• lower oesophageal sphincter
• acid exposure
• oesophageal squamocolumnar junction
• reflux oesophagitis

For a simple organ like the oesophagus, which functions primarily as a conduit, it is hard to imagine a more unpleasant neighbour than the stomach, a reservoir of concentrated acid constrained by a leaky valve. Studies using pH monitoring techniques developed in the 1970s have shown that the distal oesophagus of normal ambulatory individuals can be exposed to refluxed gastric acid (with pH <4) for up to 5% of a 24 hour monitoring period.¹ Conventionally, oesophageal pH monitoring has been performed with the pH sensor positioned at a level 5 cm above the lower oesophageal sphincter (LOS). In a study reported in this issue of Gut, Fletcher and colleagues² in Glasgow have found that conventional pH monitoring techniques have substantially underestimated the duration of acid exposure for the most distal segment of the oesophagus [see page 168].

To study acid exposure in the most distal oesophagus, the investigators devised a novel endoscopic technique for positioning a modified pH catheter, with two pH electrodes located 5 cm apart. A short prolene loop was attached to the catheter 5 mm below the distal pH electrode and the catheter was passed through the nose into the oesophagus. An endoscopic examination was performed, the junction of squamous and columnar epithelia (the Z line) in the distal oesophagus was identified, and an endoscopic clip was used to fix the prolene loop to the Z line. In this way, the distal pH electrode was anchored in the distal oesophagus at a level 5 mm above the Z line whereas the proximal electrode was located at approximately the conventional pH monitoring level.

The study group comprised 11 patients who previously had normal oesophagoscopic examinations and normal conventional 24 hour oesophageal pH monitoring tests. Using a combination of manometric and endoscopic measurements, the investigators determined that the distal oesophageal pH electrode (anchored 5 mm above the Z line) was located a mean of 6 mm below the upper border of the LOS. Thus the distal electrode was recording the pH of fluid bathing oesophageal squamous epithelium within the LOS itself.

The distal electrode recorded an oesophageal pH value <4 for a median of 11.7% of the 24 hour monitoring period whereas 5 cm proximally, oesophageal pH remained <4 for only 1.8% of the same period (p<0.001). Longer distal oesophageal acid exposures were observed both when the subjects were upright (12.7% v 2.3%; p<0.001) and supine (10.5% v 1.3%; p<0.001), and the total number of individual reflux episodes was also greater distally (168 v 33; p<0.001). The difference between distal and proximal acid exposures was especially prominent during the three hour period after dinner (21.8% v 2.8%). Thus the distal oesophageal pH electrode, tethered 5 mm above the squamocolumnar junction and within the LOS, recorded considerably greater acid exposure than the electrode located just 5 cm proximally in the body of the oesophagus. In patients who have no signs of gastro-oesophageal reflux disease (GORD), this study shows that the most distal oesophagus is exposed to concentrated acid for more than 10% of the day. The authors suggest the term “short segment reflux” to describe this phenomenon.

This study by Fletcher and colleagues² is another in a series of fascinating investigations from Glasgow elucidating how hostile is the environment at the gastro-oesophageal junction (GOJ). The inspiration for these studies was an interesting observation about postprandial acid reflux made in subjects who had sensors recording pH simultaneously in the oesophagus and in the body of the stomach.³ After a meal, the investigators noted that acid which refluxed into the oesophagus often had a pH value substantially lower than that recorded by the electrode in the gastric body. This observation suggested that the acid reflux was coming from a pocket of acid in the proximal stomach that had somehow escaped the buffering effects of ingested food. To confirm the presence of this postprandial acid pocket, pH was measured systematically at various levels throughout the stomach and oesophagus of healthy volunteers. Whereas pH in the body of the stomach reached a median level of 4.7 after a meal, an acid pocket with a median pH of 1.6 was found at the GOJ. This postprandial acid pocket had a mean length of 2 cm, beginning in the most proximal stomach and extending more than 1 cm above the Z line into the distal oesophagus.

The mechanisms underlying the intense acid exposure of the most distal oesophagus are not known. During conventional oesophageal pH monitoring in which the pH electrode is positioned 5 cm above the LOS, most episodes of acid reflux are attributed to transient LOS relaxations (TLOSRs).⁴ Although Fletcher and colleagues² did not monitor TLOSRs during their study, two important observations suggest that TLOSRs may not be the predominant mechanism for short segment reflux. Firstly, TLOSRs occur at an average rate of only 2–6 episodes per hour⁵ whereas the investigators observed approximately 7 episodes of short segment reflux per hour. Secondly, the frequency of TLOSRs decreases substantially at night (supine posture) whereas the investigators found no substantial decrease in the supine frequency of short segment reflux.

One potential mechanism for short segment reflux relates to the mechanical effect of gastric distension on the LOS. It has been proposed that gastric distension induced by eating and other factors can cause the distal portion of the LOS to be prized apart by the expanding gastric fundus.⁶ In this situation, the proximal portion of the sphincter remains closed, preventing reflux into the proximal oesophagus, but the distal portion is pulled open, thus exposing the most distal oesophagus to the gastric contents. The observation that short segment reflux is especially common after meals is consistent with this mechanism. Nevertheless, further studies are necessary to establish the physiology of short segment reflux.

Potential consequences of short segment reflux include not only acid peptic injury but also exposure of the distal oesophagus to high concentrations of nitric oxide (NO) generated from dietary nitrate (NO₃⁻) in green leafy vegetables. Most ingested nitrate is absorbed by the small intestine and excreted unchanged in the urine, but approximately 25% is concentrated by the salivary glands and secreted into the mouth where bacteria on the tongue reduce the recycled nitrate to nitrite (NO₂⁻).⁷⁸ When swallowed, nitrite encounters acidic gastric juice and the nitrite is converted rapidly to NO.⁹¹⁰ In earlier studies, the Glasgow group demonstrated that high levels of NO are generated at the GOJ, the region where swallowed nitrite first meets gastric acid.¹¹ NO can participate in nitrosation reactions that result in the deamination of the purine and pyrimidine bases of DNA, the formation of carcinogenic N-nitroso compounds from amines and amides, and the inactivation of DNA repair enzymes.^12–14 NO also can participate in redox reactions which generate reactive oxygen species that can further damage DNA.¹⁵ Thus NO can be genotoxic and, potentially, carcinogenic.

This study by Fletcher and colleagues² suggests that short segment reflux causes relentless exposure of the most distal oesophagus to acid, NO, and other noxious agents in gastric juice. Intestinal metaplasia at the end of the oesophagus (short segment Barrett’s oesophagus) is a common condition, even in patients who have no signs or symptoms of GORD.¹⁶ Intestinal metaplasia, a sequela of chronic inflammation, can predispose to cancer.¹⁶¹⁷ It seems likely that short segment reflux can cause chronic distal oesophagitis that contributes to the pathogenesis of short segment Barrett’s oesophagus and, ultimately, oesophageal adenocarcinoma, a tumour whose frequency has been rising at an impressive rate for decades.¹⁸ Nevertheless, oesophageal adenocarcinoma remains an uncommon tumour whereas short segment reflux appears to be a common, perhaps even normal, phenomenon. Considering the great frequency of short segment reflux, the fact that short segment Barrett’s oesophagus occurs so commonly perhaps is less remarkable than the fact that serious peptic and neoplastic complications of GORD occur so infrequently. Apparently, the squamous epithelium of the most distal oesophagus has ample intrinsic defence mechanisms and considerable capacity to resist injury from the noxious brew spewed by its unpleasant neighbour to the south. To paraphrase Robert Frost, good defences make good neighbours.