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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

The control of oesophageal acid exposure through gastric acid inhibition, as the basis for gastro-oesophageal reflux disease (GERD) treatment, arose from the apparent pH dependency of erosive oesophagitis and relationship to GERD symptoms.

The current perception is that reflux disease is an entirely acid-mediated condition, and antisecretory therapies, particularly proton pump inhibitors, are the treatment of choice for patients with erosive and non-erosive reflux disease. A positive patient response to an empiric trial of proton pump inhibitor (PPI) therapy, or the ‘PPI test’, is commonly suggested as a method of GERD diagnosis.

Recent studies have modified our understanding of the relationship between oesophageal acid exposure and GERD pathology, manifestations and symptoms. Whereas the use of PPIs to reduce oesophageal acid exposure in patients with erosions is associated with increased healing rates, non-erosive reflux disease patients are less likely to have an abnormal oesophageal pH profile. Patterns of oesophageal acid exposure, particularly nocturnal oesophageal acid exposure, have been linked to increased disease severity. Non-acidic reflux and the effect of PPIs on this parameter, including bile reflux and the toxicity of bile acids, may also be an important factor in GERD.

This article explores some of these assumptions, practices and relationships, including: the association between oesophageal acid exposure and erosive and non-erosive gastro-oesophageal reflux disease; the effect of PPIs on oesophageal acid exposure in erosive oesophagitis patients; the influence of nocturnal acid secretion in GERD and the use of PPIs to control this parameter; the relevance of the PPI test for reflux disease diagnosis; and PPI influence on non-acidic reflux.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Proton pump inhibitors (PPIs) provide remarkable suppression of gastric acid secretion; this translates into clinically relevant management of gastric ulcers, duodenal ulcers and gastro-oesophageal reflux disease (GERD). Given the safety and tolerability of the PPIs, it is not surprising that they are among the most prescribed drugs in North America. This short review will address several assumptions that have been made which have contributed to the use of PPIs and will include the relationship of acid exposure to erosive and non-erosive GERD, the effect of PPIs on acid exposure in erosive oesophagitis (EE), the influence of PPIs on nocturnal acid secretion, the clinical relevance of the ‘PPI test’ and the interesting possibility that PPIs may influence non-acidic reflux.

What is the relationship of acid exposure to erosive GERD?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Early in the development of drugs that suppressed acid secretion, the paradigm of heartburn was related to the exposure of gastric acid to the oesophagus. The amount of acid exposure in the oesophagus was directly linked to the severity of oesophagitis and the intensity of the symptoms of heartburn and chest pain. The use of gastric acid suppressive agents in treating erosive disease is based on the early studies, which showed that exposure to acid and pepsin at low pH levels (<4) was injurious to the oesophageal mucosa, and that this level of injury decreased with increasing oesophageal pH.1 A pH threshold was established by Schindlbeck et al., with the percentage of time with oesophageal pH <4 shown to have a sensitivity of 93% and specificity of 93% for GERD.2

The relationship of acid exposure to mucosal injury was established for the severe grades of oesophagitis. The greater the duration of time with an oesophageal pH <4, the greater the extent of the injury to the oesophagus, notably shown by Vaezi and Richter using 24-h oesophageal pH monitoring in 20 healthy subjects, 30 patients with GERD and 20 patients with Barrett's oesophagus (BE).3 As the severity of GERD increased, there was a graded increase in the percentage of time oesophageal pH <4: 2% in healthy subjects, 7% in patients with GERD with non-erosive reflux disease (NERD), 15% in patients with EE, 15% in patients with uncomplicated BE and 23% in patients with complicated BE.3 Lundell et al., in a study validating the Los Angeles (LA) classification of EE, found that, in general (but not with every grade), the percentage of time with pH <4 increased with increasing EE severity: grade A, 9%; grade B, 14%; grade C, 12%; grade D, 19%.4 The percentage of time with pH <4 in patients with normal endoscopies but with the GERD symptoms of heartburn, acid regurgitation and abdominal pain (i.e. NERD) was 7%.4

Early in PPI development, the potential risks of long-term PPI exposure mandated limiting use of omeprazole to patients with severe EE. As the long-term safety of omeprazole became understood, the use of PPIs was extended to patients with heartburn and less oesophageal injury. The success of PPIs continued the idea that extention of the supposition of acid is the only aetiology of heartburn and GERD.

Joelsson and Johnsson evaluated oesophageal acid exposure (EAE) in 190 patients with heartburn and acid regurgitation, compared with 50 normal subjects. In normal subjects, the percentage of acid exposure time was 1% of the 24-h monitoring period. This percentage was significantly higher in patients with NERD and EE vs. controls: 3% and 11% of the 24-h period, respectively. No subjects in the control group experienced reflux symptoms ≥ grade 2. Most investigators would consider 3% near, if not within, the normal range. In contrast, 50% of patients with NERD and a higher percentage of patients with EE (67%) reported symptoms ≥ grade 2.5 Although abundant recent research challenges the hypothesis that all symptomatic GERD is related to EAE, the acid hypothesis of GERD remains an ingrained prejudice.

What are the differences between acid exposure in erosive and non-erosive GERD?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

With the emergence of the concept of non-erosive GERD, the relationship of symptoms to EAE has undergone re-examination. It is commonly observed that non-erosive patients are less likely to respond to acid suppressive therapy. In patients with EE, abnormal EAE is high (75%), while only 45% of patients with non-EE have abnormal EAE.6 The non-erosive group of patients can be subdivided into two groups: those with elevated levels of EAE who would be expected to respond to acid suppression; and those with low EAE, in whom an alternative hypothesis regarding oesophageal symptoms seems necessary, as acid suppression in this group has little physiologic rationale and empiric trials of acid suppression do not provide adequate symptom relief.6 Numerous trials have shown that NERD patients can experience symptoms as severe as patients with EE. In the study by Joelsson and Johnsson, although patients with NERD had normal EAE (<4% of a 24-h period), half of these patients experienced reflux symptoms ≥ grade 2, compared with 67% of patients with EE who had abnormal EAE (>10% in 24 h).5 Given the data on symptom and reflux patterns, it is perhaps not surprising that patients with NERD are less likely to respond to acid suppression than patients with EE. One 4-week trial of omeprazole 10- and 20-mg therapy in 509 patients, without endoscopic signs of oesophagitis, produced complete heartburn relief rates in only 31% and 46% of patients, respectively.7 Although significant differences have been seen between omeprazole and esomeprazole, with respect to symptom relief in patients with EE, a review of the results of three multicentre, randomized, double-blinded, 4-week trials in NERD patients (n = 2645) given esomeprazole 40 mg, esomeprazole 20 mg or omeprazole 20 mg daily found that, although >60% of patients achieved heartburn resolution, the percentages did not differ significantly between treatments.8 This is well below the expectation of symptom resolution following the PPI therapy in patients with EE.

Perception of reflux events also causes problems with interpretation of the relationship between EAE events and the symptom of heartburn. Martinez et al. found the perceived rate of reflux events was 4% in NERD, 3% in EE and 2% in BE patients.6 Cilala et al. found that 56% of patients with NERD and 90% of patients with EE had abnormal acid exposure. As expected, when three pH sensors are positioned in the oesophagus, the majority of reflux events only expose the distal electrode (EE 73% and NERD 84%). The distribution of sensed events between patients with erosive and non-erosive reflux differs as patients with NERD have a higher proportion of sensed proximal reflux events (37% of events sensed) compared with patients with EE (13% of events sensed), suggesting a different origin of symptom generation.9

What is the effect of PPIs on acid exposure in EE?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Countless studies with all of the PPIs demonstrate that gastric acid suppression is associated with a decrease in EAE and healing of EE. During acid suppressive therapy, a longer percentage time with oesophageal pH <4 is associated with a lower 8-week EE healing rate (P < 0.05; r = 0.83).10 A decrease in EAE following the PPI therapy has become so well accepted as part of our medical knowledge that PPI changes in EAE are of little clinical or academic interest. An example of the decrease in EAE is demonstrated in a study by Galmiche et al. of 92 patients with GERD with either NERD or LA grade A–C EE and treated with either rabeprazole or omeprazole. After 7 days of treatment with 20-mg rabeprazole a day or 20-mg omeprazole a day, the EAE for 24 h fell from baseline values of 12% (rabeprazole) and 12% (omeprazole) to 2% and 3%, respectively (Figure 1).11 In a meta-analysis of healing with PPIs, 84% ± 11% of patients were healed with 12 or fewer weeks of therapy when healing was defined as endoscopic resolution of EE.12 The information regarding symptom resolution is more difficult to obtain as diary records of symptoms usually only cover the first 4 weeks of treatment. One study demonstrated 4-week healing of 76% for 40-mg esomeprazole a day, 70% with 20-mg esomeprazole a day and 65% with 20-mg omeprazole a day, with complete symptom resolution obtained in 65%, 61% and 57%, respectively.13 Although this meta-analysis shows fairly good concordance, it is somewhat surprising that there is a discrepancy between healing and symptom resolution.

image

Figure 1. Reduction of per cent time with oesophageal pH <4 with 7 days of treatment with rabeprazole 10 mg, rabeprazole 20 mg, omeprazole 20 mg and placebo.11

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Nocturnal gastric acid breakthrough

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Nocturnal gastric acid breakthrough (NAB) is defined as recovery of gastric pH <4 for at least 1 h in the overnight monitoring period. Peghini et al. studied the effects of b.d. omeprazole 20 mg in 17 patients with GERD compared with 16 male volunteers given omeprazole 20 mg b.d. and 12 volunteers given lansoprazole 30 mg b.d. Nocturnal acid breakthrough was found in three quarters of all participants within 12 h of taking the evening PPI dose.14 The same group of investigators evaluated gastric and oesophageal pH studies in 76 patients taking b.d. PPIs (omeprazole 20 mg or lansoprazole 30 mg) and 31 normal subjects given the same regimen to determine if the recovery of acid secretion resulted in periods of nocturnal oesophageal reflux.15 There was no statistically significant difference in NAB among patient groups: 69% of patients with GERD, 80% of patients with BE and 68% of normal subjects. Oesophageal pH <4 during NAB was observed in 31% of 24-h pH studies in patients with GERD, 50% of the pH studies in patients with BE and 9% of normal subjects (P < 0.03 for BE and GERD patients vs. controls). Given the high EE healing rates seen with PPIs, the clinical importance of these findings may be small. However, it is clear that, even given a morning and an evening dose of a PPI, subjects will still have significant gastric acid. Gastric acid is refluxed into the oesophagus during the nocturnal hours significantly more often in patients with GERD than in healthy subjects.15 The presumptive mechanism of NAB is related to the normal diurnal variation in plasma histamine levels. High histamine levels at about 4:00 am may stimulate gastric acid through the histamine pathway rather than the food-stimulated gastrin pathway. The challenge of suppressing nocturnal acid secretion may be related to differences in the degree of proton pump binding when there is a burst of gastric acid secretion following a meal compared with the slower crescendo of acid secretion, which occurs during the night as histamine levels increase.

There are few good studies assessing the physiology of NAB and the impact on EAE. In patients taking a PPI b.d., 70% of normals and GERD patients have NAB.14 Katz et al.15 evaluated the prevalence of NAB associated with distal oesophageal acid reflux in patients on PPIs b.d. Although a retrospective study design was used and the controls were not on PPI therapy, the results are important. NAB was found in 69% of GERD patients and 68% of controls. Abnormal EAE during the periods of gastric acid breakthrough was seen in 31% of patients with GERD and only 2% of normal subjects, suggesting an increased effort should be directed at the control of nocturnal gastric acid secretion in patients with GERD.

One approach to management has been the administration of an evening dose of PPI with the intention of inactivating acid pump function closer to the period of concern. Pehlivanov et al.16 found 20 mg of rabeprazole given before the evening meal was more successful at suppressing NAB than the usual morning dose (baseline 8 h; morning dose 4 h; evening dose 3 h). A similar dosing concept explored the potential control of NAB with omeprazole (40-mg) dosing combined with sodium bicarbonate (IR-OME) given once a day or b.d.17 Pantoprazole 40 mg was the comparator. On day 1, NAB was high (patients with NAB: IR-OME 88% and pantoprazole 97%). After six morning doses of PPI, NAB was seen in 53% of patients taking IR-OME and 78% of patients taking pantoprazole 40 mg. An additional evening dose of PPI decreased the percentage of patients with nocturnal gastric acid exposure to 12% in the IR-OME group and 71% in the pantoprazole group. Additional effort is required to determine the significance and management strategy surrounding the observations regarding NAB.

Returning to the proposed diurnal variation of histamine as the physiology of NAB, it is interesting to note that the addition of a bedtime dose of an H2 receptor agonist (H2RA) to PPI therapy has been shown to be effective in controlling NAB. Xue et al. investigated the effects of ranitidine 300 mg, famotidine 40 mg or nizatidine 300 mg at bedtime, added to a b.d. regimen of PPI therapy (either omeprazole 20 mg or lansoprazole 30 mg).18 Three groups of patients were evaluated: those receiving PPI therapy alone (group 1; n = 60); those receiving PPI treatment plus the H2RA bedtime dose (group 2; n = 45); and a smaller group of patients tested while taking PPIs alone and then with the addition of the H2RA (group 3; n = 11). The median percentage of time with nocturnal intragastric pH >4 was significantly lower in group-1 patients (51%), compared with patients in group 2 (96%; P < 0.0001). This measure also increased significantly in group 3 after the bedtime H2RA dose was added (from 55% to 97%; P = 0.0013). NAB was seen in 82% of patients in group 1 and only 40% of patients in group 2 (P < 0.0001). Mean duration of EAE during episodes of NAB was significantly longer in group 1 patients (42 min) vs. group 2 patients (18 min; P = 0.04).18 Results from a study by Fackler et al., however, suggest that tachyphalaxis to the acid suppression effects of H2RAs may limit the long-term efficacy.19 In this trial, the gastric and oesophageal pH of 18 healthy subjects and 16 patients with GERD were tested at baseline, after 2 weeks of b.d. omeprazole 20-mg therapy, and 1, 7 and 28 days after the addition of ranitidine 300 mg once daily at night to the PPI regimen. Although all four on-therapy measurements showed a significant decrease in per cent time with supine pH <4 compared with the baseline measurement (P = 0.001), only on the day 1 measurement did the addition of an H2RA to the PPI regimen result in a significant reduction in per cent time with supine gastric pH <4 compared with PPI alone (P < 0.001). This improved efficacy over the PPI regimen alone was lost with continued H2RA dosing as shown by tests conducted at 1 week and 1 month.19

Trial of PPIs to diagnose GERD

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Perhaps it is inevitable that a medication class as safe and effective as the PPI class of drugs would lead to empiric trials in patients without the diagnostic testing usually associated with establishing a proper diagnosis. This has been encouraged and studied in patients with heartburn symptoms on the basis of the hypothesis that a rapid symptomatic response to standard PPIs in patients with symptoms of GERD validates a diagnosis of GERD. Several assumptions occur in the studies used to support this hypothesis. Firstly, it is assumed that the GERD symptom profile used to enroll patients in the study is efficacious in enriching the study population of patients with acid-mediated GERD, while limiting the inclusion of patients with other gastric acid-related diseases. Secondly, it is expected that most patients with GERD respond to standard PPI therapy. Thirdly, in patients with symptoms of GERD, other acid-sensitive diseases are unlikely to be responsible for their symptoms. Fourthly, symptom response (subjective) is equivalent to oesophageal pH and endoscopy (objective) for the diagnosis of GERD. Based on the preceding discussion, the assumptions necessary to accept the hypothesis that response to a PPI test can diagnose GERD are flawed. Numans et al.20 extracted 15 studies from 5771 published manuscripts for a meta-analysis to determine the correlation of symptom response to a PPI and objective testing for GERD. It is disappointing, but perhaps expected, that 38–90% of suspected patients responded to the PPI test. In those patients with objective evidence of GERD by diagnostic testing, 20–40% did not improve with a trial of PPI therapy. The authors concluded that the PPI test did not confidently establish a diagnosis of GERD. Despite this evidence-based medicine evaluation, current practice patterns of using the PPI test to diagnose GERD will most likely continue.

Do PPIs influence non-acidic reflux?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

The underlying pathophysiology of GERD depends on the movement of gastric contents into the oesophagus. Gastric acid causes the most difficulty with the induction of symptoms, but non-acidic reflux has become an important research interest. The success of PPIs in the management of patients with GERD raises the important question as to whether PPIs decrease the amount of non-acidic reflux, decrease the symptoms associated with non-acidic reflux or change the gastric refluxant. Several mechanisms may be proposed. As gastric fluid accompanies the secretion of acid, it is possible that suppressing gastric acid secretion decreases gastric volume. PPIs could enhance oesophageal motility or improve gastric emptying, thereby decreasing gastro-oesophageal reflux (GER). The alkaline gastric environment obtained by gastric acid suppression may precipitate bile acids, making them less toxic, or PPIs may influence the spectrum of bile acids in the stomach.

Does suppression of gastric acid secretion decrease gastric volume?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Early in the development of the H2RAs, dramatic changes in the volume of gastric fluid led to the utilization of H2RAs as preoperative medication for many patients, especially obstetric emergencies. As preoperative preparation includes decreasing the risk of volume, as well as acid aspiration, most of the research into the effect of PPIs on gastric volume has come from the anesthesia literature.

The two parameters defining aspiration risk are a gastric pH of 3 or less and a fluid volume of at least 0.4 mL/kg. Single-dose ranitidine was superior to double-dose rabeprazole or lansoprazole for both pH (5 vs. 4) and volume (0.1 mL/kg vs. 0.22 mL/kg). However, both rabeprazole and lansoprazole were superior to placebo.21 PPIs do decrease gastric volume, but not to the same extent as H2RAs, and the PPI effect probably represents an incremental, rather than substantial, change in volume.

Do PPIs enhance oesophageal motility?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Healing of severe oesophagitis improves the disturbed oesophageal motility associated with marked inflammation, whether the healing occurs in relationship to PPIs or H2RAs. In addition, both omeprazole22 and pantoprazole23 decrease bile reflux into the oesophagus, suggesting PPIs may improve oesophageal motility as part of their mechanism of action (Table 1).23 After 28 days of pantoprazole, there was no effect on oesophageal physiology including contraction amplitude, duration of contractions, area under the plasma concentration–time curve (AUC – mmHg × s) and slope (mmHg/s). PPIs have no demonstrable effect on oesophageal motility.

Table 1.  Effect of 28 days of pantoprazole 40 mg therapy on oesophageal motility23
 BaselineDay 28P-value
Contraction amplitude, mmHg36 ± 335 ± 30.368
Duration of contraction, second4 ± 0.154 ± 0.110.691
Propulsive waves, %66 ± 458 ± 40.037
AUC, mmHg × s60 ± 560 ± 50.877
Slope, mmHg/s38 ± 336 ± 30.266

Do PPIs improve gastric emptying?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Enhanced gastric emptying decreases the volume of gastric contents, which should decrease the amount of GER. Rabeprazole, given at 20 mg a day for 7 days,24 did not change solid-phase gastric emptying, myoelectric activity measured by electrogastrography or gastric water volume to fullness. A more recent study by Tougas et al.25 evaluated omeprazole (20 mg b.d. × 14 days), and actually discovered delayed gastric emptying expressed by duration of lag phase (P < 0.007), time to gastric half emptying (P < 0.003), gastric retention at 60 min (P < 0.002) and gastric retention at 120 min (P < 0.04). Although this study can be faulted in demonstrating impaired gastric emptying, as it did not evaluate gastric emptying at 4 h, there is definitely no improvement in gastric emptying. The effect seen with omeprazole may explain why PPIs have been shown to decrease bile reflux but do not seem to effect oesophageal motility. It may be that, with a delay in gastric emptying, there is a change in antroduodenal motility that prevents bile from coming into the stomach – hence, the finding of decreased bilirubin in the stomach seen by Marshall et al.22

Is the alkaline environment of the stomach caused by PPI-precipitated bile?

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

Bile acid injury in the stomach has been an area of controversy since the popularity of the Billroth II anastamosis was used in the treatment of peptic ulcer disease. Endoscopic observation identified bile reflux into the gastric remnant and associated erythematous and edematous mucosa. Controversy occurred because many of the patients with obvious ‘gastritis’ had no symptoms. This information was used to advance the argument that bile did not cause the upper gastrointestinal symptoms. The issues surrounding bile acid effects in the gastrointestinal tract are complex, and bile acid-induced changes in the stomach are being re-evaluated. The complexity of pathophysiology occurs because of the varying ability of bile acids to induce symptoms26 and the unique solubility pH of each bile acid. As the gastric pH changes with acid secretion, or acid suppression by PPIs, the possibility of gastric mucosal injury changes, as precipitated bile acids do not injure gastric mucosa. At a neutral pH, the most gastrotoxic bile acids are unconjugated dihydroxy bile acids. Acidification precipitates unconjugated and glycine-conjugated bile acids and is linked with less toxicity. Increasing pH may increase the potency of some bile acids, particularly the unconjugated forms. However, an acidic pH does not affect taurine conjugate toxicity – hence, the finding of high concentrations of taurine conjugates in patients with an increased acid reflux. A pH between 4 and 7, then, may allow for oesophageal exposure to bile acids in a two-phase state: ionized and un-ionized.

An additional component of bile acid physiology is the formation of secondary bile acids through bacterial action.27, 28 Secondary bile acids are increased in the gastric fluid of patients taking PPIs, indicating the likelihood that changes in gastric pH allow bacterial contamination of the small bowel with the effect of changing the composition of the bile acid pool. The secondary bile acids have been suggested to be related to the dysplasia associated with Barrett's dysplasia. The available information does not support a beneficial role of PPIs in the problem of bile reflux gastritis and oesophageal symptoms of GERD associated with duodenogastro-oesophageal reflux (DGER). In fact, PPIs may enhance bile toxicity.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References

The aetiology of GERD is commonly and somewhat mistakenly considered only in terms of the presence of excess or abnormal gastric acid reflux into the oesophagus. However, although some studies have shown lower EAE in patients with NERD than in those with injury to the oesophageal mucosa,4 patients with non-erosive disease can experience symptoms as severe as patients with EE.5, 29 Thus, whereas GERD symptoms are related to abnormal EAE in some patients with NERD, in others they are not. PPI therapy decreases EAE in patients with EE,11 and this reduction is associated with increased rates of EE healing.10 Nocturnal acid reflux, associated with more severe oesophageal injury,30, 31 is influenced by PPI treatment, and PPI formulations and dosing regimens can be manipulated to provide better nocturnal acid suppression. The success of PPIs in healing EE and relieving symptoms in erosive patients has led to the use of empiric PPI therapy in patients with GERD. This PPI test for GERD has become a mainstay of reflux disease diagnosis. However, it is of questionable use20 and reinforces the assumption that all reflux is acid mediated. Other factors, including DGER and chemical sensitivity of the oesophagus, may also contribute to GERD pathology, and symptoms have been shown to occur with non-acid reflux.32 PPIs influence non-acidic reflux in interesting ways that may influence symptoms in GERD patients.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. What is the relationship of acid exposure to erosive GERD?
  5. What are the differences between acid exposure in erosive and non-erosive GERD?
  6. What is the effect of PPIs on acid exposure in EE?
  7. Nocturnal gastric acid breakthrough
  8. Trial of PPIs to diagnose GERD
  9. Do PPIs influence non-acidic reflux?
  10. Does suppression of gastric acid secretion decrease gastric volume?
  11. Do PPIs enhance oesophageal motility?
  12. Do PPIs improve gastric emptying?
  13. Is the alkaline environment of the stomach caused by PPI-precipitated bile?
  14. Conclusion
  15. References
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