Studies of the Pathophysiology of Gastroesophageal Reflux Disease, Barrett's Oesophagus and Adenocarcinoma of the Oesophagus and Gastroesophageal Junction

Acid reflux from the stomach up into the lower gullet is now the commonest disease in the developed world. It produces symptoms of heartburn which occur weekly in 25% of the population. In addition to troublesome symptoms, the reflux of acid in some patients induces changes in the lining of the lower gullet which may progress to cancer. The cancer of the gullet associated with reflux disease is the most rapidly increasing cancer in the developed world and Scotland has the highest incidence of this cancer. Our research is focused on the cause of the marked rise in these disorders and the reason why Scotland has such a high incidence. Some of our current studies focus on the role of central obesity. We have shown that the raised intra-abdominal pressure associated with central obesity increases acid reflux into the oesophagus. However, we have also shown that central obesity damages the lower end of the oesophagus in asymptomatic subjects by allowing the stomach acid to come in contact with the lining of the lower end of the oesophagus without full reflux occurring. This may explain why 50% of the cancers occur in subjects without any symptoms of reflux. We are also investigating the hypothesis that the rise in reflux disease and oesophageal cancer may be related to the falling incidence of Helicobacter pylori infection. We have previously shown that this infection which is present in 20% of the Scottish population causes a fall in acid secretion with increasing age. We are currently investigating the effects of the infection on the acid secreting mucosa closest to the lower gullet to determine whether local changes induced by Helicobacter pylori infection may have afforded protection from reflux disease and oesophageal cancer in the past.

Our studies indicate that most damage occurs at the junction between the stomach and the oesophageal lining which lies within the valve called the lower oesophageal sphincter. Previously, studies of the environment of this region has been impossible. To allow us to study this, we have developed two new measuring probes. The first is high resolution pH and consists of twelve pH sensors spaced 1cm apart. In addition, we have developed a novel probe which allows us to constantly monitor the location of the junction between the stomach and the oesophagus. This involves clipping a magnet to the site and detecting it by a probe with electronic sensors again spaced 1cm apart over 12cm. These two probes are used in conjunction with high resolution manometry which measure the pressor profile at 1cm increments. These new recording techniques allow us for the first time to investigate what is happening at the junction between the stomach and the oesophagus and the effects of obesity and Helicobacter pylori on this.

Gastroesophageal reflux occurs when there is complete loss of tone of the lower oesophageal sphincter allowing gastric acid to freely pass into the body of the oesophagus. These episodes occur when there are transient lower oesophageal sphincter relaxations. Gastroesophageal reflux can be detected by placing a pH probe in the body of the oesophagus in pH at that site. The probe is traditionally placed 5cm above the upper border of the lower oesophageal sphincter as during breathing and swallowing the gastroesophageal junction moves up and down several centimetres and this would produce artefactual fall in pH if the probe were placed nearer the oesophageal junction.

Over recent years, it has become apparent that most of the damage to the oesophagus is caused by gastric acid occurring right at the junction between the gastric and oesophageal mucosa. Erosive oesophagitis is most common at this site. In addition, columnar metaplasia of the oesophageal mucosa and the associated adenocarcinoma is also most prevalent at this site. Previous studies of acid reflux as mentioned above only monitored the environment 5cm above the sphincter and therefore there has been very little information regarding what is happening right at the junction between the stomach and oesophagus which is the region which lies within the sphincter itself.

Over the past ten years we have been developing novel probes to allow us to investigate the luminal environment within the sphincter at the junction between the stomach and the oesophagus. We developed two novel probes. The first is high resolution pH. In contrast to placing a single pH probe 5cm above the lower oesophageal sphincter, we have a special probe with twelve pH sensors situated 1cm apart. One of the problems of studying the environment at the gastroesophageal junction is the constant movement of this area. In order to allow us to correct for this, we have also developed a novel probe which allows us to constantly monitor the precise location of the gastroesophageal junction. This involves clipping a small magnet endoscopically to the squamo-columnar junction and then passing a probe with electronic sensors situated again at 1cm intervals over a length of 12cm. These allow us to constantly detect the location of the gastroesophageal junction with an accuracy of 1-2mm. We also utilise high resolution manometry which allows us to measure the pressure from the stomach to the oesophagus at 1cm intervals over a length of 32cm. In our studies, we pass these three probes alongside each other which allows, for the first time, detailed analysis of the lumen environment at the gastroesophageal junction and within the lower oesophageal sphincter. By using this new technology we are investigating a number of questions.
(i) Effects of central obesity on acid exposure at the gastroesophageal junction. To date, we have observed that in asymptomatic subjects with central obesity gastric acid is able to move proximally within the lower oesophageal sphincter and come in contact with the distal oesophageal mucosa, causing columnar metaplasia. This is occurring in subjects without traditional reflux disease and may explain why 50% of patients presenting with cancer at the gastroesophageal junction or gastric cardia, have no symptoms of reflux disease. We have introduced new terminology to describe reflux disease in view of our findings. It is recommended that traditional reflux disease be re-named transphincteric reflux, whereas this new entity which we have observed be called intrasphincteric reflux.

We are investigating the malignant potential of the columnar metaplasia induced by this intrasphincteric reflux compared with the malignant potential of Barrett’s oesophagus which is associated with transphincteric reflux. These studies involve immuno-histochemistry and a range of molecular markers.

In addition to central obesity, another reason for a marked increase in oesophageal adenocarcinoma may be the fall in prevalence of Helicobacter pylori infection. In H. pylori infected subjects, gastric acid secretion decreases throughout life falling by about 50% between the ages of 20 and 70. In the uninfected population, acid secretion remains stable. This may partly explain the prevalence of these complications in the Western population. However, our studies also indicate that damage produced by gastric acid to the distal oesophageal mucosa by intrasphincteric reflux may be driven by the acid secretory capacity of the most proximal gastric mucosa. We have shown that density of parietal cells in normal subjects from the gastric mucosa lying within 2mm of the oesophageal squamous mucosa is almost equivalent to that of the body of the stomach. Previously, it was believed that there was a significant length of cardia mucosa lying between the oesophageal mucosa and the gastric acid mucosa and which did not secrete acid. However, our detailed studies of this region indicate that in H. Pylori negative subjects that is not the case. The previous reports of a long segment of cardia are likely to be due to local effects of Helicobacter pylori infection causing atrophic gastritis. It is known that Helicobacter pylori produces severe atrophy at mucosal interfaces and therefore likely to cause marked loss of parietal cells in the mucosa near to the junction between the stomach and oesophagus. We are therefore performing detailed studies of density of parietal cells in the most proximal stomach and implications of this for damage to the oesophageal mucosa and the potential protective effects of Helicobacter pylori on this.

Our studies also indicate that damage induced on the distal oesophageal mucosa by gastric acid may be partly determined by the acid secreting mucosa of the gastric mucosa which is immediately distal to the gastroesophageal junction rather than by the overall ability of the stomach to secrete acid. This has potential implications for treatment of reflux disease. Conventionally, reflux disease is treated by suppressing gastric acid with H2 antagonists or proton pump inhibitors. These reduce acid secretion throughout the stomach and have unwanted effects including predisposition to infection and rebound acid hypersecretion. If it is only the acid secretion of the gastric mucosa near the oesophageal junction which is causing the problem, then targeted at this region could achieve the same benefits without the side effects associated with overall gastric acid secretion.

Publications

1. Combet E, Elmesmari A, Presteon T, Crozier A, McColl K E L. Dietary phenolic acids and ascorbic acid: influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids. Free Radical Biology and Medicine 2010;48:763-771.
2. Derakhshan M H, Robertson E V, Fletcher J, Jones G-R, Lee Y Y, Wirz A A and McColl K E L. Mechanism of association between BMI and dysfunction of the gastroesophageal brrier in patients with normal endoscopy. Gut 2012;61:337-343.
3. Derakhshan M H, Liptrot S, Paul J, Brown I L, Morrison D J and McColl K E L. Oesophageal and gastric intestinal-type adenocarcinomas show same male predominance – due to 17 year delayed development in females. Gut 2009;58:16-23.
4. Fletcher J, Derakhshan M H, Jones G-R, Wirz A A and McColl K E L. BMI is superior to symptoms in predicting response to proton pump inhibitor: randomised trial in patients with upper gastrointestinal symptoms and normal endoscopy. Gut 2011;60:442-448.
5. Freedman N D, Derakhshan M H, Abnet C C, Schatzkin A, Hollenbeck A R and McColl K E L. Male predominance of upper gastrointestinal adenocarcinoma cannot be explained by differences in tobacco smoking in men versus women. European Journal of Cancer, 2010;46:2473-2478.
6. Lee Y Y, Seenan J P, Whiting J G, Robertson E V, Derakhshan M H, Wirz A A, Smith D, hardy C, Kelman A, Connolly P, McColl K E L. Development and validation of a probe allowing accurate and continuous monitoring of location of squamo-columnar junction. Medical Engineering and Physis 2012; 34:279-289.
7. Lee Y Y, Whiting J G H, Robertson E V, Derakhshan M H, Wirz A A, Smith D, Morrison D J, Kelman A W and McColl K E L. Kinetics of transient hiatus hernia during transient lower esophageal sphincter relaxations and swallows in healthy subjects. Neurogastroenteroogy and Motility, 2012;24:990-e539
8. Malfertheiner P, McColl K E L and Chan F. Peptic ulcer disease: further work is requird to reduce inequalities – Author’s reply. Lancet, 2010; 375(9714):554.
9. McColl KEL. Serum IGF-1 linking visceral obesity with esophageal adenocarcinoma: unconvincing evidence. American Journal of Gastroenterology, 2012;107:205-206.
10. McColl KEL. The elegance of the gastric mucosal barrier: designed by nature for nature. Gut, 2012;61:787-788.
11. McColl KEL. Helicobacter pylori infection. New England Journal of Medicine, 2010;362:1597-1604.
12. McColl KEL and Going JJ. Aetiology and classification of adenocarcinoma of the gastroesophageal junction/cardia. Gut, 2010;59:282-284.
13. Ng M T H, van’t Hof R, Crocket J C, Hope M E, Berry S, Thomson J, McLean M H, McColl K E L, El-Omar E M and Hold G L. Increase in NF-kappa B binding affinity of the variant C Allele of the toll-like receptor 9-1237T/C Polymorphism is associated with Helicobacter pylori-induced gastric disease. Infection and Immunity, 2010;78:1345-1352.
14. Robertson E V, Lee Y Y, Derakhshan M H, Wirz A A, Whiting J R H, Seenan J P, Connolly P and McColl K E L. High resolution esophageal manometry; addressing thermal drift of the manoscan system. Neurogastroenterology and Motility, 2011;24:61-e11.
15. Seenan J P, Wirz A A, Robertson E V, Clarke A T, Manning J J, Kelman A W, Gillen G, Ballantyne S, Derakhshan M H and McColl K E L. Effect of nitrite delivered in saliva on postprandial gastroesophageal function. Scandinavian Journal of Gastroenterology, 2012;47:387-396.
16. Watabe H, Mitsushima T, Derakhshan M H, Yamaji Y, Okamoto M, Kawabe T, Omata M and McColl K E L. Study of association between atrophic gastritis and body mass index: A cross-sectional study in 10,197 Japanese subjects. Digestive Diseases and Sciences, 2009;54:988-995.