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Title: Environmental factors relevant to the rising incidence of gastro-oesophageal reflux disease
Author: Mitchell, David Ross
ISNI:       0000 0004 7427 4354
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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Gastro-oesophageal reflux disease (GORD) is one of the commonest chronic conditions in the western world with a reported prevalence of 10-20% in Europe and the USA. The disease involves an interplay between factors promoting reflux of gastric juice and failure of defensive forces designed to neutralise the resulting acidity. Transient lower oesophageal relaxations, the acid pocket and the presence of a hiatus hernia are important factors. Acid reflux can cause benign oesophageal injury, including oesophagitis, oesophageal ulceration and peptic structuring, as well as malignant complications like Barrett’s oesophagus and oesophageal adenocarcinoma (OAC). GORD, Barrett’s and OAC rates have been rising over the last few decades in the Western World and the reasons for this are unclear. Helicobacter pylori (H. pylori) is a common bacterial infection of the stomach present in the majority of the world’s human population. It is known to cause chronic gastritis, and can be complicated by the development of peptic ulcer disease, gastric adenocarcinoma and gastric MALT lymphoma. An unexplained observation regarding H. pylori infection is its negative association with gastro-oesophageal reflux disease and its malignant complications. The prevalence of H. pylori infection appears to be falling, especially within the Western World. It is possible that H. pylori infection is protecting against the development of oesophageal disease from acid reflux and one possible explanation is the infection causing a reduction in gastric acid secretory function. For this to be true, the protective effect from H. pylori must be apparent in the majority of those infected. There is little available data on the effect of H. pylori infection within the general population. The few previous studies assessing gastric acid secretion have used H. pylori infected healthy volunteers, rather than subjects representative of the general population. The incidence of central obesity is rising in both children and adults across the world. Obesity is strongly associated with gastro-oesophageal reflux and its complications of Barrett’s oesophagus and OAC. Central adiposity seems to be of particular importance. The nature of this association is incompletely understood and both mechanical and humoral effects of central obesity may be important. In the first study we investigated whether the incidences of OAC and gastric adenocarcinoma, as well as their time trends, may be inversely related pointing to a common environmental factor exerting opposite effects on these cancers. We used cross-sectional data from “Cancer Incidence in Five Continents” (CI5) Volume X and GLOBOCAN 2012. Relevant ICD-10 codes were used to locate oesophageal and gastric cancers anatomically, and ICD-O codes for the histological diagnosis of OAC. For longitudinal analyses, age standardized rates (ASRs) of OAC and total gastric cancer (TGC) were extracted from CI5C-Plus. Estimated (2012) ASRs were available for 51 countries and these showed significant negative correlations between OAC 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 analysed for 38 populations through 1989–2007 and showed significant decreases for TGC in 89% and increases for OAC 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 OAC and low incidence of gastric cancer had previously resembled countries with a high incidence of gastric cancer and low incidence of OAC. The negative association between gastric cancer and OAC in both current incidences and time trends is consistent with a common environmental factor predisposing to one and protecting from the other. In our second study we assessed the gastric acid secretory capacity in different anatomical regions in H. pylori positive and negative volunteers in a Western population. 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 pHmetry (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. 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 (LOS) 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 LOS 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. In conclusion, H. pylori positives have reduced intragastric acidity which most markedly affects the postprandial acid pocket. In the third and final study we investigated the effect of increasing abdominal pressure by waist belt on reflux in patients with reflux disease. We performed a prospective study of patients with oesophagitis (n = 8) or Barrett's oesophagus (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 measurements 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 radio-opaque 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). 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). Gastro-oesophageal acid reflux at each of the pH sensors extending 5.5 cm proximal to the peak lower oesophageal 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 oesophageal 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 oesophageal 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. In conclusion 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General) ; RC Internal medicine