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Integrated acidity and the pathophysiology of gastroesophageal reflux disease
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 5, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02353-X
Integrated Acidity and the Pathophysiology of Gastroesophageal Reflux Disease Jerry D. Gardner, M.D., Sheila Rodriguez-Stanley, Ph.D., and Malcolm Robinson, M.D. Science for Organizations, Inc., Chatham, New Jersey; and Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
OBJECTIVES: The aim of this study was to demonstrate that integrated esophageal and gastric acidity values, calculated from 24-h pH recordings, can provide more precise quantitative temporal data than the conventional pH parameters historically associated with gastroesophageal reflux disease (GERD) investigations. METHODS: Esophagogastroduodenoscopy results and pH tracings from 20 GERD subjects with ⱖ10% esophageal acid contact time were studied. Integrated gastric and esophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h recording period. RESULTS: Integrated esophageal acidity correlated with grade of esophagitis. Two quite distinct GERD subtypes were identified, with either a monophasic or biphasic pattern of integrated esophageal acidity. “Biphasic” subjects differed from “monophasic” subjects in terms of magnitude and pattern of integrated esophageal acidity. Although both groups had significant integrated nocturnal gastric acidity, only the biphasic GERD subjects had concomitant increases in nocturnal integrated esophageal acidity. Esophagitis grade was correlated with magnitude rather than pattern of integrated esophageal acidity, and it was possible to calculate a reflux coefficient that seems to provide an estimate of the quantitative motor disturbance present in GERD. CONCLUSIONS: Integrated esophageal and gastric acidity provide quantitative measures of GERD pathophysiology and, compared to conventional pH parameters, should enhance evaluation of therapeutic interventions. (Am J Gastroenterol 2001;96:1363–1370. © 2001 by Am. Coll. of Gastroenterology)
tional pH recordings generate as many as 900 measurements per hour, most analyses reduce data to a single value such as percentage of time that pH is either ⬎4.0 or ⬍4.0, or perhaps to number of reflux episodes. In many antisecretory studies, only gastric or esophageal pH values are assessed. Although there is no doubt that gastric acidity is directly involved in GERD pathogenesis, relationships between gastric and esophageal acidity are not clear. Lack of focus on gastric acid may relate to the general belief that gastric acid secretion is usually normal in GERD (7). The widely accepted rating of acid reflux as percentage of time that pH ⬍4 (1– 6) only approximates actual esophageal acid exposure. For example, individual patients with esophageal pH data indicating a median pH of 1.5 for 4 h versus a median pH of 3.5 for a similar period would have identical values for the percentage of time that esophageal pH is ⬍4, even though esophageal acid exposure, assessed as the product of acid concentration and time, would differ by a factor of 100. Pathological consequences of these two seemingly “identical” acid exposures might be dramatically different. In the present study, data from simultaneous, 24-h esophageal and gastric pH recordings from documented GERD were used to calculate integrated esophageal and gastric acidity. This enabled precise quantification of temporal gastric and esophageal acidity as well as the characterization of two GERD subtypes. The pH data used for the present report were previously analyzed and reported using conventional parameters (8).
MATERIALS AND METHODS
INTRODUCTION
This study was approved by the Western Institutional Review Board, Olympia, WA, with written informed consent by all subjects.
Continuous esophageal pH recordings are widely used to study gastroesophageal reflux disease (GERD) and its treatment (1– 6). Gastric pH recordings are less used clinically, but monitoring of gastric pH has been used for the pharmacological comparison of various antisecretory agents (3– 6). Continuous pH recordings are usually displayed as graphs of pH versus time or as percentage of time with pH above or below a particular value (often 4.0). Although conven-
Subjects The enrollees were 15 men and five women, ages 24 – 61, with clinical GERD. All underwent screening upper GI endoscopy, and all had esophageal pH ⱕ4 for at least 10% of 24 h. Subjects were not tested for Helicobacter pylori infection. Subjects were excluded if treated with a histamine H2-receptor antagonist, sucralfate, or a prostaglandin analog within 3 days; with a proton pump inhibitor or bismuth
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Figure 1. Patterns for integrated esophageal acidity and gastric acidity. All values for each patient were expressed as a percentage of the value at the last hour. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal acidity and seven subjects with a biphasic pattern for esophageal activity.
subsalicylate within 7 days; or with an investigational drug within 30 days before study entry. Subjects were also excluded for deep esophageal ulcers, esophageal strictures, gastric ulcers, or duodenal ulcers within 6 months before study entry, previous gastric or esophageal surgery, pyloric stenosis, or cancer other than basal cell skin cancer. Of the 19 subjects with technically satisfactory recordings, four had grade 3 esophagitis, 11 had grade 2 esophagitis, two had grade 1 esophagitis, and two had no visible esophagitis by the Hetzel-Dent grading scale (9). Study Design The study was conducted at the Oklahoma Foundation for Digestive Research on the campus of the University of Oklahoma Health Sciences Center. Subjects completed two pH monitoring sessions, with at least 7–10 days between sessions. Subjects remained in the study center for the 24-h recordings and received three defined meals. Breakfast was provided at 9:00 –9:30, lunch at 13:00 –14:00, and dinner at 18:00 –19:00 each day of pH monitoring. Smoking, ingestion of food or liquids between meals, and use of antisecretory medications other than those studied were prohibited during pH recordings. Gastric and esophageal pH were monitored with an ambulatory, disposable, dual channel antimony electrode pH catheter and recording system (Medtronic Synectics, Shoreview, MN), with one electrode 10 cm below and one 5 cm above the upper margin of the manometrically defined lower esophageal sphincter. Electrodes were calibrated to pH 1.07
and 7.01 using solutions composed of 59 mmol/L KNO3, 27 mmol/L KCl (pH 1.07) and 16.5 mmol/L Tris buffer, 40 mmol/L KNO3, 96 mmol/L KCl (pH 7.01). Data every 4 s were collected using a portable data storage unit (Digitrapper, Medtronic Synectics) and processed in DOS mode using temperature-compensating software (Polygram for Windows, Version 2.04, Medtronic Synectics), Measurements are described as acid “concentration” although pH electrodes actually measure hydrogen ion “activity.” Methods exist to adjust hydrogen ion activity to hydrogen ion concentration (10, 11). Electrode calibrations to pH 1 and 7 in the manufacturer-provided polyelectrolyte solutions result in measured hydrogen ion activity closely approximating hydrogen ion concentration. Therefore, no additional adjustments of measured hydrogen ion activity were used. Analytical Procedures Polygram software (Medtronics Synectics) calculates conventional esophageal and gastric pH recording indices, e.g., number of esophageal reflux episodes, number of reflux episodes ⬎5 min, percentage of recording with esophageal pH ⬍4, and percentage of recording with gastric pH ⬍4. Polygram software records pH values every 4 s and fills in values for the other 3 s, resulting in one value per second for each electrode. To calculate integrated acidity, 1-s interval pH data were used. Both recordings were analyzed for all 20 subjects, although technically unsatisfactory data from one subject with a malfunctioning gastric electrode were omit-
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Integrated Acidity and the Pathophysiology of GERD
Table 1. Esophageal pH Cutoffs vs 24-h Integrated Esophageal Acidity pH ⬍3 (%)
pH ⬍4 (%)
pH ⬍5 (%)
pH ⬍6 (%)
7.5 17.0 29.6 54.5 r2 0.68 0.62 0.55 0.38 p ⬍0.0001 ⬍0.0001 0.0003 0.0049
24-h Integrated Esophageal Acidity (mmol 䡠 h/L) 24.4
Values are medians from 19 subjects. Values of r2 and p for values are from linear, least-squares regression analysis of % time with pH less than particular values vs integrated esophageal acidity.
ted. Integrated gastric and esophageal acidity were calculated for each second of recording as follows: 1. Acid concentration (mmol/L) ⫽ 1000 ⫻ 10⫺pH 2. Acidity (mmol 䡠 h/L) ⫽ (acid in mmol/L at time “t”⫹ acid in mmol/L at time “t⫺1”)/2 ⫻ (t – t⫺1) 3. Acidity values were summed cumulatively per second. Integrated acidity is expressed as mmol/L ⫻ time, i.e., mmol 䡠 h/L. 4. Integrated acidity was analyzed for each hour of the recording. Integrated acidity at any given time is cumulative, and mean acid concentration up to that point in time can be calculated by dividing integrated acidity by time. For example, mean gastric acid concentration for hours 8:00 to 24:00 can be calculated by dividing the integrated gastric acidity at 24:00 by 16. Mean hourly acid concentration was calculated as integrated acidity at time “t” minus integrated acidity at time “t⫺1.” Recordings started at 08:00 h. Conventional pHbased indices were also calculated. Of 38 technically satisfactory records, 34 were for 24 h, three were for 23 h, and one was for 22 h. For missing data, the last values calculated were carried forward. Statistical analyses were completed using Microsoft Excel 97 or GraphPad for InStat version 3.01 Windows software. Even though many results were not normally distributed, means ⫾ SEM are used to illustrate variations. In instances when one or two large negative values substantially distorted mean values, medians are presented instead. The 24-h values for conventional indices, integrated acidity, and reflux coefficient were analyzed using the Mann-Whitney test.
RESULTS As illustrated in Figure 1, integrated esophageal and gastric acidity increased progressively over 24 h. Increases in integrated gastric acidity were not constant, however, because meal ingestion transiently decreased intragastric acidity. Table 1 gives median percentages of time with esophageal pH ⬍3, ⬍4, ⬍5, or ⬍6 along with 24-h integrated esophageal acidity. Note that integrated acidity is expressed as a single number versus several numbers potentially required for interpreting all of the conventional pH data.
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Table 2. Gastric pH Cutoffs vs 24-h Integrated Gastric Acidity pH ⬍1 (%)
pH ⬍2 (%)
pH ⬍3 (%)
pH ⬍4 (%)
18.9 74.2 82.6 90.6 r2 0.90 0.38 0.26 0.24 p ⬍0.0001 .0053 .0240 .0336
24-h Integrated Gastric Acidity (mmol 䡠 hr/L) 1557
Values are medians from 19 subjects. Values of r2 and p for values are from linear, least-squares regression analysis of pH less than particular values vs integrated gastric acidity.
Table 2 gives median values for the percentage of recordings with gastric pH ⬍1, ⬍2, ⬍3, or ⬍4 and for 24-h integrated gastric acidity. Table 2 results use the same data found in Figure 1. As with integrated esophageal acidity, integrated gastric acidity correlated with pH values with the lower pH cutoffs correlating best. In the present study, integrated acidity analyses disclosed two distinct reflux patterns when individual data were expressed as percentages of maximal values (Fig. 1, left panel). Subjects could be divided into two groups based on attaining 50% of maximal integrated esophageal acidity before or after 23:00. As illustrated in Figure 1 (left panel), 12 monophasic subjects reached 50% maximal esophageal acidity before 23:00. In these monophasic subjects, an acid plateau occurred at about 2:00 and tended to remain stable thereafter. Monophasic subjects attained 50% of maximal acidity by 17:00. Seven subjects with a biphasic esophageal acidity pattern reached 50% maximal esophageal acidity either at or after 23:00. These subjects demonstrated slow increases in acidity until 23:00 with more rapidly increasing acidity until the end of the recording (Fig. 1, left panel). In biphasic subjects, 50% of maximal esophageal acidity was reached by 1:00. Figure 1 (right panel) shows virtually identical patterns of gastric acidity in these two groups of subjects with distinctly different esophageal acidity patterns. Curves were stratified based on visual inspection rather than any formal quantitative or statistical analysis of the records. Using a value of 23:00 to stratify records produced two clearly different groups and in addition, 23:00 h seemed to be a good estimate of when these subjects became recumbent for sleep. Stratification by time was intended to illustrate potential clinical utility of integrated esophageal and gastric acidity, not to argue in favor of 23:00 over 22:00 or 24:00. As illustrated in Figure 2 (left panel), integrated esophageal acidity in biphasic subjects was significantly greater (p ⬍ 0.05) than with monophasic esophageal acidity from 3:00 until the end of recording. In contrast, integrated gastric acidity did not differ between mono- or biphasic esophageal acidity (Fig. 2). Table 3 shows generally higher conventional pH parameters with biphasic esophageal acidity versus monophasic esophageal acidity. Values for time esophageal pH ⬍4 were significantly different (p ⬍ 0.05), whereas numbers of esophageal reflux episodes, numbers of reflux episodes last-
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Figure 2. Integrated esophageal acidity and gastric acidity in monophasic and biphasic GERD. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal activity and seven subjects with a biphasic pattern for esophageal acidity. Circles at the top of the left panel indicate the times at which values for biphasic subjects significantly differ from corresponding values for monophasic subjects (p ⬍ 0.05).
ing ⬎5 min and times with gastric pH ⬍4 were not significantly different. The 24-h integrated esophageal acidity, mean esophageal acid concentration, and mean pH were significantly higher in biphasic than in monophasic subjects (Table 3). 24-h integrated gastric acidity and mean pH did not differentiate biphasic versus monophasic subjects (Table 3). Esophagitis grades were similar between biphasic and monophasic subjects (Table 3). Figure 3 (right panel) shows that the buffering by meals led to fluctuating mean gastric acid concentrations. Al-
though gastric acid concentrations tended to be higher in biphasic subjects and were significantly higher at 5:00 and 6:00, there were no important differences between patterns for the two types of subjects. Figure 3 (left panel) illustrates esophageal acid concentrations fluctuating in conjunction with gastric acid concentrations in both monophasic and biphasic subjects. After 24:00, however, esophageal acid concentrations decreased to near zero in monophasic subjects, remaining significantly higher in biphasic subjects over the last 6 h.
Table 3. Values for Conventional pH Indices and 24-h Integrated Esophageal and Gastric Acidity Measure Esophageal Number of reflux episodes Number of reflux episodes ⬎5 min Percent time pH ⬍ 4 24-H integrated acidity (mmol 䡠 hr/L) Mean acid concentration (mmol/L) Mean pH Gastric acid Percent time pH ⬍ 4 24-H integrated acidity (mmol 䡠 hr/L) Mean acid concentration (mmol/L) Mean pH Grade esophagitis
All (n ⫽ 19)
Monophasic (n ⫽ 12)
Biphasic (n ⫽ 7)
308 ⫾ 35 12 ⫾ 2 24 ⫾ 4 128 ⫾ 46 5.3 ⫾ 1.9 2.3
283 ⫾ 46 10 ⫾ 2 20 ⫾ 5 53 ⫾ 26 2.2 ⫾ 1.1 2.6
350 ⫾ 55 15 ⫾ 3 32 ⫾ 7* 257 ⫾ 104* 10.7 ⫾ 4.3* 2.0
90 ⫾ 2 1308 ⫾ 151 55 ⫾ 6 1.3 1.9 ⫾ 0.2
88 ⫾ 2 1116 ⫾ 166 46 ⫾ 7 1.3 1.9 ⫾ 0.3
92 ⫾ 2 1638 ⫾ 265 68 ⫾ 11 1.2 1.9 ⫾ 0.3
Values are means ⫾ SEM from numbers of subjects indicated. Mean acid concentration was calculated by dividing integrated acidity by 24, and mean pH was calculated by taking the logarithm of the mean acid concentration expressed in mmol/L. Esophagitis was graded using the Hetzel-Dent classification system Ref. (9). * Significantly different from corresponding value for monophasic subjects, p ⬍ 0.05 by Mann-Whitney test.
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Figure 3. Mean esophageal acid concentrations and mean gastric acid concentrations in monophasic and biphasic GERD. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal acidity and seven subjects with a biphasic pattern for esophageal activity. Circles at the tops of the panels indicate the times at which values for biphasic subjects significantly differ from corresponding values for monophasic subjects (p ⬍ 0.05).
Relationships between esophageal and gastric acidity can be further elucidated by dividing integrated esophageal acidity multiplied by 100 by the corresponding value for integrated gastric acidity. This can be termed the “reflux coefficient” because it gives the value for integrated esophageal acidity associated with 100 mmol 䡠 h/L of integrated gastric acidity. Figure 4 illustrates the usefulness of the reflux coefficient for comparison of different clinical conditions. Monophasic and biphasic subjects had similar reflux coefficients during daytime and evening, but nocturnal coefficients were significantly higher in biphasic subjects (Fig. 4). Table 4 summarizes integrated acidity and T50 (time for integrated esophageal acidity to reach 50% of maximal) stratified for pre-entry Hetzel-Dent esophagitis grade (9). Mean 24-h integrated esophageal acidity and grade of esophagitis were correlated. Neither the mean 24-h integrated gastric acidity nor T50 correlated with esophagitis grade.
DISCUSSION In the present study, integrated gastric and esophageal acidity were calculated from conventional 24-h pH data. Integrated acidity can be used to examine quantitative relationships between esophageal acidity and gastric acidity and helps to differentiate GERD pathophysiologies. Validation of integrated acidity has been accomplished by
Figure 4. Reflux coefficient for biphasic and monophasic subjects. Results given are means ⫾ SEMs from seven biphasic subjects and 12 monophasic subjects. Circles at the top indicate the times at which values for biphasic subjects are significantly greater than corresponding values from monophasic subjects (p ⬍ 0.05).
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Table 4. Integrated Acidity Stratified for Different Esophagitis Grades Grade Esophagitis
No. Patients
24-h Esophageal Acidity (mmol 䡠 h/L)
T50
24-h Gastric Acidity (mmol 䡠 h/L)
0 1 2 3 All r2 p
2 2 11 4 19
8.1 (7.8–8.3) 20 (16–24) 130 (7–462) 236 (16–736) 128 (7–736) 0.92 0.042
13 (10–16) 9 (8–9) 13 (6–19) 10 (5–18) 12 (5–19) 0.04 0.920
539 (533–546) 1680 (1569–1790) 1271 (536–2405) 1609 (371–2604) 1308 (371–2604) 0.48 0.351
Esophagitis was graded using the Hetzel-Dent classification system Ref. (9). Values for acidity and T50 are means (range) from the number of patients indicated. Values for r2 and p are from linear, least-squares regression analysis of mean values for acidity or T50 vs grade of esophagitis.
systematic comparisons to conventional pH indices with different pH cutoffs. Among advantages of integrated acidity over conventional indices is its full quantitation of acidity with a single value. In contrast, conventional indices only partially quantify acidity, employ arbitrary pH cutoff values, and do not permit transferring one pH cutoff to an alternative pH. There were significant correlations between integrated acidity and conventional indices; however, the strength of the correlation increased with decreasing pH cutoff values. Esophageal acid exposure is commonly expressed as pH ⬍ 4, with normal values considered as 4% or 6% of 24 h (1– 6). However, in this study, pH ⬍3 provided a higher correlation coefficient with integrated esophageal acidity. Others (2, 6) have described apparent deficiencies in published pH cutoffs for conventional indices, including the observation that only approximately 50% of patients with endoscopy-negative GERD have abnormal pH findings. Present results provide some possible explanations including the possibility that use of a pH ⬍3 cutoff might encompass more endoscopy-negative patients, still differentiating normal subjects from patients with GERD. Because of variations in esophageal acid exposure during the day, different recording times in the same subject might produce variable values for percentage of time that esophageal pH is ⬍4. For example, in a patient with monophasic GERD, omitting segments of daytime recording would decrease the percentage of time that esophageal pH was ⬍4, whereas omitting nighttime recording would increase it. The opposite situation would occur in a patient with biphasic GERD (nighttime esophageal acid exposure is greater than daytime exposure), although to a lesser extent, because biphasic subjects have some daytime esophageal acid exposure. These observations could preclude the use of abbreviated pH studies as substitutes for 24-h studies. The reflux coefficient, which indicates integrated esophageal acidity associated with 100 mmol 䡠 h/L of integrated gastric acidity, may be used to estimate the magnitude of motility disturbances present in GERD. Higher reflux coefficients indicate more esophageal acid exposure with a given level of integrated gastric acidity. In this regard, for two patients with identical integrated esophageal acidity, a patient with lower integrated gastric acidity and a higher numerical reflux coefficient presumably suffers from a more severe disturbance of motility.
Several findings in the present study illustrate potential clinical utility of integrated acidity. For example, based on values for integrated esophageal acidity, GERD patients can be classified into two groups: monophasic pattern of integrated esophageal acidity with 50% of esophageal acid exposure occurring by 17:00, and biphasic integrated esophageal acidity with 50% of occurring by 1:00. Distinct patterns of esophageal acidity in GERD have been previously reported (12–14). Patients with daytime esophageal acid exposure have been called “upright refluxers” and those with nocturnal esophageal acid exposure have been known as “supine or recumbent refluxers.” There is a clear relationship between these descriptors and the present findings of monophasic and biphasic integrated esophageal acidity. Compared to biphasic GERD subjects, monophasic subjects had little or no esophageal acidity after 2:00, lower integrated esophageal acidity, fewer esophageal reflux episodes, less esophageal pH ⬍4, and a lower reflux coefficient. Monophasic and biphasic GERD subjects were similar in terms of patterns and magnitudes of integrated gastric acidity, average grades of esophagitis, and mean gastric acid concentrations. Previous pH-based analyses have nicely correlated esophagitis grade with acid exposure (3, 14 –16). Integrated esophageal acidity and esophagitis grade were well correlated in the present study, although mono- and biphasic subjects had similar esophagitis grades despite higher mean 24-h integrated esophageal acidity in biphasic refluxers. This suggests that esophagitis grade correlates more with the magnitude of esophageal acid exposure rather than the pattern of acid exposure. Some biphasic subjects had low integrated esophageal acidity and some monophasic subjects had high integrated esophageal acidity. Gastric acidity has been somewhat neglected as the major determinant of esophageal acid exposure in GERD aside from observations that acid inhibition could diminish esophageal acid exposure (3– 6). Hirschowitz reported basal and pentagastrin-stimulated gastric acid secretion in esophagitis comparable to unspecified medical conditions without esophagitis (17–19). Others, however, have reported increased basal, peak, or maximal gastric acid secretion in GERD compared to healthy subjects (20 –23). In this regard, Williams et al. (24) established 24-h integrated gastric acidity as 890 mmol 䡠 h/L (range 263–1493) in 23 healthy H.
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pylori–negative volunteers using hourly determination of gastric pH. In the present study, 24-h integrated gastric acidity for monophasic GERD was 1116 ⫾ 166 mmol 䡠 h/L (mean ⫾ SEM; n ⫽ 12) and for biphasic GERD was 1638 ⫾ 265 mmol 䡠 h/L (n ⫽ 7). These differences may reflect different meals with different degrees of neutralization or stimulation of gastric acid secretion in the different studies. On the other hand, subjects with biphasic GERD may have increased integrated gastric acidity compared to healthy volunteers whereas monophasic GERD may not. Varying proportions of monophasic and biphasic subjects might account for different conclusions from different studies regarding increased gastric acid secretion in GERD. Integrated gastric acidity does not measure gastric acid secretion. Integrated gastric acidity is the cumulative gastric acid concentration integrated over time and underestimates gastric acid secretion, which is calculated from the amount of titratable gastric acid over time. After food-related gastric buffering, gastric acid secretion increases because of mealstimulated acid secretion (25, 26). Even during the fasting state, however, integrated acidity underestimates acid secretion because of the hyperbolic relationship between acid concentration in the gastric lumen and secretory rate. Acid concentration becomes maximal and nearly constant at high fluid secretory rates (27). Mathematically correct assessments of gastric acid inhibition using pH will underestimate inhibition of acid secretion. Conversely, direct measurement of gastric secretion overestimates antisecretory effects on intragastric acid concentration. This may be particularly important with acid suppression in GERD (2– 6), particularly if GERD happens to be associated with acid hypersecretion. In this setting, decreases in acid concentration will not be commensurate with lowered acid secretion (27). In vivo titration measures acid secretion in a volumetric way, but it is inconvenient and may not be sensitive to changes in acid secretion. For example, one intragastric titration study that measured antisecretory effects of 15 mg and 30 mg of lansoprazole and 20 mg and 40 mg omeprazole in 10 healthy subjects failed to detect significant antisecretory effects of either agent at 4, 10, 16, and 24 h after the first dose (28). Other researchers (29 –31) have described nocturnal gastric acid breakthrough (nocturnal gastric pH ⬍4 for ⱖ1 h) in patients with GERD treated b.i.d. with either 20 mg omeprazole or 30 mg lansoprazole and have speculated regarding the potential clinical significance of this phenomenon. Obviously, the critical issue is whether increased nocturnal gastric acidity will provoke abnormal esophageal acid exposure. In the present study, simultaneous measurements of integrated esophageal and gastric acidity quantified increased nocturnal gastric acidity in GERD and also identified significant esophageal acid exposure. Subjects with monophasic GERD had little if any nocturnal esophageal acid exposure despite a substantial nocturnal increase in gastric acidity. However, subjects with biphasic GERD
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demonstrated increased nocturnal gastric acidity and pronounced elevation of esophageal acidity. Future studies should clarify relationships between gastric and esophageal acidity. When integrated esophageal and gastric acidity data are available from normal subjects, relationships between gastric acidity and the presentation and severity of GERD should be further clarified. Eventually, it should be possible to estimate the decrement in gastric acidity required to normalize esophageal acid exposure in various GERD subtypes. Finally, measuring integrated gastric and esophageal acidity should be helpful in study of such conditions as endoscopy-negative reflux disease where there is a lack of concordance between symptoms and pathology (6).
ACKNOWLEDGMENTS This work was supported by grants from Eli Lilly and Company, and from Janssen Pharmaceutica to the Oklahoma Foundation for Digestive Research and consulting agreements between Science for Organizations, Inc., and Eisai Inc., and Science for Organizations, Inc. and Janssen Pharmaceutica Research Foundation. Reprint requests and correspondence: Sheila Rodriguez-Stanley, Ph.D., Oklahoma Foundation for Digestive Research, 711 Stanton L. Young Boulevard, Suite 624, Oklahoma City, OK 73104. Received Sep. 11, 2000; accepted Jan. 3, 2001
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22. Johansson K-E, Ask P, Boeryd B, et al. Oesophagitis, signs of reflux, and gastric acid secretion in patients with symptoms of gastro-oesophageal reflux disease. Scand J Gastroenterol 1986;21:837– 47. 23. Bremner RM, Crookes PF, DeMeester TR, et al. Concentration of refluxed acid and esophageal mucosal injury. Am J Surg 1992;164:522–7. 24. Williams MP, Sercombe J, Hamilton MI, et al. A placebocontrolled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998;12:1079 – 89. 25. Fordtran JS, Walsh JH. Gastric acid secretion rate and buffer content of the stomach after eating. J Clin Invest 1973;52: 645–57. 26. Feldman M, Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer. Gastroenterology 1986; 90:540 – 4. 27. Makhlouf GM, McManus JPA, Card WI. A quantitative statement of the two-component hypothesis of gastric secretion. Gastroenterology 1966;51:149 –71. 28. Dammann HG, Fuchs W, Richter G, et al. Lansoprazole versus omeprazole: Influence on meal-stimulated gastric acid secretion. Aliment Pharmacol Ther 1997;11:359 – 64. 29. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763–7. 30. Katz PO, Anderson C, Khoury R, et al. Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998;12: 1231– 4. 31. Hatlebakk JG, Katz PO, Kuo B, et al. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Aliment Pharmacol Ther 1998;11:1235– 40.
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Integrated Acidity and the Pathophysiology of Gastroesophageal Reflux Disease Jerry D. Gardner, M.D., Sheila Rodriguez-Stanley, Ph.D., and Malcolm Robinson, M.D. Science for Organizations, Inc., Chatham, New Jersey; and Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
OBJECTIVES: The aim of this study was to demonstrate that integrated esophageal and gastric acidity values, calculated from 24-h pH recordings, can provide more precise quantitative temporal data than the conventional pH parameters historically associated with gastroesophageal reflux disease (GERD) investigations. METHODS: Esophagogastroduodenoscopy results and pH tracings from 20 GERD subjects with ⱖ10% esophageal acid contact time were studied. Integrated gastric and esophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h recording period. RESULTS: Integrated esophageal acidity correlated with grade of esophagitis. Two quite distinct GERD subtypes were identified, with either a monophasic or biphasic pattern of integrated esophageal acidity. “Biphasic” subjects differed from “monophasic” subjects in terms of magnitude and pattern of integrated esophageal acidity. Although both groups had significant integrated nocturnal gastric acidity, only the biphasic GERD subjects had concomitant increases in nocturnal integrated esophageal acidity. Esophagitis grade was correlated with magnitude rather than pattern of integrated esophageal acidity, and it was possible to calculate a reflux coefficient that seems to provide an estimate of the quantitative motor disturbance present in GERD. CONCLUSIONS: Integrated esophageal and gastric acidity provide quantitative measures of GERD pathophysiology and, compared to conventional pH parameters, should enhance evaluation of therapeutic interventions. (Am J Gastroenterol 2001;96:1363–1370. © 2001 by Am. Coll. of Gastroenterology)
tional pH recordings generate as many as 900 measurements per hour, most analyses reduce data to a single value such as percentage of time that pH is either ⬎4.0 or ⬍4.0, or perhaps to number of reflux episodes. In many antisecretory studies, only gastric or esophageal pH values are assessed. Although there is no doubt that gastric acidity is directly involved in GERD pathogenesis, relationships between gastric and esophageal acidity are not clear. Lack of focus on gastric acid may relate to the general belief that gastric acid secretion is usually normal in GERD (7). The widely accepted rating of acid reflux as percentage of time that pH ⬍4 (1– 6) only approximates actual esophageal acid exposure. For example, individual patients with esophageal pH data indicating a median pH of 1.5 for 4 h versus a median pH of 3.5 for a similar period would have identical values for the percentage of time that esophageal pH is ⬍4, even though esophageal acid exposure, assessed as the product of acid concentration and time, would differ by a factor of 100. Pathological consequences of these two seemingly “identical” acid exposures might be dramatically different. In the present study, data from simultaneous, 24-h esophageal and gastric pH recordings from documented GERD were used to calculate integrated esophageal and gastric acidity. This enabled precise quantification of temporal gastric and esophageal acidity as well as the characterization of two GERD subtypes. The pH data used for the present report were previously analyzed and reported using conventional parameters (8).
MATERIALS AND METHODS
INTRODUCTION
This study was approved by the Western Institutional Review Board, Olympia, WA, with written informed consent by all subjects.
Continuous esophageal pH recordings are widely used to study gastroesophageal reflux disease (GERD) and its treatment (1– 6). Gastric pH recordings are less used clinically, but monitoring of gastric pH has been used for the pharmacological comparison of various antisecretory agents (3– 6). Continuous pH recordings are usually displayed as graphs of pH versus time or as percentage of time with pH above or below a particular value (often 4.0). Although conven-
Subjects The enrollees were 15 men and five women, ages 24 – 61, with clinical GERD. All underwent screening upper GI endoscopy, and all had esophageal pH ⱕ4 for at least 10% of 24 h. Subjects were not tested for Helicobacter pylori infection. Subjects were excluded if treated with a histamine H2-receptor antagonist, sucralfate, or a prostaglandin analog within 3 days; with a proton pump inhibitor or bismuth
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Figure 1. Patterns for integrated esophageal acidity and gastric acidity. All values for each patient were expressed as a percentage of the value at the last hour. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal acidity and seven subjects with a biphasic pattern for esophageal activity.
subsalicylate within 7 days; or with an investigational drug within 30 days before study entry. Subjects were also excluded for deep esophageal ulcers, esophageal strictures, gastric ulcers, or duodenal ulcers within 6 months before study entry, previous gastric or esophageal surgery, pyloric stenosis, or cancer other than basal cell skin cancer. Of the 19 subjects with technically satisfactory recordings, four had grade 3 esophagitis, 11 had grade 2 esophagitis, two had grade 1 esophagitis, and two had no visible esophagitis by the Hetzel-Dent grading scale (9). Study Design The study was conducted at the Oklahoma Foundation for Digestive Research on the campus of the University of Oklahoma Health Sciences Center. Subjects completed two pH monitoring sessions, with at least 7–10 days between sessions. Subjects remained in the study center for the 24-h recordings and received three defined meals. Breakfast was provided at 9:00 –9:30, lunch at 13:00 –14:00, and dinner at 18:00 –19:00 each day of pH monitoring. Smoking, ingestion of food or liquids between meals, and use of antisecretory medications other than those studied were prohibited during pH recordings. Gastric and esophageal pH were monitored with an ambulatory, disposable, dual channel antimony electrode pH catheter and recording system (Medtronic Synectics, Shoreview, MN), with one electrode 10 cm below and one 5 cm above the upper margin of the manometrically defined lower esophageal sphincter. Electrodes were calibrated to pH 1.07
and 7.01 using solutions composed of 59 mmol/L KNO3, 27 mmol/L KCl (pH 1.07) and 16.5 mmol/L Tris buffer, 40 mmol/L KNO3, 96 mmol/L KCl (pH 7.01). Data every 4 s were collected using a portable data storage unit (Digitrapper, Medtronic Synectics) and processed in DOS mode using temperature-compensating software (Polygram for Windows, Version 2.04, Medtronic Synectics), Measurements are described as acid “concentration” although pH electrodes actually measure hydrogen ion “activity.” Methods exist to adjust hydrogen ion activity to hydrogen ion concentration (10, 11). Electrode calibrations to pH 1 and 7 in the manufacturer-provided polyelectrolyte solutions result in measured hydrogen ion activity closely approximating hydrogen ion concentration. Therefore, no additional adjustments of measured hydrogen ion activity were used. Analytical Procedures Polygram software (Medtronics Synectics) calculates conventional esophageal and gastric pH recording indices, e.g., number of esophageal reflux episodes, number of reflux episodes ⬎5 min, percentage of recording with esophageal pH ⬍4, and percentage of recording with gastric pH ⬍4. Polygram software records pH values every 4 s and fills in values for the other 3 s, resulting in one value per second for each electrode. To calculate integrated acidity, 1-s interval pH data were used. Both recordings were analyzed for all 20 subjects, although technically unsatisfactory data from one subject with a malfunctioning gastric electrode were omit-
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Table 1. Esophageal pH Cutoffs vs 24-h Integrated Esophageal Acidity pH ⬍3 (%)
pH ⬍4 (%)
pH ⬍5 (%)
pH ⬍6 (%)
7.5 17.0 29.6 54.5 r2 0.68 0.62 0.55 0.38 p ⬍0.0001 ⬍0.0001 0.0003 0.0049
24-h Integrated Esophageal Acidity (mmol 䡠 h/L) 24.4
Values are medians from 19 subjects. Values of r2 and p for values are from linear, least-squares regression analysis of % time with pH less than particular values vs integrated esophageal acidity.
ted. Integrated gastric and esophageal acidity were calculated for each second of recording as follows: 1. Acid concentration (mmol/L) ⫽ 1000 ⫻ 10⫺pH 2. Acidity (mmol 䡠 h/L) ⫽ (acid in mmol/L at time “t”⫹ acid in mmol/L at time “t⫺1”)/2 ⫻ (t – t⫺1) 3. Acidity values were summed cumulatively per second. Integrated acidity is expressed as mmol/L ⫻ time, i.e., mmol 䡠 h/L. 4. Integrated acidity was analyzed for each hour of the recording. Integrated acidity at any given time is cumulative, and mean acid concentration up to that point in time can be calculated by dividing integrated acidity by time. For example, mean gastric acid concentration for hours 8:00 to 24:00 can be calculated by dividing the integrated gastric acidity at 24:00 by 16. Mean hourly acid concentration was calculated as integrated acidity at time “t” minus integrated acidity at time “t⫺1.” Recordings started at 08:00 h. Conventional pHbased indices were also calculated. Of 38 technically satisfactory records, 34 were for 24 h, three were for 23 h, and one was for 22 h. For missing data, the last values calculated were carried forward. Statistical analyses were completed using Microsoft Excel 97 or GraphPad for InStat version 3.01 Windows software. Even though many results were not normally distributed, means ⫾ SEM are used to illustrate variations. In instances when one or two large negative values substantially distorted mean values, medians are presented instead. The 24-h values for conventional indices, integrated acidity, and reflux coefficient were analyzed using the Mann-Whitney test.
RESULTS As illustrated in Figure 1, integrated esophageal and gastric acidity increased progressively over 24 h. Increases in integrated gastric acidity were not constant, however, because meal ingestion transiently decreased intragastric acidity. Table 1 gives median percentages of time with esophageal pH ⬍3, ⬍4, ⬍5, or ⬍6 along with 24-h integrated esophageal acidity. Note that integrated acidity is expressed as a single number versus several numbers potentially required for interpreting all of the conventional pH data.
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Table 2. Gastric pH Cutoffs vs 24-h Integrated Gastric Acidity pH ⬍1 (%)
pH ⬍2 (%)
pH ⬍3 (%)
pH ⬍4 (%)
18.9 74.2 82.6 90.6 r2 0.90 0.38 0.26 0.24 p ⬍0.0001 .0053 .0240 .0336
24-h Integrated Gastric Acidity (mmol 䡠 hr/L) 1557
Values are medians from 19 subjects. Values of r2 and p for values are from linear, least-squares regression analysis of pH less than particular values vs integrated gastric acidity.
Table 2 gives median values for the percentage of recordings with gastric pH ⬍1, ⬍2, ⬍3, or ⬍4 and for 24-h integrated gastric acidity. Table 2 results use the same data found in Figure 1. As with integrated esophageal acidity, integrated gastric acidity correlated with pH values with the lower pH cutoffs correlating best. In the present study, integrated acidity analyses disclosed two distinct reflux patterns when individual data were expressed as percentages of maximal values (Fig. 1, left panel). Subjects could be divided into two groups based on attaining 50% of maximal integrated esophageal acidity before or after 23:00. As illustrated in Figure 1 (left panel), 12 monophasic subjects reached 50% maximal esophageal acidity before 23:00. In these monophasic subjects, an acid plateau occurred at about 2:00 and tended to remain stable thereafter. Monophasic subjects attained 50% of maximal acidity by 17:00. Seven subjects with a biphasic esophageal acidity pattern reached 50% maximal esophageal acidity either at or after 23:00. These subjects demonstrated slow increases in acidity until 23:00 with more rapidly increasing acidity until the end of the recording (Fig. 1, left panel). In biphasic subjects, 50% of maximal esophageal acidity was reached by 1:00. Figure 1 (right panel) shows virtually identical patterns of gastric acidity in these two groups of subjects with distinctly different esophageal acidity patterns. Curves were stratified based on visual inspection rather than any formal quantitative or statistical analysis of the records. Using a value of 23:00 to stratify records produced two clearly different groups and in addition, 23:00 h seemed to be a good estimate of when these subjects became recumbent for sleep. Stratification by time was intended to illustrate potential clinical utility of integrated esophageal and gastric acidity, not to argue in favor of 23:00 over 22:00 or 24:00. As illustrated in Figure 2 (left panel), integrated esophageal acidity in biphasic subjects was significantly greater (p ⬍ 0.05) than with monophasic esophageal acidity from 3:00 until the end of recording. In contrast, integrated gastric acidity did not differ between mono- or biphasic esophageal acidity (Fig. 2). Table 3 shows generally higher conventional pH parameters with biphasic esophageal acidity versus monophasic esophageal acidity. Values for time esophageal pH ⬍4 were significantly different (p ⬍ 0.05), whereas numbers of esophageal reflux episodes, numbers of reflux episodes last-
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Figure 2. Integrated esophageal acidity and gastric acidity in monophasic and biphasic GERD. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal activity and seven subjects with a biphasic pattern for esophageal acidity. Circles at the top of the left panel indicate the times at which values for biphasic subjects significantly differ from corresponding values for monophasic subjects (p ⬍ 0.05).
ing ⬎5 min and times with gastric pH ⬍4 were not significantly different. The 24-h integrated esophageal acidity, mean esophageal acid concentration, and mean pH were significantly higher in biphasic than in monophasic subjects (Table 3). 24-h integrated gastric acidity and mean pH did not differentiate biphasic versus monophasic subjects (Table 3). Esophagitis grades were similar between biphasic and monophasic subjects (Table 3). Figure 3 (right panel) shows that the buffering by meals led to fluctuating mean gastric acid concentrations. Al-
though gastric acid concentrations tended to be higher in biphasic subjects and were significantly higher at 5:00 and 6:00, there were no important differences between patterns for the two types of subjects. Figure 3 (left panel) illustrates esophageal acid concentrations fluctuating in conjunction with gastric acid concentrations in both monophasic and biphasic subjects. After 24:00, however, esophageal acid concentrations decreased to near zero in monophasic subjects, remaining significantly higher in biphasic subjects over the last 6 h.
Table 3. Values for Conventional pH Indices and 24-h Integrated Esophageal and Gastric Acidity Measure Esophageal Number of reflux episodes Number of reflux episodes ⬎5 min Percent time pH ⬍ 4 24-H integrated acidity (mmol 䡠 hr/L) Mean acid concentration (mmol/L) Mean pH Gastric acid Percent time pH ⬍ 4 24-H integrated acidity (mmol 䡠 hr/L) Mean acid concentration (mmol/L) Mean pH Grade esophagitis
All (n ⫽ 19)
Monophasic (n ⫽ 12)
Biphasic (n ⫽ 7)
308 ⫾ 35 12 ⫾ 2 24 ⫾ 4 128 ⫾ 46 5.3 ⫾ 1.9 2.3
283 ⫾ 46 10 ⫾ 2 20 ⫾ 5 53 ⫾ 26 2.2 ⫾ 1.1 2.6
350 ⫾ 55 15 ⫾ 3 32 ⫾ 7* 257 ⫾ 104* 10.7 ⫾ 4.3* 2.0
90 ⫾ 2 1308 ⫾ 151 55 ⫾ 6 1.3 1.9 ⫾ 0.2
88 ⫾ 2 1116 ⫾ 166 46 ⫾ 7 1.3 1.9 ⫾ 0.3
92 ⫾ 2 1638 ⫾ 265 68 ⫾ 11 1.2 1.9 ⫾ 0.3
Values are means ⫾ SEM from numbers of subjects indicated. Mean acid concentration was calculated by dividing integrated acidity by 24, and mean pH was calculated by taking the logarithm of the mean acid concentration expressed in mmol/L. Esophagitis was graded using the Hetzel-Dent classification system Ref. (9). * Significantly different from corresponding value for monophasic subjects, p ⬍ 0.05 by Mann-Whitney test.
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Figure 3. Mean esophageal acid concentrations and mean gastric acid concentrations in monophasic and biphasic GERD. Values given are means ⫾ SEMs from 12 subjects with a monophasic pattern for esophageal acidity and seven subjects with a biphasic pattern for esophageal activity. Circles at the tops of the panels indicate the times at which values for biphasic subjects significantly differ from corresponding values for monophasic subjects (p ⬍ 0.05).
Relationships between esophageal and gastric acidity can be further elucidated by dividing integrated esophageal acidity multiplied by 100 by the corresponding value for integrated gastric acidity. This can be termed the “reflux coefficient” because it gives the value for integrated esophageal acidity associated with 100 mmol 䡠 h/L of integrated gastric acidity. Figure 4 illustrates the usefulness of the reflux coefficient for comparison of different clinical conditions. Monophasic and biphasic subjects had similar reflux coefficients during daytime and evening, but nocturnal coefficients were significantly higher in biphasic subjects (Fig. 4). Table 4 summarizes integrated acidity and T50 (time for integrated esophageal acidity to reach 50% of maximal) stratified for pre-entry Hetzel-Dent esophagitis grade (9). Mean 24-h integrated esophageal acidity and grade of esophagitis were correlated. Neither the mean 24-h integrated gastric acidity nor T50 correlated with esophagitis grade.
DISCUSSION In the present study, integrated gastric and esophageal acidity were calculated from conventional 24-h pH data. Integrated acidity can be used to examine quantitative relationships between esophageal acidity and gastric acidity and helps to differentiate GERD pathophysiologies. Validation of integrated acidity has been accomplished by
Figure 4. Reflux coefficient for biphasic and monophasic subjects. Results given are means ⫾ SEMs from seven biphasic subjects and 12 monophasic subjects. Circles at the top indicate the times at which values for biphasic subjects are significantly greater than corresponding values from monophasic subjects (p ⬍ 0.05).
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Table 4. Integrated Acidity Stratified for Different Esophagitis Grades Grade Esophagitis
No. Patients
24-h Esophageal Acidity (mmol 䡠 h/L)
T50
24-h Gastric Acidity (mmol 䡠 h/L)
0 1 2 3 All r2 p
2 2 11 4 19
8.1 (7.8–8.3) 20 (16–24) 130 (7–462) 236 (16–736) 128 (7–736) 0.92 0.042
13 (10–16) 9 (8–9) 13 (6–19) 10 (5–18) 12 (5–19) 0.04 0.920
539 (533–546) 1680 (1569–1790) 1271 (536–2405) 1609 (371–2604) 1308 (371–2604) 0.48 0.351
Esophagitis was graded using the Hetzel-Dent classification system Ref. (9). Values for acidity and T50 are means (range) from the number of patients indicated. Values for r2 and p are from linear, least-squares regression analysis of mean values for acidity or T50 vs grade of esophagitis.
systematic comparisons to conventional pH indices with different pH cutoffs. Among advantages of integrated acidity over conventional indices is its full quantitation of acidity with a single value. In contrast, conventional indices only partially quantify acidity, employ arbitrary pH cutoff values, and do not permit transferring one pH cutoff to an alternative pH. There were significant correlations between integrated acidity and conventional indices; however, the strength of the correlation increased with decreasing pH cutoff values. Esophageal acid exposure is commonly expressed as pH ⬍ 4, with normal values considered as 4% or 6% of 24 h (1– 6). However, in this study, pH ⬍3 provided a higher correlation coefficient with integrated esophageal acidity. Others (2, 6) have described apparent deficiencies in published pH cutoffs for conventional indices, including the observation that only approximately 50% of patients with endoscopy-negative GERD have abnormal pH findings. Present results provide some possible explanations including the possibility that use of a pH ⬍3 cutoff might encompass more endoscopy-negative patients, still differentiating normal subjects from patients with GERD. Because of variations in esophageal acid exposure during the day, different recording times in the same subject might produce variable values for percentage of time that esophageal pH is ⬍4. For example, in a patient with monophasic GERD, omitting segments of daytime recording would decrease the percentage of time that esophageal pH was ⬍4, whereas omitting nighttime recording would increase it. The opposite situation would occur in a patient with biphasic GERD (nighttime esophageal acid exposure is greater than daytime exposure), although to a lesser extent, because biphasic subjects have some daytime esophageal acid exposure. These observations could preclude the use of abbreviated pH studies as substitutes for 24-h studies. The reflux coefficient, which indicates integrated esophageal acidity associated with 100 mmol 䡠 h/L of integrated gastric acidity, may be used to estimate the magnitude of motility disturbances present in GERD. Higher reflux coefficients indicate more esophageal acid exposure with a given level of integrated gastric acidity. In this regard, for two patients with identical integrated esophageal acidity, a patient with lower integrated gastric acidity and a higher numerical reflux coefficient presumably suffers from a more severe disturbance of motility.
Several findings in the present study illustrate potential clinical utility of integrated acidity. For example, based on values for integrated esophageal acidity, GERD patients can be classified into two groups: monophasic pattern of integrated esophageal acidity with 50% of esophageal acid exposure occurring by 17:00, and biphasic integrated esophageal acidity with 50% of occurring by 1:00. Distinct patterns of esophageal acidity in GERD have been previously reported (12–14). Patients with daytime esophageal acid exposure have been called “upright refluxers” and those with nocturnal esophageal acid exposure have been known as “supine or recumbent refluxers.” There is a clear relationship between these descriptors and the present findings of monophasic and biphasic integrated esophageal acidity. Compared to biphasic GERD subjects, monophasic subjects had little or no esophageal acidity after 2:00, lower integrated esophageal acidity, fewer esophageal reflux episodes, less esophageal pH ⬍4, and a lower reflux coefficient. Monophasic and biphasic GERD subjects were similar in terms of patterns and magnitudes of integrated gastric acidity, average grades of esophagitis, and mean gastric acid concentrations. Previous pH-based analyses have nicely correlated esophagitis grade with acid exposure (3, 14 –16). Integrated esophageal acidity and esophagitis grade were well correlated in the present study, although mono- and biphasic subjects had similar esophagitis grades despite higher mean 24-h integrated esophageal acidity in biphasic refluxers. This suggests that esophagitis grade correlates more with the magnitude of esophageal acid exposure rather than the pattern of acid exposure. Some biphasic subjects had low integrated esophageal acidity and some monophasic subjects had high integrated esophageal acidity. Gastric acidity has been somewhat neglected as the major determinant of esophageal acid exposure in GERD aside from observations that acid inhibition could diminish esophageal acid exposure (3– 6). Hirschowitz reported basal and pentagastrin-stimulated gastric acid secretion in esophagitis comparable to unspecified medical conditions without esophagitis (17–19). Others, however, have reported increased basal, peak, or maximal gastric acid secretion in GERD compared to healthy subjects (20 –23). In this regard, Williams et al. (24) established 24-h integrated gastric acidity as 890 mmol 䡠 h/L (range 263–1493) in 23 healthy H.
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pylori–negative volunteers using hourly determination of gastric pH. In the present study, 24-h integrated gastric acidity for monophasic GERD was 1116 ⫾ 166 mmol 䡠 h/L (mean ⫾ SEM; n ⫽ 12) and for biphasic GERD was 1638 ⫾ 265 mmol 䡠 h/L (n ⫽ 7). These differences may reflect different meals with different degrees of neutralization or stimulation of gastric acid secretion in the different studies. On the other hand, subjects with biphasic GERD may have increased integrated gastric acidity compared to healthy volunteers whereas monophasic GERD may not. Varying proportions of monophasic and biphasic subjects might account for different conclusions from different studies regarding increased gastric acid secretion in GERD. Integrated gastric acidity does not measure gastric acid secretion. Integrated gastric acidity is the cumulative gastric acid concentration integrated over time and underestimates gastric acid secretion, which is calculated from the amount of titratable gastric acid over time. After food-related gastric buffering, gastric acid secretion increases because of mealstimulated acid secretion (25, 26). Even during the fasting state, however, integrated acidity underestimates acid secretion because of the hyperbolic relationship between acid concentration in the gastric lumen and secretory rate. Acid concentration becomes maximal and nearly constant at high fluid secretory rates (27). Mathematically correct assessments of gastric acid inhibition using pH will underestimate inhibition of acid secretion. Conversely, direct measurement of gastric secretion overestimates antisecretory effects on intragastric acid concentration. This may be particularly important with acid suppression in GERD (2– 6), particularly if GERD happens to be associated with acid hypersecretion. In this setting, decreases in acid concentration will not be commensurate with lowered acid secretion (27). In vivo titration measures acid secretion in a volumetric way, but it is inconvenient and may not be sensitive to changes in acid secretion. For example, one intragastric titration study that measured antisecretory effects of 15 mg and 30 mg of lansoprazole and 20 mg and 40 mg omeprazole in 10 healthy subjects failed to detect significant antisecretory effects of either agent at 4, 10, 16, and 24 h after the first dose (28). Other researchers (29 –31) have described nocturnal gastric acid breakthrough (nocturnal gastric pH ⬍4 for ⱖ1 h) in patients with GERD treated b.i.d. with either 20 mg omeprazole or 30 mg lansoprazole and have speculated regarding the potential clinical significance of this phenomenon. Obviously, the critical issue is whether increased nocturnal gastric acidity will provoke abnormal esophageal acid exposure. In the present study, simultaneous measurements of integrated esophageal and gastric acidity quantified increased nocturnal gastric acidity in GERD and also identified significant esophageal acid exposure. Subjects with monophasic GERD had little if any nocturnal esophageal acid exposure despite a substantial nocturnal increase in gastric acidity. However, subjects with biphasic GERD
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demonstrated increased nocturnal gastric acidity and pronounced elevation of esophageal acidity. Future studies should clarify relationships between gastric and esophageal acidity. When integrated esophageal and gastric acidity data are available from normal subjects, relationships between gastric acidity and the presentation and severity of GERD should be further clarified. Eventually, it should be possible to estimate the decrement in gastric acidity required to normalize esophageal acid exposure in various GERD subtypes. Finally, measuring integrated gastric and esophageal acidity should be helpful in study of such conditions as endoscopy-negative reflux disease where there is a lack of concordance between symptoms and pathology (6).
ACKNOWLEDGMENTS This work was supported by grants from Eli Lilly and Company, and from Janssen Pharmaceutica to the Oklahoma Foundation for Digestive Research and consulting agreements between Science for Organizations, Inc., and Eisai Inc., and Science for Organizations, Inc. and Janssen Pharmaceutica Research Foundation. Reprint requests and correspondence: Sheila Rodriguez-Stanley, Ph.D., Oklahoma Foundation for Digestive Research, 711 Stanton L. Young Boulevard, Suite 624, Oklahoma City, OK 73104. Received Sep. 11, 2000; accepted Jan. 3, 2001
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