Valerie Fyfe

Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status

Background: Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear. Aim: To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach. Methods: Nested case–control study. To each of 129 non-cardia and 44 cardia cancers, three controls were matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin. Results: Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and gastric atrophy (pepsinogen I:II <2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32 to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1). Conclusion: These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer.

Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux

Background and aims: When saliva, with its high nitrite content derived from the enterosalivary recirculation of dietary nitrate, meets acidic gastric juice, the nitrite is converted to nitrous acid, nitrosative species, and nitric oxide. In healthy volunteers this potentially mutagenic chemistry is focused at the gastric cardia. We have studied the location of this luminal chemistry in Barrett’s patients during acid reflux. Methods: Ten Barrett’s patients were studied before and after administration of 2 mmol nitrate. Using microdialysis probes we measured nitrite, ascorbic acid, total vitamin C, and thiocyanate concentrations and pH simultaneously in the proximal oesophagus, Barrett’s segment, hiatal sac, proximal stomach, and distal stomach. In a subgroup, real time nitric oxide concentrations were also measured. Results: During acid reflux, Barrett’s segment was the anatomical site with maximal potential for acid catalysed nitrosation, with its median concentration of nitrite exceeding that of ascorbic acid in two of 10 subjects before nitrate and in four of nine after nitrate. Thiocyanate, which catalyses acid nitrosation, was abundant at all anatomical sites. On entering the acidic Barrett’s segment, there was a substantial fall in nitrite and the lowest ascorbic acid to total vitamin C ratio, indicative of reduction of salivary nitrite to nitric oxide at this anatomical site. Episodes of acid reflux were observed to generate nitric oxide concentrations of up to 60 μM within the Barrett’s segment. Conclusion: The interaction between acidic gastric refluxate and nitrite rich saliva activates potentially mutagenic luminal nitrosative chemistry within Barrett’s oesophagus.

Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with Helicobacter pylori.

Background: Acid secretion is intimately associated with most upper gastrointestinal diseases. Helicobacter pylori infection is a major environmental factor modifying acid secretion. Aim: To study the association between the pattern of H pylori gastritis and gastric secretory function in a large number of subjects without specific upper gastrointestinal disease. Methods and materials: Maximal acid output (MAO) was measured in 255 patients with dyspepsia showing normal endoscopy. Activity and severity of gastritis, atrophy and H pylori infection were assessed in body and antral biopsies. The correlations of histological parameters as well as age, sex, height, weight, smoking, serum gastrin, pepsinogen I and II, and their ratio with MAO were determined. Multiple linear regression was used to show the best possible predictors of MAO. Results: Negative relationships: Body atrophy and body-combined (active and chronic) inflammatory scores showed a potent inverse correlation with MAO (correlation coefficients (CC) 0.59 and 0.50, respectively). Body:antral chronic gastritis ratio and body:antral combined inflammation ratio (both with CC = 0.49) and age (CC = 0.44) were also inversely correlated with MAO. Intestinal metaplasia at both antral and body sites had negative relationships with acid output with CC = 0.23 and 0.20, respectively. Positive relationships: Serum pepsinogen I, body H pylori density:combined inflammation ratio and pepsinogen I:II ratio with CC of 0.38, 0.38 and 0.30, respectively, correlated with MAO. The H pylori density: combined inflammation of both antrum and body positively correlated with MAO (CC = 0.29 and 0.38, respectively). Male sex and patient height also positively correlated with acid output. Modelling showed that body combined inflammatory score, body atrophy, age and serum pepsinogen I are independent predictors of acid output (R2 = 0.62). Conclusion: Combination of body gastritis, body atrophy, age and serum pepsinogen I can be used as predictors of acid-secretory state in populations infected with H pylori.

Conditions for acid catalysed luminal nitrosation are maximal at the gastric cardia

Background: Saliva has a high nitrite concentration, derived from the enterosalivary recirculation of dietary nitrate, and is the main source of nitrite entering the acidic stomach. Acidification of nitrite in the presence of secondary amines or amides generates potentially carcinogenic N-nitroso compounds. The reaction is inhibited by ascorbic acid and catalysed by thiocyanate. Aim: To determine whether there is intragastric regional variation in the chemical conditions promoting luminal nitrosation following nitrate ingestion. Methods: Using microdialysis probes, we measured concentrations of nitrite, ascorbic acid, total vitamin C, and thiocyanate simultaneously in saliva, the distal oesophagus, cardia, and the proximal and distal stomach of 17 healthy volunteers before and following intragastric nitrate (2 mmol) administration. Results: The median pH in the distal oesophagus, cardia, and proximal and distal stomach were 7, 2.6, 1.9, and 1.7, respectively, before, and were similar following nitrate administration. Mean nitrite concentration in the distal oesophagus was similar to that of saliva, being 29.1 μM and 36.7 μM, respectively, before nitrate and increasing to 181.6 μM and 203.3 μM after nitrate ingestion. Within the stomach, mean (SEM) nitrite concentration following nitrate was higher in the cardia (45.5 (12.7) μM) than in the mid (7.8 (3.1)) (p<0.01) or distal (0.8 (0.6)) (p<0.1) stomach, and ascorbic acid concentration was lower at the cardia (13.0 (6.1)) than in the mid (51 (19.2)) (p<0.02) or distal (86 (29)) (p<0.01) stomach. Consequently, the median ascorbic acid to nitrite ratio was lowest at the cardia (0.3) (p<0.01) versus the mid (7.8) or distal (40) stomach. Thiocyanate concentration was similar throughout the stomach. Conclusions: The conditions favouring luminal generation of N-nitroso compounds from dietary nitrate are maximal at the most proximal cardia region of the acidic stomach and may contribute to the high incidence of mutagenesis at this site.

Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis

Background A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting. Methods In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared. Results Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)]. Conclusion Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.

PTH-040 The effect of salivary nitrite on gastric emptying

Introduction Human saliva has a high nitrite concentration from the entero-salivary recirculation of dietary nitrate. Swallowed nitrite reacts with acidic gastric juice forming nitric oxide (NO). Increasing NO bioactivity, by inhibiting phosphodiesterase, enhances gastric accommodation and delays gastric emptying. Aims To determine (1) whether nitrite in saliva affects gastric emptying and (2) whether nitrite in saliva alters postprandial intragastric pressure (IGP). Methods 20 healthy subjects (11 males) were studied. On four separate days high-resolution manometry was performed during 15 min fasting and for 90 min following a standardised meal. Post-prandially, solutions of 0, 0.286, 2 and 14 mmol/l potassium nitrite were infused into the oral cavity. Solutions were randomised and double-blinded. Saliva was collected at baseline, 30, 60 and 90 min after the meal. Salivary nitrite concentrations were quantified by Griess reaction. Gastric emptying was assessed by means of a specially designed breath test. 14C labelled sodium acetate was incorporated, during baking, into a rolled oats flapjack which constituted part of our standardised meal. Following consumption of the flapjack, breath samples were taken at regular intervals. The quantity of 14C appearing in breath per unit time (μmol/minute) was calculated. A generalised linear regression method was used to estimate gastric half-emptying times (T½). Mean IGP was defined relative to atmospheric pressure as the lowest mean pressure recorded in the six most distal manometry sensors. Results are medians and ranges. Results Salivary nitrite concentrations at 60 min were 24.35 μmol/l (3.86–65.46), 80.42 μmol/l (20.88–158.79), 358.4 μmol/l (118.2–726.6) and 2694 μmol/l (600–8087) for the solutions containing 0, 0.286, 2 and 14 mmol/l nitrite, respectively. There was no significant difference in the rate of gastric emptying (T½) between the control solution (103.5 min, 56.2–239.1) and those containing 0.286 mmol/l (113.4 mins, 68.7–254.8, p=0.56), 2 mmol/l (121.7 min, 39.8–270.0, p=0.93) and 14 mmol/l (114.4 mins, 79.1–390.1, p=0.75). There was no difference in the increase in IGP recorded between the control solution (4.06 mm Hg, −2.64–7.31) and those containing 0.286 mmol/l (4.42 mm Hg, −4.55–8.45, p=0.61), 2 mmol/l (4.66 mm Hg, −0.94-9.16, p=0.27) and 14 mmol/l (4.24 mm Hg, −2.12–8.17, p=0.81) potassium nitrite. Conclusion Despite an excellent range of salivary nitrite concentrations, extending over and beyond the normal physiological range, no difference in the rate of gastric emptying or postprandial rise in IGP was seen. This suggests salivary nitrite does not affect gastric emptying.