GASTROENTEROLOGY
Gastric Acidity and Gastroesophageal Patterns in Patients With Esophagitis STEFANO FIORUCCI, LUCA and ANTONIO MORELLI Istituto di Gastroenterologia
ed Endoscopia
SANTUCCI,
ndoluminal pH-metry is the most reliable and accurate diagnostic test for evaluating gastroesophageal reflux (GER) in patients with esophageal symptoms, irrespective of whether or not they have endoscopic evidence of esophagitis.‘-4 However, monitoring endoluminal pH with a single esophageal
E
Reflux
SILVIA CHIUCCHIfi,
Digestiva, Universitg
Esophageal pH-metry is the test of choice for diagnosing gastroesophageal reflux. However, although it allows acid refluxes to be distinguished, it is of limited value for identifying alkaline or mixed (acid mixed with alkaline material) refluxes. To evaluate the ability of dual pH-metry to identify alkaline or mixed refluxes, the gastric acidity and gastroesophageal reflux pattern were evaluated simultaneously in 64 patients with mild-moderate esophagitis, in 28 patients with severe or complicated esophagitis, and in 20 healthy subjects. A dual esophageal gastric pa-probe allowed three different types of esophageal reflux to be distinguished: (a) acid refluxes, defined as a drop in esophageal pH to values 4 associated with rises in gastric pH to >4 values; (c) alkaline refluxes, defined as a rise in esophageal pH to >7 associated with a simultaneous increase in gastric pH to >4. Gastric acidity was more significantly reduced in patients with severe or complicated esophagitis than it was in healthy subjects (P < 0.01). The reflux pattern in both mild-moderate and severe esophagitis was characterized by mainly acid refluxes and a marked increase in the time the esophagus mucosa was exposed to acid (P < 0.001). Pure alkaline refluxes were rare (~1%) in both healthy subjects and esophagitis patients. The number of mixed refluxes was considerably higher in severe esophagitis patients than it was in either mild-moderate esophagitis patients or controls (P < 0.05). The finding of mixed refluxes in severe or complicated esophagitis suggests that biliary acids and/or pancreatic enzymes are involved in the pathogenesis of severe forms of esophagitis.
1992;103:855-661
di Perugia, Italy
electrode is limited by the fact that although it identifies acid refluxes, it is poorly specific for pure alkaline refluxes and fails to identify mixed alkaline acid refluxes.5 The interpretation of prolonged pH-metry is also hampered by the fact that although patients with severe or complicated esophagitis have more severe acid refluxes than those with moderate esophagitis, there is considerable overlapping between the two groups, which suggests that factors other than reflux of acid into the esophagus may be responsible for the variable endoscopic findings in patients with comparable acid reflux.6-‘o Reflux esophagitis is a multifactorial disease.l’ Abnormalities in esophageal body motility, lower esophageal sphincter (LES) pressure, acid secretion, and gastric emptying have all been reported in subgroups of patients with esophagi&. However, because antisecretory drugs increase the healing rate of patients with esophagitis, the reflux of acid material into the esophagus must be critically involved.1’~12 Despite this, little is known about the pattern of gastric acidity in patients with reflux esophagitis.13 Few studies have documented increased gastric acid secretion’4215in patients with esophagitis. Collen et al. recently found that GER patients who failed to respond to standard doses of ranitidine had higher basal acid secretion than responders.14 However, because reflux esophagitis has been observed in clinical conditions characterized by low or no acid secretion, such as atrophic gastritis,16-21 it has been suggested that alkaline material, refluxed from the duodenum, may be involved in the pathogenesis. Refluxes of alkaline material have recently been documented in patients with Barrett’s esophagus,7 and it has been hypothesized that differences in the composition of the material refluxed into the esophagus may account for the variable endoscopic and clinical manifestations encountered in patients with comparable patterns of acid reflux. To test this hypothesis, we simultaneously monitored gastric and esophageal pH in pa0 1992by
the American Gastroenterological 0016-5085/92/$3.00
Association
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GASTROENTEROLOGY Vol. 103,No. 3
tients with reflux esophagitis. The aims of the study were to determine (a) the gastric acidity pattern in patients with esophagitis and (b) whether the GER patterns of severe-complicated and slight-moderate esophagitis patients differed qualitatively.
Materials and Methods Ninety-two patients with endoscopically proven esophagitis, 64 with mild-moderate esophagitis, and 28 with severe esophagitis, classified according to the criteria of Savary and Miller” (Tables 1 and 2), were included in the study. Patients with gastric and duodenal ulcers were excluded. Eight patients with severe esophagitis were also affected by Barrett’s esophagus, which was endoscopically defined as the presence of the typical orange-red, columnar-appearing mucosa that extended into the tubular esophagus and displaced the squamocolumnar mucosal junction more than 2 cm. Both the tonguelike and circumferential types of Barrett’s esophagus were included. The diagnosis of Barrett’s esophagus was formulated on the basis of histological findings.23 A minimum of 4 biopsies were taken from the proximal extremity of the endoscopitally abnormal mucosa at least 2 cm above the endoscopitally located esophagus-gastric junction. The histological criteria for a diagnosis of esophagitis were those of IsmailBegi et aLZ4 GER symptoms (heartburn, regurgitation, and dysphagia) were scored on a 0 (no symptoms) to 3 (symptoms that interfere with daily activity) reference scale according to DeMeester et al.’ (Table 2). Twenty healthy subjects with no gastrointestinal symptoms who were not taking drugs acted as controls. All gave their consent after being accurately informed of the modality and aims of the study. pH Monitoring Gastric and esophageal pH were determined by positioning a single antimony electrode with two recording sites localized 1.5 cm from each other (external diameter was 2.1 mm, accuracy of 0.1 U of pH, impedance 0.4 pH units have been excluded. Antimony electrodes have a slower response than glass electrodes (3.8 seconds vs. 0.5-0.8 seconds for glass) to acid-to-alka-
Table 1. Endoscopic Endoscopic grading Grade Grade Grade Grade
0 I II III
Features
of Population
Definition No abnormalities Erythema or edema Nonconfluent erosions Confluent erosions, ulcers, stenosis, Barrett’s esophagus
Study No. of subjects 38 26 28
Table 2. Characteristics Type of esophagitis No.
of Population
Study
Slight-moderate 64
Severe 28
Sex (M/F) Age [means f SD; yr)
44/20 44 f 5
17/11 49 f 7
Symptoms (incidence) (%) Heartburn
100
100
100
100
5 0
20
Regurgitation Dysphagia Respiratory symptoms Mean symptom score (O-3) Heartburn Regurgitation Dysphagia Duration [yr (range)] Smokers Endoscopic abnormalities Hiatal hernia Esophageal ulcers Esophageal stenosis Barrett’s esophagus Gastric ulcer Duodenal ulcer Treatments (no.] Antacids HZ-blockers Prokinetic drugs “P i 0.01 vs. slight-moderate
10
1.5f 0.05 1.9+ 0.08 0.5+ 0.01 2.4(0.3-7) 38/64
1.9 f 0.1
2.0f 0.1 2.0f 0.03" 6 (l-14) 19/28
28 0 0 0 0 0
12 4 3 8 0 0
48 64 25
28 28
20
esophagitis.
line variations in pH. However, this difference is of negligible importance when measuring variations in esophageal pH in clinical situations, because the only alkaline (or mixed) reflux it would fail to record would be one of ~3-4 seconds, and oscillations of pH < 15 seconds are thought to be artifacts.“*” pH was used for positioning the esophageal probe.2g.30 The electrode was introduced via the nose of the sitting subject into the stomach until acid pH was recorded. The subject then assumed the supine position and the electrode was slowly withdrawn. A rapid change in pH from acid to above pH 5 could be identified in each case. The electrode was then placed 5 cm above the point of sudden pH changes and stabilized by anchoring the cable to the subject’s nose with adhesive tape. The position of the probe was checked by fluoroscopy at the beginning and end of each study. The sensitive sites of the probe were positioned approximately 10 cm below and 5 cm above the LES. As the length of the LES varies from 2.5 to 3.5 cm in individual subjects, the position of the gastric pH-sensitive site differs. 31 However, as it was never more than 1-2 cm, this should not have affected gastric profiles. The antimony and the skin reference electrode (Ag/AgCl) were then connected to a portable pH-meter (Mark Gold II, Synectics, Milan, Italy). This recording device measures 1 pH value every 4 seconds. Stored data were analyzed in two different ways. pH values from the esophagus were analyzed by using a-specific software (Gastrosoft, Synectics, Milan, Italy) and gastric pH values by transferring pHmetry data to a Prime 550 macrocomputer and using a specific algorithm designed with the SPSS program (SPSS, Chicago, IL). As previously reported,32 working files of indi-
vidual gastric pH profiles were obtained
by averaging
the
GASTRIC pH AND GER IN ESOPHAGITIS 857
September 1992
raw fast-acquired pH data for periods of 2 minutes. Because the gastric pH measured after meals is subject to fluctuations that are difficult to reproduce, the postprandial periods (2 hours after breakfast, lunch, and dinner) were excluded from the analysis. This should eliminate any inaccuracy caused by the sensitivity of antimony electrode to variations in temperature induced by ingestion of food that could interfere with the reproducibility of the method. Five hundred forty gastric pH values were then used to construct an 18-hour curve for each subject. The mean 18-hour gastric pH -t SE and range were calculated for each group of subjects.
Study Design Subjects were studied as outpatients and encouraged to lead a normal life and eat three nondiet meals at 8 AM, 12:30 PM, and 8:30 PM. Smoking and carbonate drinks were prohibited during the study day. Each pH-monitoring session lasted at least 23 hours. Gastric and esophageal pH tracings were evaluated simultaneously according to the scheme reported in Figure 1. Three types of esophageal reflux were considered: (a) acid refluxes, defined as a drop in esophageal pH to below 4, associated with a pH < 4 in the stomach; (b) mixed refluxes, defined as oscillations in esophageal pH with a range of 4-7 immediately preceded by, or concomitant with, an increase in gastric pH to values >4 (The time the esophageal pH took to return to basal values was considered as the duration of the reflux.); and [c) alkaline refluxes, defined as a rise in esophageal pH to values >7 associated with, or immediately preceded by, an increase in gastric pH to values >4. All three types of reflux were analyzed by the variables proposed by DeMeester et aLg (Tables 3 and 4).
Statistical
Analysis
Gastroesophageal reflux values were expressed as mean + SE and range. Gastric pH and gastric acidity were Acid reflux
I w 7 Emphageal
I
Mixed reflux
I
I
Alkaline reflux
r
I I
\
pH
PH 1
Figure 1. Diagrammatic representation of the criteria used for the simultaneous analysis of gastric Ifine lines) and esophageal (thick line) pH. Esophageal acid reflux is a decrease in the esophagus pH to ~4 associated with an acid gastric pH. Mixed refluxes are characterized by a decrease in esophageal pH from the baseline to a value >4 associated with increases in the gastric pH to >4. Alkaline refluxes are those with increases of esophageal pH to >7 associated with an increase in the gastric pH to >4.
represented by using the Box-Whisker Plot.33 Differences between the acid, alkaline, and mixed esophageal refluxes of the three groups studied were determined by the Student’s t test. Analysis of variance was applied for determining the differences between the gastric pH and acidity curves, and the x2 test was used to evaluate prevalence of symptoms between patient groups and controls.34
Results There was little difference in heartburn intensity and regurgitation in the two patient groups, whereas dysphagia was more marked in patients with severe esophagitis (Table 2). As shown in Figure 2, the level of gastric acidity was higher in healthy subjects than in patients with severe esophagitis (P < 0.001). The mean 18-hour pH was 1.60 ? 0.03 (range, 0.40-3.00) in healthy subjects against 1.90 + 0.05 (range, 0.90-2.90) in severe esophagitis patients, while it was 1.68 & 0.05 (range, 1.00-2.50) in mild-moderate reflux esophagitis patients (P < 0.01 vs. severe esophagitis; P = NS vs. healthy subjects). The acid GER of patients with mild-moderate esophagitis was more severe than that of healthy subjects (P < 0.001) and considerably less severe than that of the severe-complicated esophagitis subjects (P < 0.001) (Table 3). Sixteen of 64 (25.0%) mild-moderate and 8/28 (28.5%) severe esophagitis patients showed isolated acid refluxes. Pure alkaline refluxes were observed in 13/64 (20.3%) mild-moderate and 7/28 (25.0%) severe esophagitis patients. However, isolated rises in esophageal pH to values >7 accounted for less than 1% of time. There were no differences in symptoms between these patients and those who experienced no alkaline refluxes, nor were there any differences in the duration of pure alkaline refluxes between patients with esophagitis and healthy subjects (Table 4). However, there were significant differences in mixed esophageal refluxes (Figure 3). They were more frequent in patients with esophagitis than in healthy subjects (P < 0.01). Although 67.2% (43/64) patients with slight esophagitis and 53.6% (15/28) of patients with severe esophagitis had mixed refluxes, the duration of the mixed refluxes was significantly longer in severe esophagitis patients (P < 0.01) (Figure 3). It has previously been reported that patients with Barrett’s esophagus (there were 8 in our series) have a higher incidence of mixed and alkaline refluxes.’ When these patients were excluded from the analysis, the incidence of mixed refluxes was still greater in patients with severe esophagitis than in those with mild-moderate esophagitis or healthy subjects (P < 0.05).
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Table 3. Acid Refluxes in Healthy Subjects and Esophagitis Patients Healthy subjects Total time pH 7 were observed in 2.1 + 0.2 (0%-5%) healthy subjects, in 5.3 f 1.7 (O%12%) subjects with slight-moderate esophagitis, and in 7.8 + 2.3 (1.2-16) subjects with severe esophagitis (P < 0.01 vs. controls). Discussion The present results indicate that alkaline and mixed refluxes are an important component of severe GER. Although antimony electrodes differ in several respects from glass electrodes,27 their performance in clinical situations has been found comparable. Andersen et al.‘” and Savarino et al.,35 who carried out comparative studies by simultaneously monitoring gastric pH with antimony and glass electrodes, showed that they give identical profiles of gastric pH. Furthermore, the gastroesophageal patterns of acid refluxes registered with antimony36 and glass electrodes have been shown to differ little.‘,4*7,30 We found that the reflux of pure alkaline material into the esophagus was a rare event in both normal subjects and esophagitis patients, whereas mixed refluxes were significantly more common in the esophagitis patients. The percent time the esophageal pH remained >7 in this study was 0.5% in both mildmoderate and severe esophagitis patients. The monitoring apparatus we used does not seem to have influenced this value, because it is very close to that obtained by Mattioli et al. (0.7% of total refluxes),’ who monitored gastric and esophageal pH with three
Table 4. Alkaline
Rejluxes in Healthy Subjects and Esophagitis Healthy subjects
Total time pH >7 [min (range)] Percent of time pH >7 (range) No. of reflux episodes >5 min (range) No. of reflux episodes (range) Longest reflux episode [min (range)]
3.5 0.2 0.0 0.7 0.9
(O-SO) (O-l) (O-O) (O-6) (O-11)
glass electrodes. They also found, as we did, that mixed refluxes were more common than alkaline refluxes. In contrast, Attwood et al.’ recently reported that 8%-12% of total refluxes were alkaline in their esophagitis and Barrett’s esophagus patients. However, as they used a single esophageal electrode for monitoring pH, many rises may have been caused by other factors, e.g. deglutitive saliva. Therefore, the alkaline and mixed esophageal reflux patterns revealed by antimony electrodes are superimposable on those obtained with glass electrodes provided the methods used for monitoring and analysis are comparable. The use of a single esophageal electrode causes an overestimation of pure alkaline reflux, a phenomenon that seldom occurs when two or more gastric and esophageal electrodes are employed. In fact, alkaline refluxes accounted for 7.8% of total time in our severe esophagitis patients when isolated esophageal tracings were analyzed. The causes of reflux esophagitis are multiple. Abnormalities in esophageal motility, alterations in gastric secretion and emptying, and diet all seem to be involved. However the frequency and characteristics of the alterations vary from report to report. For instance, resting LES pressure seems to be reduced in patients with severe esophagitis, particularly when it is complicated by a systemic disease, but not in those with mild esophagitis.” Whatever the reasons, the reflux of acid into the esophagus is of crucial importance. Animal studies have shown that exposure of the esophageal mucosa to acid and pepsin causes the onset of lesions similar to those encountered in patients with esophagitis,37 and clinical studies have shown that the esophagus of esophagitis patients is considerably more exposed
Patients Mild esophagitis 6.6 0.5 0.4 0.7 2.6
(O-48) (O-3.4) (O-4) (O-5.4) (O-20)
Severe esophagitis 6.5 0.6 0.5 0.5 1.4
(O-81) (O-6.9) (O-6) (O-6) (O-15)
September
GASTRIC
1992
I
05t01
Healthy . suR1280cts
Mild . t’* E8:pkg’
I Severe Eeophagitio n-28
Figure 2. Box-Whisker plots of gastric pH and gastric acidity in healthy subjects and patients with mild esophagitis or severecomplicated esophagitis. Gastric pH was determined from 540 individual pH values obtained by determining the mean of 2-minute intervals. Postprandial pH values (2 hours) were not considered. Mean 18-hour gastric pH was significantly higher in patients with severe esophagitis than in healthy subjects (P < 0.001) or patients with mild esophagitis (Pi 0.01). **P< 0.001 vs. healthy subjects: *P i 0.01vs.severe esophagitis.
to acid material than that of healthy subjects.‘,4*5,‘5 Moreover, because antisecretory drugs, which only inhibit gastric acid secretion, are efficacious in treating patients with reflux esophagitis, reflux esophagitis is generally considered an acid-related disorder.1’~‘2 However, although a large body of evidence supports the contention that acid and pepsin are the harmful components of reflux material, several aspects remain unexplained. First, the amount of gastric acid secretion does not correlate with the severity of the esophagitis, as shown by the fact that more than two thirds of patients with reflux esophagitis complicating Zollinger-Ellison syndrome, whose acid secretion is considerably increased, have mild-moderate esophagitis.38 Second, although antisecretory drugs are highly effective in treating acidrelated disorders, such as peptic ulcers, only SO%60% patients with reflux esophagitis heal after treatment with standard doses of histamine H,-receptor antagonists.” Omeprazole, which is a longlasting inhibitor of acid secretion is more efficacious than Hz-receptor antagonists, because more than 80% of patients with erosive esophagitis recover after 8 weeks of therapy with 40 mg/day.3g However, the fact that this drug achieves a lower healing rate in reflux esophagitis than in peptic ulcer patients is clear evidence that factors other than acid refluxes are involved in the pathogenesis of this condition7*lg The reflux of alkaline material originating from the duodenum and previously refluxed into the stomach could partially explain resistance to therapy with antisecretory drugs. Biliary acids have been
pH AND GER IN ESOPHAGITIS
859
held responsible for the esophageal lesions that arise in patients with achlorhydria or after gastric surgery. Bile acids have been found to induce lesions in the esophageal mucosa in animal experiments4’ Perfusion of the esophagus with biliary acids or pancreatic enzymes has induced histological alterations similar to those encountered in reflux esophagitis in man. Moreover, bile salts are present in the normal human stomach where their concentrations range from 50 and 100 ymol/L, but may rise to 20 mmol/L in patients who have undergone gastric surgery.41 Although these concentrations are considered not to be cytotoxic, bile acids can act synergically with acid refluxed into the esophagus to cause mucosal damage and hydrogenionic retrodiffusion4’ It should be borne in mind that biliary acids are more injurious to the esophageal mucosa when they reflux into an acid environment. An environmental pH lower than the pK, of biliary acid causes its protonation and increases its liposolubility and so favors its penetration into the mucosa cells.43 Although the pH is widely used for diagnosing alkaline esophagitis,‘,7 it is not very reliable, because most refluxed bile is neutralized by gastric acid.” In consequence, it is difficult to distinguish between reflux of diluted alkaline material and normal esophageal pH, which usually ranges between 4 and 7. Techniques that have attempted to determine biliary acids directly in the esophagus have produced conflicting results. Direct measurement of biliary acids in the esophagus is difficult because the bile is diluted with gastric juice and saliva.“Although scintigraphy with radiolabeled bile acids has been applied to detecting duodenal-gastric reflux, this method is .; 5
2
T
:
"T
Figure 5. Pattern of mixed reflux in healthy subjects, patients with mild esophagitis, and patients with severe-complicated esophagitis. *P < 0.01vs.both healthy subjects and patients with mild esophagitis. 0, Healthy subjects: ?,?slight esophagitis; severe esophagitis.
860 FIORUCCI ET AL.
severely hampered by the fact that patients can be studied for only a short period in nonphysiological conditions.44 pH-metry with more than one recording point offers an alternative way of measuring reflux of alkaline material from the duodenum. By employing dual gastric and esophageal intubation the present study showed a nonrandom association between rises in the gastric fundus pH to value >4 and oscillations in esophageal pH. This suggests that alkaline material refluxed from the duodenum propagates proximally towards the esophagus. Mattioli et al.’ have reported similar results in a study where the pH was simultaneously recorded in the antrum and body of the stomach and the distal esophagus. They documented retrograde propagation of alkaline material towards the esophagus in a time-ordered succession of events in both normal subjects and reflux esophagitis patients. There is evidence that the coordinated modifications in gastric and esophageal pH observed in both Mattioli’s and our study are attributable to alterations in the composition of the gastric and esophageal contents. Although we did not measure bile acid concentrations in the stomach or esophagus, several studies have shown that rises in gastric pH are associated with an increase in biliary acid concentrations.7~8~1g~zoFurthermore, we assured that pH modifications were not due to artifacts caused by technical failure by verifying the electrode stability before and after the execution of each pH-metry recording session, The possibility that the GER pattern could have been altered by an electrode passing through the LES can be discounted, because comparable GER patterns were obtained irrespective of whether single or dual intubation was adopted.45 The present study shows that not only the reflux of acid material, but also the reflux of alkaline material mixed with gastric juice, is increased in patients suffering from severe or complicated reflux esophagitis. The finding that mixed refluxes are more frequent in severe esophagitis patients suggests that the difference in the composition of refluxed material contributes to the pathogenesis of the more severe mucosal lesions observed in these patients. This reasoning is in line with observations made in patients with Barrett’s esophagus, which is a complication of longstanding GER. Pathogenetically, patients with Barrett’s esophagus have markedly reduced LES pressure associated with an increase in the reflux of both alkaline and acid material7 Although little is known of the role of the various components of bile play in the pathogenesis of Barrett’s esophagus, it has been proposed that biliary acids present in the esophageal fluid may aggravate the mucosal damage.46 It would, therefore, seem that it might be wise to direct treatment to preventing not only acid but all forms of reflux. However, complete or partial regression of
GASTROENTEROLOGY Vol. 103,No. 3
the columnar epithelium has been observed in only a minority of patients treated with antireflux surgery, which is supposed to reduce both acid and alkaline refluxes.47*48 The fact that preliminary data indicate omeprazole induces partial regression of Barrett’s esophagus does not exclude that biliary acids and pancreatic enzymes could be implicated in its pathogenesis4’ In fact, antisecretory drugs may indirectly reduce mixed reflux by reducing the overall volume of gastric content. In the present study, a distinct pattern of gastric acidity was found in esophagitis patients. Patients with mild esophagitis had a significant increase in gastric acidity when compared with severe-complicated esophagitis patients. This is in line with previous observations that documented an increase in gastric acid secretion in several patients with erosive esophagitis.14*15 By contrast, gastric acidity of severe esophagitis patients was significantly lower than that of healthy subjects. In conclusion, our findings seem to indicate that mixed or alkaline refluxes are an important component in severe GER. Despite the fact that mixed and alkaline refluxes account for only a fraction of the total refluxes, they could act synergically with the acid. If such synergism occurs in vivo, it would partially explain why patients with comparable acid reflux can present such different endoscopic and clinical pictures. It may also help to explain why only high doses of antisecretory drugs are able to hasten healing in patients with reflux esophagitis. In fact, even low levels of acid might cause lesions in the presence of bile acid in the esophagus. References 1.
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DeMeester TR, Wang CI, Wernly JA, Pellegrini CA, Little AG, Klementschitsch P, Bermudez G, Johnson LF, Skinner DB. Technique, indications, and clinical use of 24 hour esophageal pH monitoring. J Thorac Cardiovasc Surg 1980;79:656667. 10. Robertson D, Aldersley M, Shepherd H, Smith CL. Patterns of acid reflux in complicated oesophagitis. Gut 1987;28:14849.
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49.
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Lissner SA. Influence of smoking and esophageal intubation on esophageal pH-metry. Gastroenterology 1987;92:11941197. Mittal RK. Current concepts of the antireflux barrier. Gastroenterol Clin North Am 1990;19:501-516. Fiorucci S, Clausi GC, Farinelli M, Santucci L. Pelli MA, Morelli A. Intragastric pH monitoring during antisecretory therapy in patients with gastrointestinal bleeding. Am J Gastroenterol 1989;84:1416-1420. Williamson DF, Parker RA, Kendrick JS. The Box Plot: a simple visual method to interpret data. Ann Intern Med 1989:110:916-921. Colton T. Statistics in medicine. Boston: Little Brown Company, 1976. Savarino V, Mela GS, Zentilin P, Magnolia MR, Scalabrini P. Valle F, Moretti M. Bonifacino G, Celle G. Gastric aspiration versus antimony and glass pH electrodes: a simultaneous comparative in vivo study. Stand J Gastroenterol 1989;24:434439. Johnsson F. Joelsson B, Isberg PE. Ambulatory 24 hour intraesophageal pH-monitoring in the diagnosis of gastroesophageal reflux disease. Gut 1987;28:1145-1150, Goldberg HI. Dodds WJ. Gee S, Montgomery C, Zhorulske FF. Role of acid and pepsin in acute experimental esophagitis. Gastroenterology 1969:56:223-230. Miller LS. Vinayek R, Frucht H. Gardner JD, Jensen RT, Maton PR. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology 1990;98:341-346. Zeitoun P. Comparison of omeprazole with ranitidine in the treatment of reflux esophagitis. Stand J Gastroenterol 1989;24(Suppl 166):83-87. Kivilaakso E, Fromm D, Silen W. Effect of bile salts and related compound on isolated esophageal mucosa. Surgery 1980;87:280-285. Spychal RT. Savalagi RS, Marrero JM, Saverymuttu SH, Kirkham JS. Northfield TC. Thermodynamic effects of bile acids in the stomach. Gastroenterology 1990;99:305-310, Schweitzer EJ, Harmon JW, Bass BL, Batzri S. Bile acid efflux precedes mucosal barrier disruption in rabbit oesophagus. Am J Physiol 1984;5:G480-485. Stern AI. Hogan DL, Isenberg JI. Effect of sodium taurocholate on the human gastric mucosa at acid and neutral pH’s. Gastroenterology 1984;87:1272-1276. Matikainen M, Taavitsainen M, Kalima TV. Duodenogastric reflux in patients with heartburn and esophagitis. Stand ] Gastroenterol 1981;16:253-255. Emde C. Ciluffo T, Bauerfeind P, Blum AL. Combined esophageal and gastric pH-metry in healthy volunteers. Dig Dis Sci 1989;34:79-82. Spechler SJ. Goyal RK. Barrett’s esophagus. New Engl J Med 1986;315:362-368. Brand DL, Ylvisaker JT, Gelfand M. Pope CE II. Regression of columnar esophageal (Barrett’s] epithelium after antireflux surgery. New Engl J Med 1980;302:844-848. Williamson WA, Ellis FH Jr, Gibb SP, Shahian DM, Aretz HT. Effect of antireflux operation on Barrett’s mucosa. Ann Thorac Surg 1990;49:537-541. Deviere J. Buset M, Dumonceau JM, Rickaert F. Cremer M. Regression of Barrett’s epithelium with omeprazole. N Engl J Med 1989:22:1497-1498.
Received April 30, 1991. Accented March 17. 1992 Address requests for reprints to: Antonio Morelli, M.D., Istituto di Gastroenterologia ed Endoscopia Digestiva. Policlinico Montelute, 06122 Perugia, Italy. The authors thank Marisa Framboas and Barbara Federici for technical assistance and Judy Dale for editorial assistance.
Gastric Acidity and Gastroesophageal Patterns in Patients With Esophagitis STEFANO FIORUCCI, LUCA and ANTONIO MORELLI Istituto di Gastroenterologia
ed Endoscopia
SANTUCCI,
ndoluminal pH-metry is the most reliable and accurate diagnostic test for evaluating gastroesophageal reflux (GER) in patients with esophageal symptoms, irrespective of whether or not they have endoscopic evidence of esophagitis.‘-4 However, monitoring endoluminal pH with a single esophageal
E
Reflux
SILVIA CHIUCCHIfi,
Digestiva, Universitg
Esophageal pH-metry is the test of choice for diagnosing gastroesophageal reflux. However, although it allows acid refluxes to be distinguished, it is of limited value for identifying alkaline or mixed (acid mixed with alkaline material) refluxes. To evaluate the ability of dual pH-metry to identify alkaline or mixed refluxes, the gastric acidity and gastroesophageal reflux pattern were evaluated simultaneously in 64 patients with mild-moderate esophagitis, in 28 patients with severe or complicated esophagitis, and in 20 healthy subjects. A dual esophageal gastric pa-probe allowed three different types of esophageal reflux to be distinguished: (a) acid refluxes, defined as a drop in esophageal pH to values 4 associated with rises in gastric pH to >4 values; (c) alkaline refluxes, defined as a rise in esophageal pH to >7 associated with a simultaneous increase in gastric pH to >4. Gastric acidity was more significantly reduced in patients with severe or complicated esophagitis than it was in healthy subjects (P < 0.01). The reflux pattern in both mild-moderate and severe esophagitis was characterized by mainly acid refluxes and a marked increase in the time the esophagus mucosa was exposed to acid (P < 0.001). Pure alkaline refluxes were rare (~1%) in both healthy subjects and esophagitis patients. The number of mixed refluxes was considerably higher in severe esophagitis patients than it was in either mild-moderate esophagitis patients or controls (P < 0.05). The finding of mixed refluxes in severe or complicated esophagitis suggests that biliary acids and/or pancreatic enzymes are involved in the pathogenesis of severe forms of esophagitis.
1992;103:855-661
di Perugia, Italy
electrode is limited by the fact that although it identifies acid refluxes, it is poorly specific for pure alkaline refluxes and fails to identify mixed alkaline acid refluxes.5 The interpretation of prolonged pH-metry is also hampered by the fact that although patients with severe or complicated esophagitis have more severe acid refluxes than those with moderate esophagitis, there is considerable overlapping between the two groups, which suggests that factors other than reflux of acid into the esophagus may be responsible for the variable endoscopic findings in patients with comparable acid reflux.6-‘o Reflux esophagitis is a multifactorial disease.l’ Abnormalities in esophageal body motility, lower esophageal sphincter (LES) pressure, acid secretion, and gastric emptying have all been reported in subgroups of patients with esophagi&. However, because antisecretory drugs increase the healing rate of patients with esophagitis, the reflux of acid material into the esophagus must be critically involved.1’~12 Despite this, little is known about the pattern of gastric acidity in patients with reflux esophagitis.13 Few studies have documented increased gastric acid secretion’4215in patients with esophagitis. Collen et al. recently found that GER patients who failed to respond to standard doses of ranitidine had higher basal acid secretion than responders.14 However, because reflux esophagitis has been observed in clinical conditions characterized by low or no acid secretion, such as atrophic gastritis,16-21 it has been suggested that alkaline material, refluxed from the duodenum, may be involved in the pathogenesis. Refluxes of alkaline material have recently been documented in patients with Barrett’s esophagus,7 and it has been hypothesized that differences in the composition of the material refluxed into the esophagus may account for the variable endoscopic and clinical manifestations encountered in patients with comparable patterns of acid reflux. To test this hypothesis, we simultaneously monitored gastric and esophageal pH in pa0 1992by
the American Gastroenterological 0016-5085/92/$3.00
Association
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tients with reflux esophagitis. The aims of the study were to determine (a) the gastric acidity pattern in patients with esophagitis and (b) whether the GER patterns of severe-complicated and slight-moderate esophagitis patients differed qualitatively.
Materials and Methods Ninety-two patients with endoscopically proven esophagitis, 64 with mild-moderate esophagitis, and 28 with severe esophagitis, classified according to the criteria of Savary and Miller” (Tables 1 and 2), were included in the study. Patients with gastric and duodenal ulcers were excluded. Eight patients with severe esophagitis were also affected by Barrett’s esophagus, which was endoscopically defined as the presence of the typical orange-red, columnar-appearing mucosa that extended into the tubular esophagus and displaced the squamocolumnar mucosal junction more than 2 cm. Both the tonguelike and circumferential types of Barrett’s esophagus were included. The diagnosis of Barrett’s esophagus was formulated on the basis of histological findings.23 A minimum of 4 biopsies were taken from the proximal extremity of the endoscopitally abnormal mucosa at least 2 cm above the endoscopitally located esophagus-gastric junction. The histological criteria for a diagnosis of esophagitis were those of IsmailBegi et aLZ4 GER symptoms (heartburn, regurgitation, and dysphagia) were scored on a 0 (no symptoms) to 3 (symptoms that interfere with daily activity) reference scale according to DeMeester et al.’ (Table 2). Twenty healthy subjects with no gastrointestinal symptoms who were not taking drugs acted as controls. All gave their consent after being accurately informed of the modality and aims of the study. pH Monitoring Gastric and esophageal pH were determined by positioning a single antimony electrode with two recording sites localized 1.5 cm from each other (external diameter was 2.1 mm, accuracy of 0.1 U of pH, impedance 0.4 pH units have been excluded. Antimony electrodes have a slower response than glass electrodes (3.8 seconds vs. 0.5-0.8 seconds for glass) to acid-to-alka-
Table 1. Endoscopic Endoscopic grading Grade Grade Grade Grade
0 I II III
Features
of Population
Definition No abnormalities Erythema or edema Nonconfluent erosions Confluent erosions, ulcers, stenosis, Barrett’s esophagus
Study No. of subjects 38 26 28
Table 2. Characteristics Type of esophagitis No.
of Population
Study
Slight-moderate 64
Severe 28
Sex (M/F) Age [means f SD; yr)
44/20 44 f 5
17/11 49 f 7
Symptoms (incidence) (%) Heartburn
100
100
100
100
5 0
20
Regurgitation Dysphagia Respiratory symptoms Mean symptom score (O-3) Heartburn Regurgitation Dysphagia Duration [yr (range)] Smokers Endoscopic abnormalities Hiatal hernia Esophageal ulcers Esophageal stenosis Barrett’s esophagus Gastric ulcer Duodenal ulcer Treatments (no.] Antacids HZ-blockers Prokinetic drugs “P i 0.01 vs. slight-moderate
10
1.5f 0.05 1.9+ 0.08 0.5+ 0.01 2.4(0.3-7) 38/64
1.9 f 0.1
2.0f 0.1 2.0f 0.03" 6 (l-14) 19/28
28 0 0 0 0 0
12 4 3 8 0 0
48 64 25
28 28
20
esophagitis.
line variations in pH. However, this difference is of negligible importance when measuring variations in esophageal pH in clinical situations, because the only alkaline (or mixed) reflux it would fail to record would be one of ~3-4 seconds, and oscillations of pH < 15 seconds are thought to be artifacts.“*” pH was used for positioning the esophageal probe.2g.30 The electrode was introduced via the nose of the sitting subject into the stomach until acid pH was recorded. The subject then assumed the supine position and the electrode was slowly withdrawn. A rapid change in pH from acid to above pH 5 could be identified in each case. The electrode was then placed 5 cm above the point of sudden pH changes and stabilized by anchoring the cable to the subject’s nose with adhesive tape. The position of the probe was checked by fluoroscopy at the beginning and end of each study. The sensitive sites of the probe were positioned approximately 10 cm below and 5 cm above the LES. As the length of the LES varies from 2.5 to 3.5 cm in individual subjects, the position of the gastric pH-sensitive site differs. 31 However, as it was never more than 1-2 cm, this should not have affected gastric profiles. The antimony and the skin reference electrode (Ag/AgCl) were then connected to a portable pH-meter (Mark Gold II, Synectics, Milan, Italy). This recording device measures 1 pH value every 4 seconds. Stored data were analyzed in two different ways. pH values from the esophagus were analyzed by using a-specific software (Gastrosoft, Synectics, Milan, Italy) and gastric pH values by transferring pHmetry data to a Prime 550 macrocomputer and using a specific algorithm designed with the SPSS program (SPSS, Chicago, IL). As previously reported,32 working files of indi-
vidual gastric pH profiles were obtained
by averaging
the
GASTRIC pH AND GER IN ESOPHAGITIS 857
September 1992
raw fast-acquired pH data for periods of 2 minutes. Because the gastric pH measured after meals is subject to fluctuations that are difficult to reproduce, the postprandial periods (2 hours after breakfast, lunch, and dinner) were excluded from the analysis. This should eliminate any inaccuracy caused by the sensitivity of antimony electrode to variations in temperature induced by ingestion of food that could interfere with the reproducibility of the method. Five hundred forty gastric pH values were then used to construct an 18-hour curve for each subject. The mean 18-hour gastric pH -t SE and range were calculated for each group of subjects.
Study Design Subjects were studied as outpatients and encouraged to lead a normal life and eat three nondiet meals at 8 AM, 12:30 PM, and 8:30 PM. Smoking and carbonate drinks were prohibited during the study day. Each pH-monitoring session lasted at least 23 hours. Gastric and esophageal pH tracings were evaluated simultaneously according to the scheme reported in Figure 1. Three types of esophageal reflux were considered: (a) acid refluxes, defined as a drop in esophageal pH to below 4, associated with a pH < 4 in the stomach; (b) mixed refluxes, defined as oscillations in esophageal pH with a range of 4-7 immediately preceded by, or concomitant with, an increase in gastric pH to values >4 (The time the esophageal pH took to return to basal values was considered as the duration of the reflux.); and [c) alkaline refluxes, defined as a rise in esophageal pH to values >7 associated with, or immediately preceded by, an increase in gastric pH to values >4. All three types of reflux were analyzed by the variables proposed by DeMeester et aLg (Tables 3 and 4).
Statistical
Analysis
Gastroesophageal reflux values were expressed as mean + SE and range. Gastric pH and gastric acidity were Acid reflux
I w 7 Emphageal
I
Mixed reflux
I
I
Alkaline reflux
r
I I
\
pH
PH 1
Figure 1. Diagrammatic representation of the criteria used for the simultaneous analysis of gastric Ifine lines) and esophageal (thick line) pH. Esophageal acid reflux is a decrease in the esophagus pH to ~4 associated with an acid gastric pH. Mixed refluxes are characterized by a decrease in esophageal pH from the baseline to a value >4 associated with increases in the gastric pH to >4. Alkaline refluxes are those with increases of esophageal pH to >7 associated with an increase in the gastric pH to >4.
represented by using the Box-Whisker Plot.33 Differences between the acid, alkaline, and mixed esophageal refluxes of the three groups studied were determined by the Student’s t test. Analysis of variance was applied for determining the differences between the gastric pH and acidity curves, and the x2 test was used to evaluate prevalence of symptoms between patient groups and controls.34
Results There was little difference in heartburn intensity and regurgitation in the two patient groups, whereas dysphagia was more marked in patients with severe esophagitis (Table 2). As shown in Figure 2, the level of gastric acidity was higher in healthy subjects than in patients with severe esophagitis (P < 0.001). The mean 18-hour pH was 1.60 ? 0.03 (range, 0.40-3.00) in healthy subjects against 1.90 + 0.05 (range, 0.90-2.90) in severe esophagitis patients, while it was 1.68 & 0.05 (range, 1.00-2.50) in mild-moderate reflux esophagitis patients (P < 0.01 vs. severe esophagitis; P = NS vs. healthy subjects). The acid GER of patients with mild-moderate esophagitis was more severe than that of healthy subjects (P < 0.001) and considerably less severe than that of the severe-complicated esophagitis subjects (P < 0.001) (Table 3). Sixteen of 64 (25.0%) mild-moderate and 8/28 (28.5%) severe esophagitis patients showed isolated acid refluxes. Pure alkaline refluxes were observed in 13/64 (20.3%) mild-moderate and 7/28 (25.0%) severe esophagitis patients. However, isolated rises in esophageal pH to values >7 accounted for less than 1% of time. There were no differences in symptoms between these patients and those who experienced no alkaline refluxes, nor were there any differences in the duration of pure alkaline refluxes between patients with esophagitis and healthy subjects (Table 4). However, there were significant differences in mixed esophageal refluxes (Figure 3). They were more frequent in patients with esophagitis than in healthy subjects (P < 0.01). Although 67.2% (43/64) patients with slight esophagitis and 53.6% (15/28) of patients with severe esophagitis had mixed refluxes, the duration of the mixed refluxes was significantly longer in severe esophagitis patients (P < 0.01) (Figure 3). It has previously been reported that patients with Barrett’s esophagus (there were 8 in our series) have a higher incidence of mixed and alkaline refluxes.’ When these patients were excluded from the analysis, the incidence of mixed refluxes was still greater in patients with severe esophagitis than in those with mild-moderate esophagitis or healthy subjects (P < 0.05).
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Table 3. Acid Refluxes in Healthy Subjects and Esophagitis Patients Healthy subjects Total time pH 7 were observed in 2.1 + 0.2 (0%-5%) healthy subjects, in 5.3 f 1.7 (O%12%) subjects with slight-moderate esophagitis, and in 7.8 + 2.3 (1.2-16) subjects with severe esophagitis (P < 0.01 vs. controls). Discussion The present results indicate that alkaline and mixed refluxes are an important component of severe GER. Although antimony electrodes differ in several respects from glass electrodes,27 their performance in clinical situations has been found comparable. Andersen et al.‘” and Savarino et al.,35 who carried out comparative studies by simultaneously monitoring gastric pH with antimony and glass electrodes, showed that they give identical profiles of gastric pH. Furthermore, the gastroesophageal patterns of acid refluxes registered with antimony36 and glass electrodes have been shown to differ little.‘,4*7,30 We found that the reflux of pure alkaline material into the esophagus was a rare event in both normal subjects and esophagitis patients, whereas mixed refluxes were significantly more common in the esophagitis patients. The percent time the esophageal pH remained >7 in this study was 0.5% in both mildmoderate and severe esophagitis patients. The monitoring apparatus we used does not seem to have influenced this value, because it is very close to that obtained by Mattioli et al. (0.7% of total refluxes),’ who monitored gastric and esophageal pH with three
Table 4. Alkaline
Rejluxes in Healthy Subjects and Esophagitis Healthy subjects
Total time pH >7 [min (range)] Percent of time pH >7 (range) No. of reflux episodes >5 min (range) No. of reflux episodes (range) Longest reflux episode [min (range)]
3.5 0.2 0.0 0.7 0.9
(O-SO) (O-l) (O-O) (O-6) (O-11)
glass electrodes. They also found, as we did, that mixed refluxes were more common than alkaline refluxes. In contrast, Attwood et al.’ recently reported that 8%-12% of total refluxes were alkaline in their esophagitis and Barrett’s esophagus patients. However, as they used a single esophageal electrode for monitoring pH, many rises may have been caused by other factors, e.g. deglutitive saliva. Therefore, the alkaline and mixed esophageal reflux patterns revealed by antimony electrodes are superimposable on those obtained with glass electrodes provided the methods used for monitoring and analysis are comparable. The use of a single esophageal electrode causes an overestimation of pure alkaline reflux, a phenomenon that seldom occurs when two or more gastric and esophageal electrodes are employed. In fact, alkaline refluxes accounted for 7.8% of total time in our severe esophagitis patients when isolated esophageal tracings were analyzed. The causes of reflux esophagitis are multiple. Abnormalities in esophageal motility, alterations in gastric secretion and emptying, and diet all seem to be involved. However the frequency and characteristics of the alterations vary from report to report. For instance, resting LES pressure seems to be reduced in patients with severe esophagitis, particularly when it is complicated by a systemic disease, but not in those with mild esophagitis.” Whatever the reasons, the reflux of acid into the esophagus is of crucial importance. Animal studies have shown that exposure of the esophageal mucosa to acid and pepsin causes the onset of lesions similar to those encountered in patients with esophagitis,37 and clinical studies have shown that the esophagus of esophagitis patients is considerably more exposed
Patients Mild esophagitis 6.6 0.5 0.4 0.7 2.6
(O-48) (O-3.4) (O-4) (O-5.4) (O-20)
Severe esophagitis 6.5 0.6 0.5 0.5 1.4
(O-81) (O-6.9) (O-6) (O-6) (O-15)
September
GASTRIC
1992
I
05t01
Healthy . suR1280cts
Mild . t’* E8:pkg’
I Severe Eeophagitio n-28
Figure 2. Box-Whisker plots of gastric pH and gastric acidity in healthy subjects and patients with mild esophagitis or severecomplicated esophagitis. Gastric pH was determined from 540 individual pH values obtained by determining the mean of 2-minute intervals. Postprandial pH values (2 hours) were not considered. Mean 18-hour gastric pH was significantly higher in patients with severe esophagitis than in healthy subjects (P < 0.001) or patients with mild esophagitis (Pi 0.01). **P< 0.001 vs. healthy subjects: *P i 0.01vs.severe esophagitis.
to acid material than that of healthy subjects.‘,4*5,‘5 Moreover, because antisecretory drugs, which only inhibit gastric acid secretion, are efficacious in treating patients with reflux esophagitis, reflux esophagitis is generally considered an acid-related disorder.1’~‘2 However, although a large body of evidence supports the contention that acid and pepsin are the harmful components of reflux material, several aspects remain unexplained. First, the amount of gastric acid secretion does not correlate with the severity of the esophagitis, as shown by the fact that more than two thirds of patients with reflux esophagitis complicating Zollinger-Ellison syndrome, whose acid secretion is considerably increased, have mild-moderate esophagitis.38 Second, although antisecretory drugs are highly effective in treating acidrelated disorders, such as peptic ulcers, only SO%60% patients with reflux esophagitis heal after treatment with standard doses of histamine H,-receptor antagonists.” Omeprazole, which is a longlasting inhibitor of acid secretion is more efficacious than Hz-receptor antagonists, because more than 80% of patients with erosive esophagitis recover after 8 weeks of therapy with 40 mg/day.3g However, the fact that this drug achieves a lower healing rate in reflux esophagitis than in peptic ulcer patients is clear evidence that factors other than acid refluxes are involved in the pathogenesis of this condition7*lg The reflux of alkaline material originating from the duodenum and previously refluxed into the stomach could partially explain resistance to therapy with antisecretory drugs. Biliary acids have been
pH AND GER IN ESOPHAGITIS
859
held responsible for the esophageal lesions that arise in patients with achlorhydria or after gastric surgery. Bile acids have been found to induce lesions in the esophageal mucosa in animal experiments4’ Perfusion of the esophagus with biliary acids or pancreatic enzymes has induced histological alterations similar to those encountered in reflux esophagitis in man. Moreover, bile salts are present in the normal human stomach where their concentrations range from 50 and 100 ymol/L, but may rise to 20 mmol/L in patients who have undergone gastric surgery.41 Although these concentrations are considered not to be cytotoxic, bile acids can act synergically with acid refluxed into the esophagus to cause mucosal damage and hydrogenionic retrodiffusion4’ It should be borne in mind that biliary acids are more injurious to the esophageal mucosa when they reflux into an acid environment. An environmental pH lower than the pK, of biliary acid causes its protonation and increases its liposolubility and so favors its penetration into the mucosa cells.43 Although the pH is widely used for diagnosing alkaline esophagitis,‘,7 it is not very reliable, because most refluxed bile is neutralized by gastric acid.” In consequence, it is difficult to distinguish between reflux of diluted alkaline material and normal esophageal pH, which usually ranges between 4 and 7. Techniques that have attempted to determine biliary acids directly in the esophagus have produced conflicting results. Direct measurement of biliary acids in the esophagus is difficult because the bile is diluted with gastric juice and saliva.“Although scintigraphy with radiolabeled bile acids has been applied to detecting duodenal-gastric reflux, this method is .; 5
2
T
:
"T
Figure 5. Pattern of mixed reflux in healthy subjects, patients with mild esophagitis, and patients with severe-complicated esophagitis. *P < 0.01vs.both healthy subjects and patients with mild esophagitis. 0, Healthy subjects: ?,?slight esophagitis; severe esophagitis.
860 FIORUCCI ET AL.
severely hampered by the fact that patients can be studied for only a short period in nonphysiological conditions.44 pH-metry with more than one recording point offers an alternative way of measuring reflux of alkaline material from the duodenum. By employing dual gastric and esophageal intubation the present study showed a nonrandom association between rises in the gastric fundus pH to value >4 and oscillations in esophageal pH. This suggests that alkaline material refluxed from the duodenum propagates proximally towards the esophagus. Mattioli et al.’ have reported similar results in a study where the pH was simultaneously recorded in the antrum and body of the stomach and the distal esophagus. They documented retrograde propagation of alkaline material towards the esophagus in a time-ordered succession of events in both normal subjects and reflux esophagitis patients. There is evidence that the coordinated modifications in gastric and esophageal pH observed in both Mattioli’s and our study are attributable to alterations in the composition of the gastric and esophageal contents. Although we did not measure bile acid concentrations in the stomach or esophagus, several studies have shown that rises in gastric pH are associated with an increase in biliary acid concentrations.7~8~1g~zoFurthermore, we assured that pH modifications were not due to artifacts caused by technical failure by verifying the electrode stability before and after the execution of each pH-metry recording session, The possibility that the GER pattern could have been altered by an electrode passing through the LES can be discounted, because comparable GER patterns were obtained irrespective of whether single or dual intubation was adopted.45 The present study shows that not only the reflux of acid material, but also the reflux of alkaline material mixed with gastric juice, is increased in patients suffering from severe or complicated reflux esophagitis. The finding that mixed refluxes are more frequent in severe esophagitis patients suggests that the difference in the composition of refluxed material contributes to the pathogenesis of the more severe mucosal lesions observed in these patients. This reasoning is in line with observations made in patients with Barrett’s esophagus, which is a complication of longstanding GER. Pathogenetically, patients with Barrett’s esophagus have markedly reduced LES pressure associated with an increase in the reflux of both alkaline and acid material7 Although little is known of the role of the various components of bile play in the pathogenesis of Barrett’s esophagus, it has been proposed that biliary acids present in the esophageal fluid may aggravate the mucosal damage.46 It would, therefore, seem that it might be wise to direct treatment to preventing not only acid but all forms of reflux. However, complete or partial regression of
GASTROENTEROLOGY Vol. 103,No. 3
the columnar epithelium has been observed in only a minority of patients treated with antireflux surgery, which is supposed to reduce both acid and alkaline refluxes.47*48 The fact that preliminary data indicate omeprazole induces partial regression of Barrett’s esophagus does not exclude that biliary acids and pancreatic enzymes could be implicated in its pathogenesis4’ In fact, antisecretory drugs may indirectly reduce mixed reflux by reducing the overall volume of gastric content. In the present study, a distinct pattern of gastric acidity was found in esophagitis patients. Patients with mild esophagitis had a significant increase in gastric acidity when compared with severe-complicated esophagitis patients. This is in line with previous observations that documented an increase in gastric acid secretion in several patients with erosive esophagitis.14*15 By contrast, gastric acidity of severe esophagitis patients was significantly lower than that of healthy subjects. In conclusion, our findings seem to indicate that mixed or alkaline refluxes are an important component in severe GER. Despite the fact that mixed and alkaline refluxes account for only a fraction of the total refluxes, they could act synergically with the acid. If such synergism occurs in vivo, it would partially explain why patients with comparable acid reflux can present such different endoscopic and clinical pictures. It may also help to explain why only high doses of antisecretory drugs are able to hasten healing in patients with reflux esophagitis. In fact, even low levels of acid might cause lesions in the presence of bile acid in the esophagus. References 1.
DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976;184:459-470, 2. Atkinson M. Monitoring oesophageal pH. Gut 1987;28:509514. 3. Emde C, Garner A, Blum AL. Technical aspects of intraluminal pH-metry in man: current status and recommendations. Gut 1987;28:1177-1188, 4. Schindlbeck NE, Heinrich C, Konig A, Dendorfer A, Pace F, Muller-Lissner SA. Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease. Gastroenterology 1987;93:85-90. 5. Schlesinger PK, Donahue PE, Schmid B, Layden TJ. Limitations of 24-hour intraesophageal pH monitoring in the hospital setting. Gastroenterology 1985;89:797-804. 6. Donald IP, Ford GA, Wilkinson SP. Is 24-hr ambulatory oesophageal pH monitoring useful in a district general hospital? The Lancet 1987;1:89-92. 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. Mattioli S, Pilotti V, Felice V, Lazzari A, Zannoli R, Bacchi ML, Loria P, Tripodi A, Gozzetti G. Ambulatory 24-hr pH monitoring of esophagus, fundus, and antrum. Dig Dis Sci 1990;35:929-938.
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DeMeester TR, Wang CI, Wernly JA, Pellegrini CA, Little AG, Klementschitsch P, Bermudez G, Johnson LF, Skinner DB. Technique, indications, and clinical use of 24 hour esophageal pH monitoring. J Thorac Cardiovasc Surg 1980;79:656667. 10. Robertson D, Aldersley M, Shepherd H, Smith CL. Patterns of acid reflux in complicated oesophagitis. Gut 1987;28:14849.
31. 32.
1488. 11. 12.
13.
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21.
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Received April 30, 1991. Accented March 17. 1992 Address requests for reprints to: Antonio Morelli, M.D., Istituto di Gastroenterologia ed Endoscopia Digestiva. Policlinico Montelute, 06122 Perugia, Italy. The authors thank Marisa Framboas and Barbara Federici for technical assistance and Judy Dale for editorial assistance.
