study of patients with esophagitis or Barrett's esophagus, we found belt compression increased acid reflux following a meal. The intragastric pressure rise inducing this effect is well within the range associated with differing waist circumference and likely to be relevant to the association between obesity and reflux disease.

Services for spondyloarthritis: a survey of patients and rheumatologists.

Objectives: There have been significant advances in axial spondyloarthritis (axSpA), with implications for service delivery. We evaluated the state of axSpA rheumatology services and how people with axSpA perceive their care. Methods: An online patient survey was emailed to all members of the National Ankylosing Spondylitis Society and advertised widely via social media. Separately, a Web-based questionnaire about axSpA services was sent to rheumatologists at all 172 acute hospital trusts in the UK. Results: From the National Ankylosing Spondylitis Society survey, data for 1979 surveys (56% males) were available for analysis. The majority of respondents had longstanding disease and identified their diagnosis as AS, with only 44% aware of the term axSpA. Eighty-two per cent of respondents were currently attending a rheumatologist, with 43% on biologic agents. Satisfaction scores for rheumatology care were high. Respondents' concerns included access during disease flares and adverse effects of analgesics. From the rheumatology survey, the concept and terminology of axSpA was widely accepted by respondents (88%). The majority of centres had at least one rheumatologist with a specialist interest in axSpA (62%), dedicated axSpA clinics (58%) or a multidisciplinary team for axSpA (64%). BASDAI (99%), BASFI (74%) and BASMI (65%) were routinely performed. All centres had access to MRI scans, but scanning protocols varied and were often sub-optimal. Conclusion: Although overall satisfaction with rheumatology care was high, the results indicate significant unmet patient needs and discrepancies in service provision. This information will inform the development of quality standards for axSpA in order to improve quality and deliver equitable care for all patients.

Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux.

BACKGROUND AND AIMS: Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. METHODS: We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. RESULTS: Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5 mm, p=0.01). There was no excessive acid reflux 5 cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11 mm above the pH transition point after the meal when supine (pH<4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p<0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p<0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). CONCLUSIONS: Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.

The gastric acid pocket is attenuated in H. pylori infected subjects.

OBJECTIVE: Gastric acid secretory capacity in different anatomical regions, including the postprandial acid pocket, was assessed in Helicobacter pylori positive and negative volunteers in a Western population. DESIGN: We studied 31 H. pylori positive and 28 H. pylori negative volunteers, matched for age, gender and body mass index. Jumbo biopsies were taken at 11 predetermined locations from the gastro-oesophageal junction and stomach. Combined high-resolution pH metry (12 sensors) and manometry (36 sensors) was performed for 20 min fasted and 90 min postprandially. The squamocolumnar junction was marked with radio-opaque clips and visualised radiologically. Biopsies were scored for inflammation and density of parietal, chief and G cells immunohistochemically. RESULTS: Under fasting conditions, the H. pylori positives had less intragastric acidity compared with negatives at all sensors >1.1 cm distal to the peak lower oesophageal sphincter (LES) pressure (p<0.01). Postprandially, intragastric acidity was less in H. pylori positives at sensors 2.2, 3.3 and 4.4 cm distal to the peak LES pressure (p<0.05), but there were no significant differences in more distal sensors. The postprandial acid pocket was thus attenuated in H. pylori positives. The H. pylori positives had a lower density of parietal and chief cells compared with H. pylori negatives in 10 of the 11 gastric locations (p<0.05). 17/31 of the H. pylori positives were CagA-seropositive and showed a more marked reduction in intragastric acidity and increased mucosal inflammation. CONCLUSIONS: In population volunteers, H. pylori positives have reduced intragastric acidity which most markedly affects the postprandial acid pocket.

ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.

Worldwide Inverse Association between Gastric Cancer and Esophageal Adenocarcinoma Suggesting a Common Environmental Factor Exerting Opposing Effects.

OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) is increasing while adenocarcinoma of the stomach is decreasing. We have investigated whether the incidences of these two cancers and their time trends might be inversely related pointing to a common environmental factor exerting opposite effects on these cancers. METHODS: For cross-sectional analyses data were abstracted from "Cancer Incidence in Five Continents" (CI5) Volume X and GLOBOCAN 2012. Relevant ICD-10 codes were used to locate esophageal and gastric cancers anatomically, and ICD-O codes for the histological diagnosis of EAC. For longitudinal analyses, age standardized rates (ASRs) of EAC and total gastric cancer (TGC) were extracted from CI5C-Plus. RESULTS: Estimated (2012) ASRs were available for 51 countries and these showed significant negative correlations between EAC and both TGC (males: correlation coefficient (CC)=-0.38, P=0.006, females: CC=-0.41, P=0.003) and non-cardia gastric cancer rates (males: CC=-0.41, P=0.003 and females: CC=-0.43, P=0.005). Annual incidence trends were analyzed for 38 populations through 1989-2007 and showed significant decreases for TGC in 89% and increases for EAC in 66% of these, with no population showing a fall in the latter. Significant negative correlation between the incidence trends of the two cancers was observed in 27 of the 38 populations over the 19-50 years of available paired data. Super-imposition of the longitudinal and cross-sectional data indicated that populations with a current high incidence of EAC and low incidence of gastric cancer had previously resembled countries with a high incidence of gastric cancer and low incidence of EAC. CONCLUSIONS: The negative association between gastric cancer and EAC in both current incidences and time trends is consistent with a common environmental factor predisposing to one and protecting from the other.

Short-segment and intrasphincteric gastroesophageal reflux.

PURPOSE OF REVIEW: The traditional gold standard for measuring gastroesophageal acid reflux has been by placing a pH sensor 5 cm proximal to the lower esophageal sphincter. It is known that damage induced by reflux is maximal near to the gastroesophageal junction and this has stimulated interest in determining acid reflux at that site. RECENT FINDINGS: The extent of esophageal exposure from refluxing gastric acid is inversely related to the distance proximal to the gastroesophageal junction. In addition, the pH transition point from gastric to esophageal pH can be displaced proximally within the lower esophageal sphincter without complete loss of sphincter tone. This intrasphincteric reflux is associated with proximal extension of cardia mucosa because of columnar metaplasia of the most distal esophageal squamous mucosa. SUMMARY: The most distal esophageal mucosa is exposed to substantially greater gastric acid refluxate than that recorded at the traditional site 5 cm proximal to the lower esophageal sphincter.

The Role of the Acid Pocket in Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease is one of the commonest chronic conditions in the western world and its prevalence is increasing worldwide. The discovery of the acid pocket explained the paradox of acid reflux occurring more frequently in the postprandial period despite intragastric acidity being low due to the buffering effect of the meal. The acid pocket was first described in 2001 when it was detected as an area of low pH immediately distal to the cardia using dual pH electrode pull-through studies 15 minutes after a meal. It was hypothesized that there was a local pocket of acid close to the gastroesophageal junction that escapes the buffering effect of the meal, and that this is the source of postprandial acidic reflux. The presence of the acid pocket has been confirmed in other studies using different techniques including high-resolution pHmetry, Bravo capsule, magnetic resonance imaging, and scintigraphy. This review aims to describe what we know about the acid pocket including its length, volume, fluid constituents, and its relationship to the lower esophageal sphincter and squamocolumnar junction. We will discuss the possible mechanisms that lead to the formation of the acid pocket and examine what differences exist in patients who suffer from acid reflux. Treatments for reflux disease that affect the acid pocket will also be discussed.

In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity.

INTRODUCTION: Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. METHODS: We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barrett's oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver-intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barrett's patients with/without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. RESULTS: Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barrett's and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barrett's showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=-0.538, p=0.001). CONCLUSIONS: These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux.

Waist belt and central obesity cause partial hiatus hernia and short-segment acid reflux in asymptomatic volunteers.

OBJECTIVE: There is a high incidence of inflammation and metaplasia at the gastro-oesophageal junction (GOJ) in asymptomatic volunteers. Additionally, the majority of patients with GOJ adenocarcinomas have no history of reflux symptoms. We report the effects of waist belt and increased waist circumference (WC) on the physiology of the GOJ in asymptomatic volunteers. DESIGN: 12 subjects with normal and 12 with increased WC, matched for age and gender were examined fasted and following a meal and with waist belts on and off. A magnet was clipped to the squamo-columnar junction (SCJ). Combined assembly of magnet-locator probe, 12-channel pH catheter and 36-channel manometer was passed. RESULTS: The waist belt and increased WC were each associated with proximal displacement of SCJ within the diaphragmatic hiatus (relative to upper border of lower oesophageal sphincter (LOS), peak LOS pressure point and pressure inversion point, and PIP (all p<0.05). The magnitude of proximal migration of SCJ during transient LOS relaxations was reduced by 1.6-2.6 cm with belt on versus off (p=0.01) and in obese versus non-obese (p=0.04), consistent with its resting position being already proximally displaced. The waist belt, but not increased WC, was associated with increased LOS pressure (vs intragastric pressure) and movement of pH transition point closer to SCJ. At 5 cm above upper border LOS, the mean % time pH <4 was <4% in all studied groups. Acid exposure 0.5-1.5 cm above SCJ was increased, with versus without, belt (p=0.02) and was most marked in obese subjects with belt. CONCLUSIONS: Our findings indicate that in asymptomatic volunteers, waist belt and central obesity cause partial hiatus herniation and short-segment acid reflux. This provides a plausible explanation for the high incidence of inflammation and metaplasia and occurrence of neoplasia at the GOJ in subjects without a history of reflux symptoms.

Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions.

A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population-based cohort study, 928 randomly selected, healthy, Helicobacter pylori-infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person-years of follow-up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons-years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2-9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5-21.5). Opium (HR: 3.2; 95% CI: 1.4-7.7), hookah (HR: 3.4; 95% CI: 1.7-7.1) and cigarette use (HR: 3.2; 95% CI: 1.4-7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83-98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high-incidence gastric cancer area.

Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa.

BACKGROUND & AIMS: In the West, a substantial proportion of subjects with adenocarcinoma of the gastric cardia and gastroesophageal junction have no history of reflux. We studied the gastroesophageal junction in asymptomatic volunteers with normal and large waist circumferences (WCs) to determine if central obesity is associated with abnormalities that might predispose individuals to adenocarcinoma. METHODS: We performed a study of 24 healthy, Helicobacter pylori-negative volunteers with a small WC and 27 with a large WC. Abdominal fat was quantified by magnetic resonance imaging. Jumbo biopsy specimens were taken across the squamocolumnar junction (SCJ). High-resolution pH-metry (12 sensors) and manometry (36 sensors) were performed in upright and supine subjects before and after a meal; the SCJ was visualized fluoroscopically. RESULTS: The cardiac mucosa was significantly longer in the large WC group (2.5 vs 1.75 mm; P = .008); its length correlated with intra-abdominal (R = 0.35; P = .045) and total abdominal (R = 0.37; P = .034) fat. The SCJ was closer to the upper border of the lower esophageal sphincter (LES) in subjects with a large WC (2.77 vs 3.54 cm; P = .02). There was no evidence of excessive reflux 5 cm above the LES in either group. Gastric acidity extended more proximally within the LES in the large WC group, compared with the upper border (2.65 vs 4.1 cm; P = .027) and peak LES pressure (0.1 cm proximal vs 2.1 cm distal; P = .007). The large WC group had shortening of the LES, attributable to loss of the distal component (total LES length, 3 vs 4.5 cm; P = .043). CONCLUSIONS: Central obesity is associated with intrasphincteric extension of gastric acid and cardiac mucosal lengthening. The latter might arise through metaplasia of the most distal esophageal squamous epithelium and this process might predispose individuals to adenocarcinoma.

Measuring movement and location of the gastroesophageal junction: research and clinical implications.

Understanding the physiology of gastroesophageal junction (GEJ) is important as failure of its function is associated with reflux disease, hiatus hernia, and cancer. In recent years, there have been impressive developments in high resolution technologies allowing measurement of luminal pressure, pH, and impedance. One obvious deficiency is the lack of technique to monitor the movement and location of the GEJ over a prolonged period of time. Proximal movement of the GEJ during peristalsis and transient lower esophageal sphincter relaxations (TLESRs) is due to shortening of the longitudinal muscle of the esophagus. Techniques for measuring shortening include fluoroscopic imaging of mucosal clip, high-frequency intraluminal ultrasound, and high resolution manometry, but these techniques have limitations. Short segment reflux is recently found to be more common than traditional reflux and may account for the high prevalence of intestinal metaplasia and cancer seen at GEJ. While high resolution pHmetry is available, there is no technique that can reliably and continuously measure the position of the squamocolumnar junction. A new technique is recently reported allowing a precise and continuous measurement of the GEJ based on the principle of Hall effect. Reported studies have validated its accuracy both on the bench and against the gold standard, fluoroscopy. It has been used alongside high resolution manometry in studying the behavior of the GEJ during TLESRs and swallows. While there are challenges associated with this new technique, there are promising ongoing developments. There is exciting time ahead in research and clinical applications for this new technique.

Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy.

INTRODUCTION: The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology. METHODS: (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied. RESULTS: (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p<0.001) and supine (R=0.40, p<0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p<0.001; expiration: R=0.78, p<0.001) and inspiratory GOPG (R=0.50, p<0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=-0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP. CONCLUSION: The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.

Sociocultural and dietary practices among Malay subjects in the north-eastern region of Peninsular Malaysia: a region of low prevalence of Helicobacter pylori infection.

BACKGROUND AND AIM: The prevalence of Helicobacter pylori infection is exceptionally low among the Malays in the north-eastern region of Peninsular Malaysia. The reasons are unknown. Our aim was to compare environmental factors that differed in relation to H. pylori prevalence among Malays born and residing in Kelantan. METHODS: A case-control study was conducted among Malays in Kelantan who underwent upper endoscopy between 2000 and 2008. Helicobacter pylori status was determined by gastric histology. Sociocultural and dietary factors were assessed using a validated investigator-directed questionnaire administered after 2008, and the data were analyzed using logistic regression analysis. RESULTS: The study group consisted of 161 subjects (79 H. pylori positive and 82 controls). Univariable analysis identified five poor sanitary practices associated with an increased prevalence of H. pylori infection: use of well water, use of pit latrine, less frequent boiling of drinking water, and infrequent hand wash practice after toilet use and before meals. Multivariable logistic regression analysis identified three variables inversely associated with H. pylori infection: frequent consumption of tea (OR: 0.023, 95% CI: 0.01-0.07), frequent use of "budu" or local anchovy sauce (OR: 0.09, 95% CI: 0.1-0.7), and frequent use of "pegaga" or centenella asiatica (OR: 0.25, 95% CI: 0.1-0.65). CONCLUSIONS: Under the assumption that sanitary, sociocultural, and dietary habits have not changed over the years, we can conclude that an increased risk of H. pylori was associated with unsanitary practices whereas protection was associated with consumption of tea and locally produced foods, "pegaga" and "budu." These dietary factors are candidates for future study on the effects on H. pylori transmission.

Effect of nitrite delivered in saliva on postprandial gastro-esophageal function.

OBJECTIVE: Acid reflux produces troublesome symptoms (heartburn) and complications including esophagitis, Barrett's esophagus, and adenocarcinoma. Reflux occurs due to excessive and inappropriate relaxation of the lower esophageal sphincter. An important mediator of this is nitric oxide, high concentrations of which are generated within the lumen when swallowed saliva meets gastric acid. Saliva contains nitrite, derived from the enterosalivary recirculation of dietary nitrate, which is reduced to nitric oxide by gastric acid. The aim of this study was to investigate whether salivary nitrite contributes to dysfunction of the lower esophageal sphincter. MATERIALS AND METHODS: In 20 volunteers, studies of gastro-esophageal function were performed on four separate days, following consumption of a standardized meal, with saliva nitrite concentrations modified differently each day by intra-oral nitrite infusion. RESULTS: The infusions produced an appropriate range in saliva nitrite concentrations, from below to well above the physiological range. The standardized meal induced expected physiological changes in gastro-esophageal function confirming the recordings were sensitive and robust. Esophageal acid exposure (primary outcome) was similar on each study day. Secondary outcomes, including number and duration of reflux events, rate of transient lower esophageal sphincter relaxations, lower esophageal sphincter pressure and rate of gastric emptying were also unaffected by variations in saliva nitrite concentration. CONCLUSIONS: Nitrite in swallowed saliva does not modify gastro-esophageal junction function or predispose to gastro-esophageal reflux. The wide range in saliva nitrite concentrations, the sensitivity of the physiological recordings and the number of subjects studied make it very unlikely that an effect has been missed.

BMI is superior to symptoms in predicting response to proton pump inhibitor: randomised trial in patients with upper gastrointestinal symptoms and normal endoscopy.

OBJECTIVES: In most patients undergoing endoscopy for upper gastrointestinal (GI) symptoms in the Western world, no macroscopic abnormality or evidence of Helicobacter pylori infection is identified. Following this negative investigation, proton pump inhibitor (PPI) therapy is usually prescribed. The aim of this study was to assess the value of such treatment compared with placebo and to identify predictors of response. DESIGN: Prospective parallel randomised study. SETTING: Dyspepsia Research Clinic. PARTICIPANT: 105 patients (49 men, median age 44 years, IQR 22) with normal endoscopy and H pylori negative with ongoing upper GI symptoms following 2-week run-in period. Intervention Full demographic symptom severity and characteristics were assessed and 24 h oesophageal pH metry and oesophageal manometry were performed prior to randomisation to 2 weeks of treatment with lansoprazole 30 mg/day or placebo (2:1), with reassessment of symptom severity during the second week of treatment. PRIMARY OUTCOME: 50% reduction in Glasgow Dyspepsia Severity Score (GDSS). RESULTS: According to intention to treat analysis, the response was 35.7% for the active group and 5.7% for the placebo group (p < 0001). The only non-invasive independent predictor of response to PPI in multivariable analysis was the patient's body mass index (BMI) (p = 0.003). The association of BMI with response to PPI was apparent across the full range of quartiles (p values for trend=0.01). BMI had a similar predictive value to either 24 h oesophageal pH metry or manometry. Predominant symptom and symptom subgroups were unhelpful in predicting the response to PPI. Including all pretreatment assessments, only BMI (p < 0.05) and lower oesophageal sphincter pressure (p < 0.05) were independent predictors of response. CONCLUSION: The response to PPI therapy is likely to be related to underlying acid reflux. The strong predictive value of BMI is probably due to its association with underlying reflux disease and the fact that it is a more objective and reproducible measure than symptom characteristics. It is recommended that BMI should be measured in patients with upper GI symptoms. Trial Registration Number ISRCTN 32863375.