Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Pathophysiology
 

Can temporal evaluation of reflux events in Barrett's esophagus patients allow for understanding of mucosal damage?

A. Anggiansah, R.E.K. Marshall, W.J. Owen (London)

Pathogenesis of Barrett's esophagus

It is generally accepted that Barrett's esophagus is a metaplastic condition acquired as a result of chronic gastroesophageal reflux (GER). Barrett's esophagus is characterised by impaired lower esophageal sphincter (LES) function and ineffective esophageal body motility [1]. These motility patterns are generally associated with severe esophageal acid exposure on pH monitoring, particularly in the supine position [2]. The importance of gastric contents (acid and pepsin) in causing esophageal mucosal damage is well recognized. However, the role of duodenal contents (bile acids, trypsin and lysolecithin) in the pathogenesis of Barrett's esophagus is controversial. These constituents have all been shown to cause pH dependent esophageal damage in animal studies [3].

Reasons for the development of Bilitec™ 2000

The difficulty in evaluating the role of duodenal contents in duodeno-gastroesophageal reflux (DGER) has been the lack of a satisfactory, well-tolerated, ambulatory technique for its measurement. Esophageal aspiration and scintigraphy are both performed over a short period of time, with the patient stationary. Neither of these therefore represents normal physiological conditions. The validity of pH monitoring as an indirect method of detecting DGER, although ambulatory, has been widely questioned [4]. As a result, Bilitec™ 2000, a fibre-optic spectrophotometric probe, was developed as a direct, ambulatory method of detecting duodenal contents in the esophagus. The probe identifies the characteristic absorption spectrum of bilirubin, using this as a marker for the presence of duodenal contents [5].

Studies to date

Using combined esophageal pH and bilirubin monitoring, studies have shown that as acid reflux increases, so DGER increases, both being greatest in Barrett's esophagus. Furthermore, there is a good correlation between total acid and bilirubin reflux times and a poor correlation between total alkaline exposure and bilirubin reflux times [6]. These correlations, however, do not consider the temporal relationship between individual acid, alkaline and bilirubin reflux episodes and the overall patterns of acid, alkaline and bilirubin reflux.

What, therefore, are the temporal relationships between gastric and esophageal pH and esophageal bilirubin reflux in Barrett's esophagus?

We aimed to answer this by investigating 113 patients with reflux symptoms: 63 with nonerosive gastroesophageal reflux disease (GERD) (group 1), 23 with erosive GERD (group 2) and 27 Barrett's esophagus (group 3) [7]. All patients underwent static manometry (Gaeltec Ltd, Isle of Skye) followed by 24 hour ambulatory combined esophageal and gastric pH and esophageal bilirubin monitoring (Synectics Medical, Sweden). The proximal pH sensor was placed alongside the bilirubin sensor 5 cm above the manometrically determined LES, the distal pH sensor lying 15 cm distal to the proximal pH sensor in the body of the stomach. Patients were asked to finish their evening meal at least 2 hours before retiring to bed, and not to eat or drink again until getting up in the morning. By studying the supine period when reflux in Barrett's esophagus is severe, the effects of food and drink on esophageal and gastric pH are minimized.

The supine period was analysed to determine the nocturnal patterns of acid reflux, bilirubin reflux, esophageal alkaline exposure (pH > 7) and gastric alkaline exposure (pH > 4). The supine period was divided into quarters, and reflux times calculated for each quarter, to determine how each parameter varied over the night time.

Temporal patterns of reflux during the supine period

Figure 1. Patterns of acid reflux throughout the night in each supine quarter.

The patterns of acid reflux, bilirubin reflux, and esophageal and gastric alkaline exposure over the four quarters of the supine period are shown in Figures 1-4 respectively. There is a significant change in acid reflux through the night (p < 0.001), being greatest in the first half of night (Figure 1). This pattern shows significant differences between the groups (p < 0.001), occurring only ingroups 2 and 3, with virtually nosupine acid reflux in group 1. Esophageal alkaline exposure occurs in all four quarters of the night (Figure 2). Although esophageal alkaline exposure tends to increase towards the end of night, this trend does not achieve significance (p = 0.79). In addition, there is no significant difference in pattern between the groups (p = 0.15). There is little supine esophageal bilirubin reflux in groups 1 and 2, but marked amounts in group 3 (Figure 3). In group 3, there is no significant change in bilirubin reflux over the four quarters (p = 0.098), occurring throughout the night. There is also no difference in pattern between the three groups (p = 0.103). Gastric alkaline exposure occurs mainly in group 3 (Figure 4), increasing towards the end of the night (p < 0.001), in contrast to groups

Figure 2. Nocturnal esophageal alkaline exposure. All 3 groups show a tendency for alkaline exposure to occur towards the end of the night, although this does not represent a significant change (p = 0.79).

Figure 3. Nocturnal esophageal bilirubin reflux is principally a feature of group 3, where it exists in all quarters of the supine period without a significant change (p = 0.098).

Figure 4. Nocturnal gastric alkaline exposure is a feature of group 3 almost exclusively, where it occurs mainly in the last quarter of the night (p < 0.001).

1 and 2, who experience virtually no gastric alkaline exposure and thus show a different pattern to group 3 (p < 0.001).

Discussion

It has long been appreciated that damage to esophageal mucosa by duodenal contents depends on luminal pH. Bile acids which reflux into the esophagus via an acid-secreting stomach are predominately taurine conjugated. Conjugated bile acids are more injurious to esophageal mucosa at an acid pH, while unconjugated bile acids and trypsin are more noxious at pH 7. Lysolecithin can cause damage at an acid pH. Under normal circumstances these constituents appear together, and the synergistic and inhibitory interaction of conjugated bile acids with trypsin and pepsin have also been studied. It has been found that unconjugated bile acids, when combined with trypsin, increased the damage. On the other hand, conjugated bile acids, when combined with pepsin, reduced the damage [3]. It must be important, therefore, when investigating the adverse effects of duodenal contents on esophageal mucosa, to consider both esophageal and gastric pH. This is because despite the good correlation between total acid and bilirubin reflux times, if one examines 24 hour traces it appears that acid and bilirubin reflux episodes do not always occur simultaneously (Figure 5).

Acid and bilirubin reflux and esophageal and gastric alkaline exposure show distinct temporal patterns throughout the night. Gastric acid secretion is known to be greatest early in the night as a continuation of evening meal stimulated output, decreasing to near normal basal levels by half way through the night [8]. This would explain the predominance of gastroesophageal acid reflux in the first half of the night. The increased esophageal alkalinity in Barrett's esophagus in this study mirrors the findings of Attwood et al. [9], who in a combined pH/aspiration study also demonstrated a good correlation between alkaline reflux and increased esophageal bile acid concentrations [10]. Other studies, however failed to show such a relationship, questioning the use of pH monitoring as a means of detecting DGER [6, 11]. Aspiration studies have shown that gastric bile acids exist in the stomach of esophagitis patients throughout the night at concentrations several times greater than in healthy controls [8]. Gastric bile acid concentrations are also raised in Barrett's patients [6]. In Barrett's esophagus, the combination of an incompetent poor LES function and ineffective clearance mechanisms both result in and exacerbate severe supine reflux. This may explain the reasons why our findings showed gastroesophageal bilirubin reflux occurring in all four quarters of the night. The increased gastric alkalinity in the second half of the night has been previously noted [12] although its origins are still uncertain. In this study it occurs as gastroesophageal acid reflux declines. One explanation is that the buffering capacity of the stomach becomes overwhelmed as duodenogastric reflux continues throughout the night and gastric acid production declines, this being manifested as a reduction in acid reflux and increased gastric alkalinity.

This study has shown that the pH relationship between the stomach and esophagus is constantly changing, providing conditions in which all the constituents of duodenal contents are able to cause damage. Trypsin does not always enter an acidic stomach only to be denatured, but could pass through an alkaline stomach into an alkaline esophagus. Bile acids also exist at a wide pH range suitable for intracellular accumulation and subsequent damage, and are not necessarily precipitated out and thus inactivated by an acid stomach.

Figure 5. 24-hour tracing of esophageal (top) and gastric (middle) pH and esophageal bilirubin (bottom) monitoring in a patient with Barrett's esophagus. Note the severe acid reflux in the first half of the night, the severe supine bilirubin reflux associated with both an acid and a normal esophageal pH, and the marked gastric alkaline exposure in the second half of the night.

In particular, patients with Barrett's esophagus experience severe pathological DGER throughout the night which is associated, particularly in the last quarter of the night, with alkaline conditions in the stomach and esophagus. This would provide ideal conditions for duodenal contents to cause esophageal damage. Therefore this study provide further clues to the pathogenesis of the severe mucosal damage seen in Barrett's esophagus.

References

1. Singh P, Taylor RH, Colin-Jones DG. Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett's metaplasia is present. Am J Gastroenterol 1994;89:349-356.

2. Leite LP, Johnson BT, Barrett J, Castell JA, Castell DO. Ineffective esophageal motility (IEM): the primary finding in patients with non-specific esophageal motility disorder. Dig Dis Sci 1997;42:1853-1858.

3. Vaezi MF. Duodenogastroesophageal reflux. In: Castell DO, Richter JE, eds. The esophagus. Philadelphia: Lippincott, Williams & Wilkins, 1999:421-436.

4. Singh S, Bradley LA, Richter JE. Determinants of oesophageal "alkaline" pH environment in controls and patients with gastro-oesophageal reflux disease. Gut 1993;34:309-316.

5. Bechi P, Falciai R, Baldini F, Cosi F, Pucciani F, Boscherini S. A new fibreoptic sensor for ambulatory enterogastric reflux detection. Fiberopt Med Fluoresc Sens Appl 1992;1648:130-135.

6. Champion G, Richter JE, Vaezi MF, Singh S, Alexander R. Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus. Gastroenterology 1994;107:747-754.

7. Marshall REK, Anggiansah A, Owen WA, Owen WJ. The temporal relationship between oesophageal bile reflux and pH in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 1998;10:385-392.

8. Fiorucci S, Distrutti E, Di Matteo F, Brunori P, Santucci L, Mallozzi E. Circadian variations in gastric acid and pepsin secretion and intragastric bile acid in patients with reflux oesophagitis and healthy controls. Am J Gastroenterol 1990;90:270-276.

9. Attwood SE, DeMeester TR, Bremner CG, Barlow AP, Hinder RA. Alkaline gastroesophageal reflux: implications in the development of complications in Barrett's columnar-lined lower esophagus. Surgery 1989;106:764-770.

10. Attwood SE, Ball CS, Barlow AP, Jenkinson L, Norris TL, Watson A. Role of intragastric and intraoesophageal alkalinisation in the genesis of complications in Barrett's columnar line lower oesophagus. Gut 1993;34:11-15.

11. Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192-1199.

12. Savarino V, Mela GS, Zentilin P, Mele MR, Mansi C, Remagnino AC, Vigneri S, Malesci A, Belicchi M, Lapertosa G, Celle G. The time pattern of gastric acidity in Barrett's esophagus. Dig Dis Sci 1996;41:1379-1383.


Publication date: August 2003 OESO©2015