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
 

What is the relationship between esophageal exposure to bilirubin and esophageal pH or symptoms?

C.G. Streets, C.G. Bremner (Los Angeles)

Gastroesophageal reflux disease (GERD) is characterized by the reflux of gastric contents into the distal esophagus. The adverse action of gastric acid and pepsin on esophageal mucosa is well established, but the role of bile salts, including bilirubin, remains the subject of much conjecture [1, 2]. Although the refluxate usually contains acidic gastric contents, some individuals additionally reflux duodenal contents, notably bile and the pancreatic enzyme trypsin, by a process termed duodeno-gastroesophageal reflux (DGER). Determining the relative importance of bilirubin in the pathogenesis of GERD has been complicated by the observation that those patients with severe and complicated GERD also tend to have greater exposure to both acid and bile [3].

Acid reflux into the esophagus generates a well-understood symptom complex and can be accurately diagnosed using the technique of ambulatory 24-hour esophageal pH monitoring [4]. However, the story is very different in the case of bile reflux.

Esophageal pH

Ambulatory 24-hour esophageal pH monitoring has been extensively used to detect the presence of the hydrogen ion in the esophagus [5]. Bile has an alkaline pH and can reach the esophagus by reflux, initially through the pylorus and then through the lower esophageal sphincter (LES) - the process of DGER. It would therefore seem reasonable to expect that a more neutral or less acidic pH in the esophagus might indicate the presence and reflux of bile.

Initially, alkaline reflux (i.e. pH > 7) was used as an indicator for refluxed duodenal contents. A number of studies have shown that a distal esophageal pH > 7 was associated with severe GERD and complicated Barrett's esophagus. In 1978, Pellegrini et al. discovered that patients with predominantly alkaline reflux had more severe esophagitis. It was thought that this alkaline reflux was the result of DGER [6]. Attwood et al. showed that patients with Barrett's esophagus had increased alkaline reflux compared with esophagitis patients and normal volunteers. When the patients with complicated Barrett's esophagus were studied, it was found that they in turn had greater alkaline reflux than those with uncomplicated Barrett's esophagus [7]. Stein et al., using concurrent gastric and esophageal pH monitoring, were able to show that complications of GERD occurred more frequently in patients with alkaline duodenogastric reflux and defective LES. Esophageal alkaline reflux was increased only in those GERD patients who also had duodenogastric alkaline reflux [8]. Attwood et al. were able to show that although esophageal percent total time pH < 4 was similar in subjects with Barrett's columnar-lined lower esophagus, those with complications had a significantly greater percent time pH > 7. Of those patients in whom gastric and esophageal pH monitoring were performed concurrently, 71% had increased gastric alkaline exposure with the increased esophageal alkaline exposure [9]. In a study in 1994, Stein et al. moved from simply measuring the esophageal pH changes to using an ambulatory esophageal aspiration technique to study the constituents of the refluxate responsible for these pH changes. They showed that in patients with a GERD stricture or Barrett's esophagus, there was increased exposure to duodenal content, namely bile and trypsin, and that this corresponded with an increased time that the esophageal pH > 7 [10].

Other studies have questioned the validity of using a pH > 7 to diagnose DGER, and several have failed to show a correlation between an esophageal pH > 7 with the presence of bile or trypsin. These studies have consisted of measuring the pH, analyzing aspirated esophageal luminal samples, employing fiberoptic spectrophotometry to look for bilirubin in the refluxate, and considering salivary or esophageal bicarbonate as responsible for a "pseudo-alkaline reflux".

A three-channel pH catheter was used by Mattioli et al. to study esophageal, fundic and antral pH simultaneously in normal volunteers and patients with GERD or dyspepsia. Whilst this study confirmed the importance of alkacid reflux (pH > 4 and < 7) it found that true alkaline reflux occurred very rarely. When the alkaline duodenal contents refluxed into the stomach it would very quickly be acidified by the gastric secretions. The authors concluded that episodes of alkaline reflux were most likely due to saliva, food, drink and probe artifact than from true alkaline DGER [11]. Singh et al. studied normal subjects, and esophagitis and Barrett's esophagus patients using pH probes located 1cm below the upper esophageal sphincter, 5 cm above the LES and in the stomach in order to determine to what extent saliva or alkaline reflux were responsible for lower esophageal pH changes. They concluded that DGER did not occur but that saliva was responsible for alkalinization of the esophagus during the day, and that some other source of alkali, possibly bicarbonate from the esophageal submucosal glands, was responsible for the condition during the night [12]. DeVault et al. were also interested in the role of saliva on distal esophageal pH. They observed the pH changes at points 5 cm proximal and 10 cm distal to the LES during salivary stimulation in ten normal volunteers. With salivary stimulation, the esophageal pH increased in all the subjects and was accompanied by a contemporaneous increase in gastric pH in four. Their conclusion was that this pattern of gastric and esophageal increase in pH as a result of saliva might account for a high percentage of false positives when using pH > 7.0 as an indicator for DGER [13].

Gotley et al. used esophageal aspiration and pH monitoring to show that in 38 of 39 GERD patients in whom conjugated bile acids were found to be present in the esophagus, it was associated with an acidic esophageal pH. Therefore bile acids did reflux into the distal esophagus, primarily when the patient was in the supine position, but these episodes occurred with acid rather than alkaline reflux [14]. A later study by the same group found that despite increased esophageal alkaline exposure time in patients with increasing severities of GERD this did not correlate with increasing accumulation of bile acids and trypsin in esophageal aspirates [15].

In 1993, a fiberoptic spectrophotometry system (Bilitec™ 2000) became available for the detection of bilirubin independent of pH [16]. Kauer et al. performed pH and Bilitec™ monitoring to determine esophageal acid and bilirubin reflux in both normals and GERD patients. Whilst confirming that patients with Barrett's metaplasia had a greater esophageal bilirubin exposure than those with erosive esophagitis and normals, they also noted that 87% of this bilirubin exposure occurred when the esophageal pH was between 4 and 7 [17]. Caldwell et al., using similar methods, confirmed that bile reflux was greater in subjects with Barrett's esophagus than in controls and those with uncomplicated reflux, but that the esophageal pH did not differ between the groups [18]. Partial gastrectomy patients are prone to duodenogastric reflux due to an absence of a pylorus. Sears et al. studied 13 such patients with symptoms of GERD using pH and Bilitec™ monitoring. Ten had DGER and three had abnormal acid reflux. Only the latter had esophagitis. It was therefore concluded that acid and not alkali was required for DGER to cause esophagitis [19].

Bicarbonate secretion from the normal esophagus and salivary glands has been shown to increase with acidification of the esophagus and so will affect pH monitoring [20]. Also, oral infections can increase the content of bicarbonate in saliva, whilst any degree of distal esophageal obstruction, by a stricture for example, can result in pooling of saliva. The subsequent bacterial overgrowth may further increase the pH 6.

Symptoms

Unlike acid reflux where most patients will have the typical symptoms of heartburn, regurgitation and dysphagia, there do not seem to be many associations between esophageal bile reflux itself and specific symptoms. However, duodenogastric reflux of bile can result in an alkaline gastritis. This condition may present with the characteristic symptoms of constant, severe, epigastric pain that worsens with eating, nausea, bilious vomiting and weight loss [21]. The case for esophageal symptoms is not so clear. Pellegrini et al. reported that those patients with DGER had predominantly regurgitation and pulmonary symptoms rather than typical heartburn [6]. Mattioli et al., using their 3-channel pH probe were able to distinguish symptoms of gastroesophageal reflux from those of DGER. The latter group had mainly dyspeptic symptoms rather than typical gastroesophageal symptoms [11]. In a study by Bachir and Collis, the distal esophagus of normal and hiatal hernia subjects was perfused by various solutions. Acidified bile acids were found to be more irritating than acid alone [22].

Conclusion

DGER is undoubtedly increased in patients with Barrett's esophagus, but attempts to clinically quantify this reflux have proved difficult. Using ambulatory 24-hour esophageal pH monitoring and considering periods of pH > 7 as indicative of DGER has now been shown to be too simplistic and inaccurate. However introduction of the Bilitec™ 2000 spectrophotometry probe has enabled the detection of esophageal bilirubin, a consistent marker for DGER. Symptomatically, DGER has no specific effect on the esophagus but bile does irritate the stomach. Therefore DGER should be considered in patients with the symptoms of alkaline gastritis together with heartburn, regurgitation or dysphagia.

References

1. Goldberg HI, Dodds WJ, Gee S, Montgomery C, Zboralske FF. Role of acid and pepsin in acute experimental esophagitis. Gastroenterology 1969;56:223-230.

2. Lillemoe KD, Johnson LF, Harmon JW. Alkaline esophagitis: a comparison of the ability of components of gastroduodenal contents to injure rabbit mucosa. Gastroenterology 1983;85:621-628.

3. Vaezi MF, Richter JE. Synergism of acid and duodenogastroesophageal reflux in complicated Barrett's esophagus. Surgery 1995;117:699-704.

4. Jamieson JR, Stein HJ, DeMeester TR, et al. Ambulatory 24-hr esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity and reproducibility. Am J Gastroenterol 1992;87:1102-1111.

5. Johnson LF, DeMeester TR. Twenty-four hour pH monitoring of the distal esophagus:a quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325-332.

6. Pellegrini CA, DeMeester TR, Wernley JA, Johnson LF, Skinner DB. Alkaline gastroesophageal reflux. Am J Surg 1978;135:177-184.

7. Attwood SEA, 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.

8. Stein HJ, Barlow AP, DeMeester TR, Hinder RA. Complications of gastroesophageal reflux disease: role of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure, and duodenogastric reflux. Ann Surg 1992;216:3543.

9. Attwood SEA, 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 lined lower oesophagus. Gut 1993;34:11-15.

10. Stein HJ, Feussner H, Kauer W, DeMeester TR, Siewert JR. Alkaline gastroesophageal reflux: assessment by ambulatory esophageal aspiration and pH monitoring. Am J Surg 1994;167:163-168.

11. Mattioli S, Pilotti V, Felice V, Lazzari A, Zannoli R, Bacchi ML, Loria P, Tripodi A, Gozetti G. Ambulatory 24-hr pH monitoring of esophagus, fundus and antrum: a new technique for simultaneous study of gastroesophageal and duodenogastric reflux. Dig Dis Sci 1990;35:929-938.

12. 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.

13. DeVault KR, Georgeson S, Castell DO. Salivary stimulation mimics esophageal exposure to refluxed duodenal contents. Am J Gastroenterol 1993;88:1040-1043.

14. Gotley DC, Morgan AP, Cooper MJ. Bile acid concentrations in the refluxate of patients with reflux oesophagitis. Br J Surg 1988;75:587-590.

15. Gotley DC, Appleton GVN, Cooper MJ. Bile acids and trypsin are unimportant in alkaline esophageal reflux. J Clin Gastroenterol 1992;14:2-7.

16. Bechi P, Pucciani F, Baldini F, Cosi F, Falciai R, Mazzanti R, Castagnoli A, Pesseri A, Boscherni S. Long-term ambulatory enterogastric reflux monitoring. Validation of a new fiberoptic technique. Dig Dis Sci 1993;38:1297-1306.

17. Kauer WKH, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone: the need for surgical therapy re-emphasized. Ann Surg 1995;222:525-533.

18. Caldwell MTP, Lawlor P, Byrne PJ, Walsh TN, Hennessy TPJ. Ambulatory oesophageal bile reflux monitoring in Barrett's oesophagus. Br J Surg 1995;82:657-660.

19. Sears RJ, Champion GL, Richter JE. Characteristics of distal partial gastrectomy patients with esophageal symptoms of duodenogastric reflux. Am J Gastroenterol 1995;90:211-215.

20. Brown CM, Snowdon CF, Sandle LN, Rees WDW. Measurement of bicarbonate output from the intact human esophagus. Gut 1993;34:872-880.

21. Van Heerden JA, Priestley JT, Farrow GM, Phillips SF. Postoperative alkaline reflux gastritis: surgical Implications. Am J Surg 1969;118:427-433.

22. Bachir GS, Collis JL. Effect of perfusion of bile salts solutions into the oesophagus of hiatal hernia patients and controls. Thorax 1976;31:271-277.


Publication date: August 2003 OESO©2015