BILE REFLUX IN COLUMNAR-LINED ESOPHAGUS

THE COLUMNAR-LINED ESOPHAGUS 0889-8553/97 $0.00 + .20

BILE REFLUX IN COLUMNAR- LINED ESOPHAGUS

Michael F. Vaezi, PhD, MD, and Joel E. Richter, MD

Barrett's esophagus represents a metaplastic process in which the normal squamous epithelium of the lower esophagus is replaced by metaplastic columnar epithelium. This condition develops in approximately 10% of patients with gastroesophageal reflux disease (GERD)30 and often represents the end stage of reflux esophagitis. Patients with Barrett's esophagus may present with serious complications of GERD in the form of strictures, ulcerations, perforations, or adenocarcinoma."30 Although the role of acid and pepsin in the development of Barrett's esophagus is well accepted, the importance of duodenogastroesophageal reflux (DGER) in this disorder is not clear.

BARRElT'S ESOPHAGUS IS AN ACQUIRED CONDITION

Columnar epithelium lining the distal esophagus was first described in 1950 by Barrett.4 He believed that this condition was a congenital abnormality secondary to arrested regression of the esophageal glandular epithelium nor- mally lining the fetal esophagus. Allison and Johnstone' in 1953 suggested an acquired nature for Barrett's esophagus based on the presence of reflux symptoms, esophagitis, and hiatal hernia in association with esophageal columnar epithelium. The controversy persisted until 1970, when the landmark study by Bremner and colleagues,7 using an experimental model of esophageal mucosal regeneration in dogs, showed columnar rather than squamous cell regeneration after severe mucosal injury from chronic gastroesophageal reflux. Bremner suggested that columnar cells in the esophagus resulted from the proximal migra- tion of gastric cardiac columnar epithelium. Later studie~,'~ however, suggested that columnar cells were not a direct extension of the surface lining of the adjacent stomach but rather derived from a pleuripotential stem cell in the

From the Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio

GASTROENTEROLOGY CLINICS OF NORTH AMERICA

VOLUME 26 NUMBER 3 - SEPTEMBER 1997 565

566 VAEZI &I RICHTER

esophagus. The prevailing hypothesis now is that Barrett‘s mucosa develops from multipotential cells present in the basal layer of the esophageal mucosa, which differentiate into glandular cells after severe mucosal injury.”

ROLE OF ACID AND BILE IN BARREWS ESOPHAGUS

There is now overwhelming evidence supporting the association of GERD and Barrett’s esophagus. The role of individual constituents of the refluxate in the development of Barrett’s esophagus and its associated complications (ulcers, strictures, dysplasia, or adenocarcinoma) remains unknown. Gastric acid and pepsin have received the most attention. The development of Barrett’s esophagus in a few achlorhydric and postgastrectomy patients, however, suggests a possible role for duodenal contents. The duodenal constituents suspected of causing esophageal mucosal injury include bile acids and lysolecithin secreted in bile and the pancreatic enzyme *sin (Fig. 1). The role of gastric and duodenal contents in the formation of Barrett’s esophagus is reviewed here.

Importance of Acid and Pepsin

Substantial experimental and clinical evidence strongly support the importance of acid and pepsin in causing esophageal mucosal injury. Animal

show that the esophageal mucosa is relatively resistant to reflux of acid alone unless it occurs at high concentrations (pH 1.0 to 1.3). The combina- tion of acid and even small concentrations of pepsin results in macroscopic as well as microscopic esophageal mucosal injury (see Fig. l ) . 1 5

Figure 1. Proposed agents responsible for esophageal mucosal injury.

BILE REFLUX IN COLUMNAR-LINED ESOPHAGUS 567

The modern concept of peptic esophagitis was first suggested by Winkelstein in 1935,47 who proposed a role for gastric juice in the formation of esophagitis based on clinical findings in five patients. Studies by Aylwin3 were the first scientific evidence, however, identifying the importance of acid and pepsin in the development of heartburn and esophageal mucosal injury. Using continuous esophageal aspiration in patients with hiatal hernia and esophagitis, they found that patients with esophagitis had aspirates of lower pH and higher pepsin concentration than those without esophagitis. Later, Tuttle and colleagues4’ measured the pH of the distal esophagus, finding that reflux of material with pH less than 4 coincided with the onset of heartburn, whereas a rise to a more neutral pH coincided with relief of symptoms.

Subsequently a series of studies showed that patients with various grades of esophagitis, including Barrett’s esophagus, have increased frequency and duration of esophageal exposure to acid (pH <4) reflux.I4, 19, 37, In fact, the original studies by Bremner and colleagues7 implicated acid reflux in the formation of columnar epithelium in Barrett’s esophagus. In this study, a high gastric acid output produced by repeated histamine injections combined with surgery to induce reflux resulted in epithelial metaplasia in the dog esophagus. In patients with GERD, Iascone and associateszo reported a direct relationship between the severity of esophageal mucosal injury and the degree and frequency of mucosal exposure to acid reflux. Later, studies by DeMeester and co-workers” found that greater than 90% of patients with esophagitis had increased amounts of acid reflux by 24-hour esophageal pH monitoring. The same group% reported that patients with Barrett’s esophagus had significantly higher exposure times to pH less than 4 than patients who had esophagitis without columnar metaplasia. The latter patients had higher acid exposure times than healthy controls. These observations suggest a significant role for acid reflux in the development of both esophagitis and Barrett’s esophagus.

Separating the role of pepsin from acid in the production of esophagitis or Barrett’s esophagus is difficult because the optimum pH for the enzymatic activity of pepsin is below 3.= A number of studies show a positive correlation between the degree of abnormal acid and pepsin exposure and the severity of esophagitis. Bremner and colleagues8 observed that patients with increased esophageal exposure to acidic pH (corresponding to the known pKa of pepsin) had the most significant degrees of esophagitis. Gotley and co-~orkers’~ found that esophageal aspirates from patients with esophagitis have significantly higher concentrations of acid and pepsin than the aspirates from healthy controls. Furthermore, patients with Zollinger-Ellison syndrome, in whom the basal acid output is high and the low gastric pH favors pepsin activity, have a 40% to 60% incidence of esophagitis despite having normal or even increased lower esophageal sphincter ~ressures.2~ Clinical studies have confirmed the presence of severe gastroesophageal reflux of acid and pepsin in patients with Barrett’s esophagus. Additionally, these patients are characterized by markedly decreased lower esophageal sphincter pressure, increased frequency and duration of esophageal acid exposure, and delayed esophageal acid clearance.38

The frequency and duration of esophageal acid exposure are not always predictive of the degree of esophageal mucosal injury. This suggests that factors other than acid play a role in esophagitis. These factors might include the inherent resistance of esophageal mucosa to acid injury, the protective effects of saliva and bicarbonate-producing submucosal glands in the distal esophagus in neutralizing refluxed acid,’O or possibly duodenal contents that reflux into the esophagus.

568 VAEZI 81 RICHTER

Importance of Bile

Although the reflux of duodenal contents is commonly referred to as bile reflux, it is important to remember that duodenal contents contain more than just bile. Furthermore, the term alkaline reflux is often used interchangeably with bile reflux, suggesting that a rise in esophageal pH greater than 7 represents the reflux of alkaline duodenal contents into the lower esophagus. Studies, however, have questioned the accuracy of pH monitoring in identifying the reflux of duodenal contents, and suggest that the term alkaline reflux is a misnomer. Therefore, DGER may be a more appropriate term to describe the reflux of duodenal contents (bile and pancreatic enzymes) into the stomach with subse- quent reflux into the esophagus. DGER is a normal phenomenon occurring usually at night and, when excessive, may produce symptoms or mucosal injury.I7

Conjugated bile acids are an important constituent of refluxed duodenal contents in normal individuals and can contribute to esophageal mucosal injury at an acidic pH (see Fig. 1). Animal studies suggest that unconjugated bile acids and the pancreatic enzyme trypsin also may cause mucosal injury at more neutral pH values (see Fig. 1).= Some groups have interpreted the latter findings to suggest that aggressive acid suppression, although protective against the injurious effects of acid and conjugated bile acids, may in fact perpetuate DGER and esophageal injury caused by unconjugated bile acids and trypsin, potentially causing complications in patients with Barrett’s esophagus. The clinical importance of DGER in the absence of acid reflux in patients with esophageal mucosal injury and Barrett’s esophagus remains controversial. This may be because there is no gold standard for identifying DGER in humans.

Methods for Measuring Duodenogastroesophageal Reflux

Various direct and indirect methods have been employed for identifying DGER, including endoscopy, aspiration studies (both gastric and esophageal), scintigraphy, ambulatory pH monitoring, and ambulatory bilirubin monitoring (Bilitec 2000, synectics, Irving, TX). As summarized in Table 1, each test has its strengths and shortcomings. Reviewing some of the human studies using these tests can help clinicians better appreciate the role of DGER in causing esophageal mucosal injury.

Endoscopy

Yellow-green bile is frequently seen in the stomach and esophagus of patients during endoscopy; however, studies indicate that this observation is a poor indicator of DGER.3I. 40 Nasrallah and colleagues31 evaluated 110 patients with bile-stained gastric mucosa at endoscopy and found no correlation between the endoscopic finding and gastric bile acid concentrations, the degree of histo- logic injury, or the severity of endoscopic changes. These observations suggest that there is little clinical importance to bile-stained mucosa at endoscopy. Similarly, using scintigraphy and gastric pH monitoring to assess DGER, Stein and co-w~rkers~~ found poor sensitivity (37%), specificity (70%), and positive predictive value (55%) for endoscopy in the diagnosis of excessive DGER.


Table 1. ADVANTAGES AND DISADVANTAGES OF CURRENTLY AVAILABLE METHODS FOR DETECTING DUODENOGASTROESOPHAGEAL REFLUX

Method Advantages Disadvantages

Endoscopy Easy visualization of yellow/ Poor sensitivity/specificity/positive green bile predictive value

Requires sedation High cost

Aspiration Less invasive than endoscopy Short duration of study studies No sedation Requires familiarity with

Scintigraphy Noninvasive Semiquantitative at best

pH monitoring Easy to perform

Low cost enzymatic assay for bile acid

Radiation exposure High cost pH >7 not a marker for DGER Not specific for DGER Relatively noninvasive

Prolonged monitoring Ambulatory

Bilirubin Easy to perform Current design underestimates monitoring Relatively noninvasive DGER by about 30% in acidic (Bilitec) Prolonged monitoring medium (pH ~3.5)

Ambulatory Requires modified diet Good correlation with gastric

bile acid concentrations

DGER = Duodenogastroesophageal reflux.

Aspiration Techniques

One of the earliest methods used for evaluating DGER was the analysis of aspirated gastric or esophageal contents for bile acids and trypsin by enzymatic or chromatographic techniques. Using this method, Studies’O, 43 indicate that fasting bile acid concentrations may be increased in a graded fashion across the GERD spectrum, being highest among patients with Barrett’s esophagus (Fig. 2). The reports using aspiration methods in detecting DGER in patients with Barrett’s esophagus have been conflicting, in part because some enzymatic measurements of bile acids are now known to be inaccurate.28 Furthermore, these studies did not report the pH of the aspirated refluxate.

Scintigraphy

Scintigraphic studies show that DGER is a common phenomenon in normal individuals postprandially,” requiring that the evaluation of abnormal DGER be quantitative. Radionuclide techniques offer a noninvasive method for study- ing DGER; however, study results are conflicting. Matikainen and associatesE found no difference in the scintigraphic amount of DGER between 40 patients with esophagitis (10% scintigraphic reflux) and 150 healthy control subjects (14% scintigraphic reflux). Waring and colleagues% reported that patients with Barrett’s esophagus, especially those with complicated Barrett’s esophagus, had more frequent DGER detected by technetium 99m DISIDA scintigraphy than healthy volunteers.

570 VAEZI & RICHTER

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Figure 2. Individual and median fasting gastric bile acid concentration for five study populations: controls, acid reflux patients with and without esophagitis, and patients with uncomplicated and complicated Barrett's esophagus. (From Vaezi MF, Richter JE: Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease (GERD) Gastroenterology 11 1 :1192-1199, 1996; with permission.)

Ambulatory Prolonged pH Monitoring

Until recently, the most popular method for detecting DGER was ambulatory 24-hour monitoring. Using this technique, Pellegrini and ~o-workers~~ intro- duced the term alkaline reflux, suggesting that a rise in esophageal pH greater


than 7 was an indirect marker for DGER. Subsequently, Attwood and associatesz reported that alkaline reflux was greater in patients with Barrett's esophagus when compared to patients with esophagitis uncomplicated by Barrett's esophagus or normal controls. Furthermore, they found that the time that esophagus pH remained greater than 7 was significantly higher in patients with Barrett's esophagus complicated by stricture, ulcer, and dysplasia than in those who had Barrett's esophagus without complications. In contrast, the duration of esophageal pH less than 4 did not distinguish the two groups. The authors suggested that prolonged exposure to duodenal contents may promote the development of complicated Barrett's esophagus and even adenocarcinoma. The investigators, however, did not attempt to resolve the apparent physiologic paradox of patients with a marked amount of acid reflux also refluxing independently large amounts of "alkaline" material.

The validity of esophageal pH greater than 7 as a marker of DGER is compromised by several problems. Precautions must be taken to use only glass electrodes, to prohibit the ingestion of foods with pH greater than 7, to inspect patients for periodontal disease, and to dilate strictures to avoid pooling of alkaline saliva in the esophagus. Several groupsl2, 16, 26, 35 have questioned the accuracy of alkaline pH as an index of DGER. Gotley and colleagues16 found no relationship between alkaline exposure time and esophageal concentration of bile acids or trypsin. Similarly, Mattioli and colleagues,Z6 using a triple-probe pH monitor placed in the distal esophagus as well as in the gastric fundus and antrum, found that alkaline reflux (defined as a rise in pH >7 that proceeds from the antrum to the esophagus) was extremely uncommon. Singh and associ- a t e ~ ~ ~ and Devault and co-workers'Z confirmed these observations, reporting that increased saliva production and bicarbonate production by the esophageal submucosal glands were the most common causes of a rise in esophageal pH greater than 7. Finally, using an ambulatory bilirubin monitoring device combined with pH monitoring, Vaezi and Richtel"L5 reported no difference in the percentage of total time that esophageal pH remained greater than 7 between controls, patients with GERD, and patients with Barrett's esophagus (Fig. 3). Furthermore, Champion and colleagues1o found no correlation between esophageal pH greater than 7 and bile reflux into the esophageal lumen (Fig. 4), suggesting that the term alkaline refrux was a misnomer that should not be used when referring to DGER.

Ambulatory Bilirubin Monitoring (Bjlitec 2000) A new fiberoptic system that detects the presence of bilirubin (Bilitec 2000,

Synectics, Irving, TX) was developed to identify DGER in an ambulatory setting, independent of esophageal pH.5 This system relies upon the optical properties of bilirubin, the most common pigment in bile. Bilirubin has a characteristic spectrophotometric absorption band at 450 nm (Fig. 5). The basic working principle of the system is that the findings of absorption near this wavelength implies the presence of bilirubin and, therefore, represents DGER. This system is compact and similar to those used for ambulatory pH monitoring.

The system consists of a miniaturized fiberoptic probe that carries light signals into the probe tip and back to the optoelectronic recording system via a plastic fiberoptic bundle. The Teflon probe head is 9.5 mm in length and 4 mm in diameter. There is a 2.0-mm open groove in the probe across which two wavelengths of light are emitted and material sampled. Two light-emitting diodes at 470 and 565 nm are the sources used for the measurement of bilirubin and the reference signals (Fig. 5). The portable photodiode system converts the

572 VAEZI & RICHTER

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Figure 3. "Alkaline" reflux (% total time pH > 7) for five study populations: controls, acid reflux patients with and without esophagitis, and patients with uncomplicated and complicated Barrett's esophagus. Individual data and group median shown. (From Vaezi MF, Richter JE: Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 11 1:1192-1199, 1996; with permission.)

light into an electrical signal. After amplification, the signals are processed by an integrated microcomputer, and the difference in absorption between the two diodes is calculated, representing bilirubin absorption in the samples of esophageal material bathing the probe. The period between two successive pulses from the same source, representing sampling time, is 8 seconds. In addition, the software averages between the absorbances calculated over two successive samplings to decrease the noise of the measurements. A total of 5400 sample recordings may be stored during a 24-hour period.

DGER data are usually defined as percent time bilirubin absorbance greater


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Figure 4. Relationship between percentage time bilirubin absorbance greater than or equal to 0.14 as a marker of bile reflux and esophageal pH greater than 7 in a group of healthy controls, patients with GERD, and those with Barrett's esophagus. (From Champion G, Richter JE, Vaezi MF, et at: Duodenogastroesophageal reflux: Relationship to pH and importance in Barrett's esophagus. Gastroenterology 107:747-754, 1994; with permission.)

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574 VAEZI & RICHTER

than or equal to 0.14 and can be analyzed separately for total, upright, and supine periods (Fig. 6). Percent bilirubin absorbance 0.14 or greater is commonly chosen as a cutoff because studies have shown that values below this number represent scatter owing to suspended particles and mucus present in the refluxed gastric In one study45 using 20 healthy controls, the 95th percentile values for the percent of total, upright, and supine times that bilirubin was 0.14 or greater were 1.8%, 2.2%, and 1.6%.

Studies from Bechi's laboratory5 as well as the author's l abora tov show a good correlation between Bilitec readings and bile acid concentration measurements of gastric aspirates using enzymatic assays (R = 0.71, P <.01 and R = 0.82, P < .001) (Fig. 7). Furthermore, studies show that Bilitec readings corre- spond to bile acid concentrations in the range of 0.01 to 0.60 mM, which are representative of bile acid concentrations found in the human stomach (0.1 to

Because of limitations inherent in the current Bilitec model, it is only a semiquantitative means of detecting DGER. Validation studies by Vaezi and co- workers4* found that this instrument underestimates bile reflux by at least 30% in an acidic medium (pH <3.5). In solutions with pH less than 3.5, bilirubin undergoes monomer to dimer isomerization, which is reflected by a shift in the absorption wavelength from 453 nm to 400 run. Because Bilitec readings are based on the detection of absorption at 470 nm, this shift results in underestima- tion of the degree of DGER. Therefore, Bilitec measurements of DGER should always be accompanied by the simultaneous measurement of esophageal pH. Furthermore, a variety of substances may result in false-positive readings by the Bilitec probe because it indiscriminately records any substance absorbing around 470 nm. This necessitates the use of a special diet to avoid interference and false readings? Finally, it is important to remember that Bilitec measures the reflux of bilirubin and not bile acids. Although bilirubin is accompanied by bile acids in most cases, a few uncommon medical conditions (Gilbert's and Dubin-Johnson

1.0 mM).

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syndromes) may result in the disproportionate secretion of bilirubin as compared to other duodenal contents, especially bile acids.

BOTH ACID AND DUODENOGASTROESOPHAGEALREFLUX ARE IMPORTANT IN BARRElT’S ESOPHAGUS

Despite its limitations, the Bilitec system is an important advancement in the assessment of DGER in the clinical arena. Several studies using this new device are providing important insights into the role of DGER in causing esophageal mucosal injury in humans. Vaezi and R i ~ h t e e ~ , ~ ~ found a significant graded increase in both acid and DGER from controls to esophagitis patients, with the highest values observed in patients with Barrett’s esophagus (Fig. 8). The results of this study were confirmed by two independent groups.9, Furthermore, studies by Vaezi and found that simultaneous esophageal exposure to both acid and DGER was the most prevalent reflux pattern occurring in 95% of patients with Barrett’s esophagus and in 79% of GERD patients (Fig. 9). In fact, they found a strong correlation (r = .73) between acid and DGER in controls, reflux patients, and patients with Barrett’s esophagus (Fig. 10). Thus, these studies support the earlier findings in animals that suggested a possible synergy between acid and DGER in the development of esophagitis and Barrett’s esophagus.

The role of DGER in producing esophageal mucosal injury in the absence

576 VAEZI 81 RICHTER

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Illustration continued on following page

of acid reflux was not clarified until recently. Sears and colleagues% studied 13 partial gastrectomy patients with reflux symptoms and found increased DGER by Bilitec monitoring in 77%. Endoscopic esophagitis, however, was present only in those who had concomitant acid reflux. Additionally, Vaezi and RichteF observed that 24% of upper gastrointestinal symptoms reported by partial- gastrectomy patients were due to DGER in the absence of acid reflux. These studies show that DGER without excessive acid reflux can cause reflux symptoms but does not usually produce esophagitis.

BILE REFLUX IN COLUMNAR-LINED ESOPHAGUS

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Bilitec can also be used to study the effects of drug therapy on DGER. Studies by Champion and colleagues10 found that aggressive acid suppression with omeprazole (20 mg twice a day) dramatically decreased both acid and DGER in patients with severe GERD, including those with Barrett's esophagus (Fig. 11). Although not specifically studied, the authors speculated this was due to omeprazole's inhibition of both gastric acid production and volume. This finding, which was independently confirmed by Marshall and co-workers,Z4 has important implications for treating patients with Barrett's esophagus who have both acid and DGER, suggesting that medical therapy may decrease the reflux

578 VAEZI & RICHTER

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Figure 9. Prevalence of esophageal exposure to acid and DGER in the GERD subgroups. Esophageal exposure to acid and DGER occurred in 50% of patients without esophagitis, 79% of patients with esophagitis, 95% of patients with Barrett’s esophagus. Open bar = acid only; solid bar = acid +/DGER+; shaded bar = DGER only; dotted bar = acid-/ DGER - . (From Vaezi MF, Richter JE: Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1 11 :1192-1199, 1996; with permission.)

of both constituents to a degree similar to that of antireflux surgery. Further- more, the higher intragastric and intraesophageal pH environment created by the proton pump inhibitors inactivates conjugated bile acids, the main DGER ingredients implicated in causing esophageal mucosal injury.’”

CONCLUSION

Both animal and human studies strongly suggest that acid is the key factor in causing esophageal injury and Barrett’s esophagus in patients with GERD. Studies using an advanced technique to identify DGER spectrophotometrically and independent of pH (Bilitec 2000), however, found that duodenal contents often are present in the esophageal refluxate. The degree of esophageal exposure to acid and DGER showed a graded and similar increase from controls to esophagitis patients, with the highest values observed in patients with Barrett’s esophagus. This close relationship raises the possibility that synergistic actions of acid, pepsin, and conjugated bile acids may be contributing to the development of Barrett’s metaplasia and possibly even adenocarcinoma. Human studies show that DGER in nonacidic environments (i.e., partial-gastrectomy patients) may cause symptoms but does not cause esophageal mucosal injury. Despite suggestions to the contrary by several surgical groups, aggressive acid suppres-


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Figure 10. Relationship between acid ("/. time pH < 4) and DGER ("/. time bilirubin absorbance greater than or equal to 0.14) reflux in normal healthy controls, patients with GERD, and patients with Barrett's esophagus. (From Vaezi MF, Richter JE: Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 111:1192-1199, 1996; with permission.)

580 VAEZI & RICHTER

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sion with proton pump inhibitors decreases both acid reflux and DGER, perhaps by decreasing the volume of gastric contents available to reflux into the esophagus. Furthermore, the high intragastric and intraesophageal pH environment produced by proton pump inhibitors inactivates conjugated bile acids, the main DGER ingredients implicated in causing esophagitis. Thus, the proton pump inhibitors effectively heal esophagitis even in Barrett’s esophagus patients.

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2. Athvood SEA, DeMeester TR, Bemner CG, et al: Alkaline gastroesophageal reflux: Implications in the development of complications in Barrett’s columnar-lined lower esophagus. Surgery 106764-776,1989

3. Aylwin J A The physiological basis of reflux esophagitis in sliding distal diaphragmatic hernia. Thorax 83845,1953

4. Barrett NR Chronic peptic ulcer of the esophagus and ”esophagitis.” Br J Surg 38:175,1950

5. Bechi P, Paucciani F, Baldini F, et al: Long-term ambulatory enterogastric reflux monitoring: Validation of a new fiberoptic technique. Dig Dis Sci 381297-136,1993

6. Bremner CG: Barrett‘s esophagus. In DeMeester TR, Matthews HJ (eds): International Trends in General Thoracic Surgery: Benign Esophageal Disease. Toronto, Mosby, 1987, p 227


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Department of Gastroenterology The Cleveland Clinic Foundation

9500 Euclid Avenue Cleveland, OH 44195

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BILE REFLUX IN COLUMNAR-LINED ESOPHAGUS