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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Aliment Pharmacol Ther 2010; 32: 334–343

Summary

Background  The importance of weakly acidic and weakly alkaline reflux in gastro-oesophageal reflux disease (GERD) is gaining recognition.

Aim  To quantify the proportions of reflux episodes that are acidic (pH <4), weakly acidic (pH 4–7) and weakly alkaline (pH >7) in adult patients with GERD, and to evaluate their correlation with symptoms.

Methods  Studies were identified by systematic PubMed and Embase searches. Data are presented as sample-size weighted means and 95% confidence intervals.

Results  In patients with GERD taking a proton pump inhibitor (PPI), 80% (76–84%) of reflux episodes were weakly acidic or weakly alkaline and 83% (78–88%) of reflux symptom episodes were associated with weakly acidic or weakly alkaline reflux episodes. In patients with GERD not taking a PPI, 63% (59–67%) of reflux episodes were acidic and 72% (57–87%) of reflux symptom episodes were associated with acid reflux episodes. Six studies presented data separately for weakly alkaline reflux, which accounted for <5% of all reflux episodes, both on and off PPI therapy.

Conclusions  Weakly acidic reflux underlies the majority of reflux episodes in patients with GERD on PPI therapy, and is the main cause of reflux symptoms occurring despite PPI therapy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Gastro-oesophageal reflux disease (GERD) is a chronic disease that affects 10–20% of adults in the USA and Europe,1 and its cardinal symptoms are heartburn and regurgitation.2 GERD develops when the reflux of stomach contents causes troublesome symptoms or complications.2 Episodes of gastro-oesophageal reflux occur mainly during transient lower oesophageal sphincter relaxations (TLESRs).3 The frequency and duration of TLESRs are similar between individuals with and without GERD. However, as a group, individuals with GERD have an increased risk of reflux occurring during such episodes.3, 4

The study of gastro-oesophageal reflux has been revolutionized by the development of combined 24-h oesophageal pH and multichannel intraluminal impedance (MII) monitoring.5, 6 MII detects gastro-oesophageal reflux episodes based on changes in resistance to alternating electrical current between a series of paired electrodes. One of the first studies to combine oesophageal pH-monitoring with MII in humans was conducted about a decade ago in a small group of healthy volunteers.7 The investigators noted that only about half of all reflux episodes detected by MII were also detected by pH-metry, concluding that the remainder were due to relatively pH-neutral reflux.

Combined oesophageal MII and pH-monitoring allow for the timed correlation of oesophageal pH changes with reflux events and achieve high sensitivity for the detection of acid (pH <4), weakly acidic (pH 4–7) and weakly alkaline (pH >7) reflux episodes. Use of this technology is bringing into focus the potential role of weakly acidic and weakly alkaline reflux in GERD and in the production of symptoms that are associated with reflux episodes.8 However, available data on the proportion of reflux episodes that are acidic, weakly acidic or weakly alkaline in patients with GERD have not been evaluated using a systematic approach before.

This systematic review of the literature assesses the proportions of reflux episodes that are acidic, weakly acidic or weakly alkaline in patients with GERD, and evaluates how these episodes are associated with use of PPIs and symptoms.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Systematic literature searches

Investigational studies of adult patients with GERD on or off PPI therapy were identified by systematic searches of the literature up to September 2009 in PubMed and Embase. A flow chart of the systematic searches and search strings used is shown in Figure 1. To be eligible for inclusion, studies needed to provide data on the proportions of acid (pH <4), weakly acidic (pH 4–7) and weakly alkaline (pH >7) reflux episodes, based on oesophageal pH-metry and MII monitoring. Studies reported in a language other than English were excluded, as were studies that did not report on the proportion of acid vs. weakly acidic and/or weakly alkaline reflux episodes, or did not provide data sufficient for these proportions to be calculated [e.g. studies providing only data on the median (not mean) number of episodes per patient, or studies reporting only on the proportion of time that oesophageal pH was acidic and weakly acidic and/or weakly alkaline]. Studies on the effects of surgery on reflux were not included in this review.

image

Figure 1.  Flow chart of systematic literature searches.

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Statistical analysis

Sample-size-weighted means and sample-size-weighted 95% confidence intervals (CI) were calculated for all pooled prevalence data.9

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The literature searches identified 21 studies involving 664 patients with GERD that fulfilled the inclusion criteria for this review (Figure 1). Twelve of the studies reported the data of 374 patients taking a PPI and 16 studies reported the data of 382 patients not taking a PPI. The majority of the identified studies recruited patients who had a history of reflux symptoms despite taking a PPI. Information on study design is summarized in Table 1. More details on the patient populations and reflux–symptom correlation data are provided in the online supplementary Tables S1, S2 and S3.

Table 1.   Overview of the 21 studies included in the review
Ref.Patients (n)PPI statusPersistent GERD symptoms despite PPI therapyGastro-oesophageal pathologyNumber of reflux episodes analysedTime period of analysisMeal periods included in analysis
  1. BO, Barrett’s oesophagus; GERD, gastro-oesophageal reflux disease; HH, hiatal hernia; NR, not reported; PPI, proton pump inhibitor; pts, patients; RO, reflux oesophagitis.

  2. * The study also included a GABAB agonist or alginate treatment arm, data for which are not reported here.

  3. † The study also included patients without GERD, for whom the data are not included here.

Aanen et al., 20083819Off PPINRNR119924 hNo
Beaumont and Boeckxstaens, 200939 23*On PPIYesHH (n = 11)185124 hNo
Blonski et al., 200912110Off PPI (n = 40); on PPI (n = 70)YesNRNR24 h and 2 h postprandialYes
Bredenoord et al., 200640 12†Off PPINRRO (n = 6)NR24 hNo
Bredenoord et al., 200636 28Off PPINRNRNR24 hNo
Bredenoord et al., 200841 14Off PPINRNRNR24 hNo
Bredenoord et al., 200919 50†Off PPIPts without RO: no; pts with RO or BO: NRRO (n = 30); BO (n = 10)NR24 hNo
Conchillo et al., 200820 26†Off PPINRRO (n = 13)NR24 hNo
Emerenziani et al., 200811 52Off PPI (n = 52); on PPI (n = 12)NoRO (n = 20)298424 hNR
Hemmink et al., 200842 30Off PPI (n = 30); on PPI (n = 30)YesRO (n = 3)NR24 hNo
Iwakiri et al., 200916 13On PPIYesNone91624 hNo
Khan et al., 200943 30†On PPIYesNRNR24 hNR
Orr et al., 200710 15Off PPI (n = 15); on PPI (n = 15)NRNR112One nightNo
Pace et al., 200721 20Off PPI (n = 7); on PPI (n = 13)NRRO (n = 6)113724 hNR
Tutuian et al., 200817120On PPIYesNR354724 hNR
Vela et al., 200113 12Off PPI (n = 12); on PPI (n = 12)NRNR47824 hNR
Vela et al., 200318 9*†Off PPINRNR25324 hNR
Weigt et al., 200714 32Off PPI (n = 16); on PPI (n = 16)NRNR359124 hNo
Xiao et al., 200922 42†Off PPINRRO (n = 20)NR24 hNo
Zerbib et al., 20081520On PPIYesRO (n = 1); BO (n = 3)127324 hNo
Zentilin et al., 20054410*Off PPINRRO (n = 3)1121 hNo

Seven of the studies reported data for patients on and off PPI therapy (271 patients in total). Information on the mean number of reflux episodes and symptom episodes is shown in Table 2. Overall, the number of reflux episodes did not differ significantly between patients on and off PPI therapy, although one study that reported only on reflux during sleep observed a decrease in the number of reflux episodes with PPI treatment.10 Reflux symptom frequency was 20–70% higher in patients off PPI therapy than in those on PPI therapy in studies of patients who had reflux symptoms despite PPI treatment. The effect was even more pronounced in a study that included only patients with a history of favourable response to PPI therapy, in which the frequency of reflux symptom episodes in those on PPI treatment was 14 times that in patients off PPI therapy.11

Table 2.   Number of reflux episodes and reflux symptoms in individuals with GERD on and off PPI therapy
ReferenceMean number of reflux episodes per patientP value (difference on vs. off PPI)Mean number of reflux symptoms per patientP value (difference on vs. off PPI)Ratio reflux symptoms off PPI/on PPI
On PPIOff PPIOn PPIOff PPI
  1. GERD, gastro-oesophageal reflux disease; NR, not reported; N.S., not significant; PPI, proton pump inhibitor.

Blonski et al., 200912Overall: 1.7/h Postprandial: 4.5/ hOverall: 2.3/h Postprandial: 5.1/hOverall: N.S. Postprandial: N.S.NRNR
Emerenziani et al., 20081136/24 h41/24 hN.S.0.7/24 h10/24 hNR14
Hemmink et al., 20084269/24 h73/24 hN.S.3/24 h5/24 h<0.011.7
Orr et al., 20071039/night73/night<0.01NRNR
Pace et al., 20072161/24 h50/24 hNRNRNR
Vela et al., 20011322/2 h postprandial18/2 h postprandialN.S.11/2 h postprandial13/2 h postprandialNR1.2
Weigt et al., 200714NRNR35/24 h44/24 hNR1.3

Patients with GERD taking a PPI

The majority of reflux episodes in patients with GERD taking a PPI were of pH >4, that is, weakly acidic or weakly alkaline (mean: 80%; 95% CI: 76–84%); only a small proportion of reflux episodes were acidic (mean: 20%; 95% CI: 16–24%) (Figure 2). Three studies presented data separately for weakly alkaline reflux, which accounted for less than 5% of all reflux episodes (Table S1). The proportion of reflux episodes that were acidic vs. weakly acidic or weakly alkaline was similar overall during the 24-h recording period compared with the postprandial period following an evening meal in a study that assessed the two time periods separately (overall: 18% acidic vs. 82% weakly acidic/alkaline; postprandial: 20% acidic vs. 80% weakly acidic/alkaline).12

image

Figure 2.  The proportion of acid and weakly acidic or weakly alkaline reflux episodes in 374 patients with gastro-oesophageal reflux disease (GERD) taking a proton pump inhibitor (PPI) (13 treatment arms) and 356 patients with GERD not taking a PPI (22 treatment arms). For studies that reported separately on weakly acidic and weakly alkaline reflux episodes, these data were combined. Symbols denote proportions for each treatment arm and horizontal lines show mean proportions, weighted by the number of patients included in each treatment arm.

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Most reflux-related symptom episodes were associated with reflux episodes that were weakly acidic or weakly alkaline (mean: 83%; 95% CI: 78–88%); only a minority of reflux-related symptoms were associated with acid reflux (mean: 17%; 95% CI: 12–22%) (Figure 3; Table S3).13–17 The mean proportion of acid reflux episodes that were symptomatic was 53% (95% CI: 50–56%), which was similar to the mean proportion of weakly acidic or weakly alkaline reflux episodes that were symptomatic (47%; 95% CI: 44–50%).13, 15, 17 In a study that assessed heartburn and regurgitation separately, and in which participants could report more than one symptom during each symptom event, symptomatic acid reflux episodes were just as commonly associated with heartburn as with regurgitation (67% vs. 67%); in contrast, symptomatic weakly acidic or weakly alkaline reflux episodes were more commonly associated with regurgitation (98%, vs. 10% with heartburn).13

image

Figure 3.  The proportion of symptom-related reflux episodes that were acidic and weakly acidic or weakly alkaline in 174 patients with gastro-oesophageal reflux disease on proton pump inhibitor (PPI) therapy. Four studies reported on reflux symptoms combined and one study reported separately on heartburn and regurgitation. The following symptoms were recorded: heartburn, regurgitation (Zerbib et al., 2008); heartburn, regurgitation, acid taste (Vela et al., 2001); heartburn, chest pain, dysphagia, throat pain, oppression (Iwakiri et al., 2009); typical and atypical reflux symptoms (not specified further) (Tutuian et al., 2008); heartburn, regurgitation, chest pain, upper abdominal pain, coughing, sore throat, globus, pressure, burning of the tongue (Weigt et al., 2007). The horizontal line indicates the mean proportion of acid reflux episodes (symptomatic and asymptomatic combined), weighted by the number of patients included in each study.

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Patients with GERD not taking a PPI

In patients with GERD not taking a PPI, most reflux episodes were acidic (mean: 63%; 95% CI: 59–67%); the mean proportion of episodes that were weakly acidic or weakly alkaline was 37% (95% CI: 33–41%) (Figure 2). Four studies presented data separately for weakly alkaline reflux, which accounted for less than 5% of all reflux episodes (Table S2).

Most reflux-related symptom episodes were associated with acid reflux episodes (mean: 72%; 95% CI: 57–87%); only a minority of reflux-related symptom episodes were associated with reflux episodes that were weakly acidic or weakly alkaline (mean: 28%; 95% CI: 13–43%) (Figure 4; Table S3).11, 13, 14, 18 In a study that assessed reflux episodes in the postprandial period, the proportion of reflux episodes that were acidic vs. weakly acidic or weakly alkaline was 64% vs. 36% respectively, following an evening meal, compared with 61% vs. 39% respectively, overall during the 24-h recording period.12

image

Figure 4.  The proportion of symptom-related reflux episodes that were acidic and weakly acidic or weakly alkaline in 82 patients with gastro-oesophageal reflux disease off proton pump inhibitor (PPI) therapy. One study reported separately on patients without and with reflux oesophagitis (RO); three studies did not report on oesophageal injury. The following symptoms were recorded: heartburn, regurgitation (Emerenziani et al., 2008); heartburn, regurgitation, acid taste (Vela et al., 2001; Vela et al., 2003); heartburn, regurgitation, chest pain, upper abdominal pain, coughing, sore throat, globus, pressure, burning of the tongue (Weigt et al., 2007). The horizontal line indicates the mean proportion of acid reflux, weighted by the number of patients included in each study.

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The mean proportion of reflux episodes that were symptomatic was slightly higher for acid reflux than for weakly acidic or weakly alkaline reflux (acidic: 60%; 95% CI: 52–68%; weakly acidic/alkaline: 40%; 95% CI: 32–48%).13, 18 In a study that assessed heartburn and regurgitation separately, and in which participants could report more than one symptom during each symptom event, both symptomatic acid reflux episodes and symptomatic weakly acidic or weakly alkaline reflux episodes were more commonly associated with heartburn than with regurgitation (acid – heartburn: 84%, regurgitation: 56%; weakly acidic/alkaline – heartburn: 71%, regurgitation, 52%).13

The proportion of reflux episodes that were acidic did not differ between patients without reflux oesophagitis (mean: 65%; 95% CI: 56–74%) and those with reflux oesophagitis (mean: 63%; 95% CI: 57–69%) in the five studies that reported data separately for these two patient groups (Figure 5).11, 19–22 Similarly, the proportion of reflux episodes that were weakly acidic or weakly alkaline did not differ between patients without reflux oesophagitis (mean: 35%; 95% CI: 26–44%) and those with reflux oesophagitis (mean: 37%; 95% CI: 31–43%). However, in one study that reported separately on patients without or with Los Angeles grade A, B and C/D reflux oesophagitis, and with Barrett’s oesophagus, the proportion of reflux episodes that were acidic increased with increasing oesophageal injury (Table S2); participants who were on PPI therapy had to discontinue PPI use at least 5 days before the study.19

image

Figure 5.  The proportion of acid and weakly acidic or weakly alkaline reflux episodes in 177 patients with gastro-oesophageal reflux disease off proton pump inhibitor (PPI) therapy without (n = 82; five treatment arms) and with (n = 95; eight treatment arms) reflux oesophagitis. For studies that reported separately on weakly acidic and weakly alkaline reflux episodes, these data were combined. Symbols denote proportions for each treatment arm and horizontal lines show mean proportions, weighted by the number of patients included in each treatment arm.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Our systematic review of data from 664 patients with GERD shows that the proportion of reflux episodes that are acidic as opposed to weakly acidic or weakly alkaline differs considerably between patients who are taking a PPI and those who are not. In patients taking a PPI, 20% (95% CI: 16–24%) of reflux episodes were acidic, whereas in patients not on PPI therapy the proportion was 63% (95% CI: 59–67%). There is a paucity of data on the proportion of reflux episodes that are weakly acidic and weakly alkaline in individuals with GERD whose symptoms respond to PPI treatment, with only one of the studies in this review including such a patient population.23 The overall number of reflux episodes does not differ between patients on and off PPI therapy, although PPIs may reduce the number of nocturnal reflux episodes.10 However, patients on PPI therapy have a decreased symptom frequency compared with those not taking a PPI and, not surprisingly, this is particularly noticeable in patients who have a history of reduction in reflux symptoms in response to PPI therapy.11 The decrease in acid reflux with PPIs results from their ability to elevate gastric and oesophageal pH levels, making them effective in the treatment of acid-related reflux symptoms and complications.24, 25 Most patients with GERD, with or without reflux oesophagitis, experience resolution of their reflux symptoms when on PPI therapy.25, 26 However, about 20–40% of patients with GERD report partial- or non-response of their reflux symptoms to PPI therapy in clinical studies conducted in the secondary care practice setting.26

Refluxate with pH <4 is not the only type capable of triggering symptoms during PPI treatment: our review shows that, in patients with GERD who have reflux symptom episodes despite taking a PPI, more than 80% of reflux-related symptom episodes (mean: 83%; 95% CI: 78–88%) are associated with weakly acidic or weakly alkaline reflux. Only a small minority of reflux-related symptoms are associated with acid reflux in these patients, and improved acid suppression is thus unlikely to address partial- or nonresponse to PPI therapy. Furthermore, a majority of patients taking a PPI were already on twice-daily doses. Recent large clinical trials that evaluated more potent acid-suppressive agents, such as the dual-release PPI, dexlansoprazole, and the potassium-competitive acid blocker AZD0865 failed to show clinical superiority of these agents to traditional PPIs.27, 28

The pharmacological inhibition of TLESRs is a promising new approach to the treatment of GERD and in particular treatment of reflux symptoms that occur despite PPI therapy. Baclofen, a γ-aminobutyric acid type B (GABAB) receptor agonist, has been shown to inhibit the triggering of TLESRs, thereby reducing acid as well as weakly acidic and weakly alkaline reflux.29 The clinical use of baclofen is, however, limited by its adverse effects on the central nervous system, which include dizziness and somnolence. In a recent proof-of-concept study, the newly developed GABAB receptor agonist lesogaberan, which appears to act predominantly in the periphery, significantly reduced reflux symptoms in patients with GERD with symptoms despite PPI therapy, and was well tolerated.30

Another potential approach is treatment with a metabotropic glutamate receptor 5 (mGluR5) antagonist, which has been shown to inhibit TLESRs in animal studies.29 The mGluR5 negative allosteric modulator ADX10059 significantly reduced the number of symptomatic reflux episodes in patients with GERD in clinical trials.31 However, as with baclofen, clinical use of ADX10059 may be limited by commonly occurring adverse effects on the central nervous system, including dizziness and nausea.31

Antireflux surgery has also been shown to reduce the overall number of reflux episodes, including those that are acid and weakly acidic or weakly alkaline.32 However, a study of endoscopic anti-reflux therapy showed significant post-operative reductions in the number of acid reflux episodes only, with no significant decreases in the number of weakly acidic or weakly alkaline reflux episodes.33

One of the mechanisms through which weakly acidic or weakly alkaline reflux is believed to generate oesophageal symptoms is through mechanical stimulation, because large volumes of refluxate can trigger heartburn irrespective of its acidity. Oesophageal balloon distension commonly results in heartburn in patients with GERD, as well as in healthy volunteers, indicating that intra-oesophageal mechanical stimulation can trigger this reflux symptom.34, 35 However, mechanical stimulation does not explain why, in patients with GERD who are taking a PPI, the predominant symptom associated with symptomatic weakly acidic or weakly alkaline reflux episodes seems to be regurgitation, whereas in patients with GERD who are not taking a PPI, it seems to be heartburn.13

Proximal oesophageal extent of the refluxate is also associated with an increased likelihood of reflux symptoms. In the study by Zerbib et al., included in this review, 53% of proximal reflux events were associated with symptoms, compared with 34% of distal events (< 0.05).15 Weakly acidic and weakly alkaline reflux was as likely as acid reflux in the proximal oesophagus to cause reflux symptoms. Similarly, Emerenziani et al. observed that the frequency of symptomatic reflux events in the proximal oesophagus was more than twofold that in the distal oesophagus in patients with GERD, irrespective of acidity (acid reflux – proximal: 25%, distal: 11%; weakly acidic/alkaline reflux – proximal: 27%, distal: 8%; < 0.05).23 Bredenoord et al. observed that, compared with individuals without GERD, patients with GERD and a positive symptom–reflux association had a significantly higher proportion of reflux episodes that reached the proximal oesophagus (controls: 20%, vs. 36% and 34% in GERD patients with physiological and pathophysiological oesophageal acid exposure time, respectively; < 0.05).36

The proportion of reflux episodes that were acidic, vs. weakly acidic or weakly alkaline, in the 2 h following a meal was similar to that during the total 24-h monitoring period in patients with GERD on or off PPI therapy in the study by Blonski et al.12 However, when restricting the monitoring period to 20-min time windows immediately before and after a meal, Bredenoord et al. observed a higher proportion of acid reflux episodes in the postprandial than in the preprandial period (53% vs. 33%; P not reported).36 Similarly, Beaumont et al. observed a significantly enlarged postprandial acid pocket in the stomach of patients with GERD, compared with healthy volunteers, as well as an increased number of acid reflux episodes in the postprandial period in both healthy volunteers and patients with GERD.37

Our systematic review of the literature encountered several limitations. These included the absence in some studies of relevant baseline patient demographics, such as frequency and severity of reflux symptoms and whether or not these responded to PPI therapy, as well as inconsistencies between studies in the definitions and methods used to define associations between reflux episodes and reflux symptoms. Most studies included only individuals who had persistent reflux symptoms despite PPI therapy, and this will potentially have led to selection bias in the reported data. In addition, the analysis of reflux-related symptom episodes did not examine separately the different types of persistent symptoms. It is noteworthy that, despite these limitations, the results obtained by our systematic review are remarkably consistent.

In conclusion, weakly acidic gastro-oesophageal reflux comprises a substantial part of all reflux episodes in patients with GERD on PPI therapy. Whereas the total number of reflux episodes does not differ between patients on and off PPI therapy, in those patients who are on PPI therapy, weakly acidic reflux episodes form the large majority of all reflux episodes. In patients with GERD who have reflux symptoms despite PPI therapy, weakly acidic reflux episodes are the main cause of these symptoms. In future, drugs that prevent the refluxate from reaching the oesophagus may provide symptom relief in patients with GERD who have an unsatisfactory response to PPI therapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Declaration of personal interests: Professor G.E. Boeckxstaens has obtained unrestricted grants from AstraZeneca and has been a member of advisory boards of AstraZeneca. Professor A. Smout: None. Declaration of funding interests: Dr Anja Becher from Oxford PharmaGenesis™ provided medical writing support funded by AstraZeneca R&D Mölndal, Sweden. Professor G.E. Boeckxstaens is supported by a grant of the Flemish Government [Odysseus program, Fonds Wetenschappelijk Onderzoek (FWO), grant G.0905.08].

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Table S1. Acid, weakly acidic and weakly alkaline reflux episodes as a proportion of total reflux episodes in individuals with GERD on PPI therapy.

Table S2. Acid, weakly acidic and weakly alkaline reflux episodes as a proportion of total reflux episodes in individuals with GERD off PPI therapy.

Table S3. Correlation of acid versus weakly acidic/alkaline reflux episodes with symptoms in individuals with GERD on or off PPI therapy.

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