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Summary

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

When patients with the typical reflux symptoms of heartburn, regurgitation, or both, undergo endoscopy, up to 75% will not have endoscopic oesophagitis or evidence of Barrett's oesophagus. These patients have been described as having endoscopic negative or, more commonly, non-erosive reflux disease (NERD).

Patients without oesophagitis, but with a positive pH test, can be diagnosed with gastro-oesophageal reflux disease (GERD). Some experts also consider a response to proton pump inhibitor therapy as proof of GERD in a patient with the correct symptoms and a negative endoscopy.

Patients with normal acid exposure, but who report symptoms with a majority of their reflux episodes documented during an ambulatory pH study, have also been considered to have NERD, although others have labelled them as having ‘functional heartburn’.

Finally, there are some patients who have reflux symptoms and respond to reflux therapy, but have no demonstrable reflux by either endoscopy or ambulatory reflux testing. Whether these patients are part of the GERD spectrum or have another diagnosis is not clear.

It seems that the most widely used definition of functional disease (the Rome II criteria) would include these patients as having functional heartburn, as it was defined as ‘greater than or equal to 12 weeks of either continuous or intermittent symptoms of burning retrosternal discomfort or pain without pathologic GERD, achalasia, or other motility disorders with a recognized pathologic basis’.

This article reviews potential differences in pathophysiology between erosive oesophagitis and NERD; explores whether symptoms can help distinguish NERD patients from erosive oesophagitis patients; and explores the evaluation and therapy of these patients.


Pathophysiology of non-erosive reflux disease

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

Gastro-oesophageal reflux disease (GERD) is defined as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the oesophagus.1 The aetiology of reflux centres around dysfunction of the lower oesophageal sphincter (LES) and, in some patients, problems with distal oesophageal motility. It is well established that patients with severe oesophagitis and Barrett's oesophagus frequently have low baseline LES pressures.2 These patients usually, but not always, have pathologic amounts of acid exposure when studied with ambulatory pH testing.3 Non-erosive reflux disease (NERD) patients have lower oesophageal acid exposures, on average, and are more likely to have a normal acid exposure. For example, over 90% of patients with Barrett's oesophagus and more than 75% of oesophagitis patients were demonstrated to have pathologic acid exposure, compared with only 45% of symptomatic patients without oesophageal damage.4 In addition to lower acid exposures, the oesophageal exposure to other gastric substances, including bile, is less common in NERD patients, compared with those with oesophagitis and more complicated reflux disease.5

The percentage of patients with reflux symptoms and a negative endoscopy, who have pathologic acid exposure or a positive symptom index, varies greatly. A recent study suggested that about 50% of patients studied in a tertiary centre had pathologic acid exposure. Of those with normal acid exposure, 37% had a positive symptom index.4 The perception of individual reflux events is similar, or perhaps enhanced, in patients with NERD, compared with events in erosive oesophagitis (EE), and those reflux events tend to extend more proximally in NERD patients.6 Oesophageal hypersensitivity, both to acid and nonspecific stimulation with an intra-oesophageal balloon, has been hypothesized as the aetiology of symptoms in NERD, particularly in the patients with normal overall acid exposure.7 NERD patients have a greater response to the modified acid perfusion test (Bernstein test) than do patients with EE, Barrett's oesophagus or normal controls.8 Why a patient with an intact oesophageal mucosa experiences increased sensitivity to both refluxed acid and acid perfusion (in a Bernstein test) is not known, but some experts contend that NERD patients have an abnormality in tissue resistance to acid in the oesophagus.9 This could be due to oesophageal sensitization by repeated acid exposure, as at least one investigator has reported that this ‘hypersensitivity’ is resolved with acid suppression therapy.10 Others have suggested than non-oesophageal factors (both physiologic and psychologic) might influence this sensitivity. For example, Meyer et al. found that fat infusion into the duodenum increased oesophageal sensitivity to infused acid.11 Psychologic stress does not seem to increase oesophageal acid exposure, but may lower perception levels to acid and hence increase symptoms.12

It appears that reflux may have a different pattern if it causes oesophagitis, and particularly if it results in more significant complications, such as strictures and Barrett's oesophagus. In a study of 220 GERD patients, patients with complicated reflux disease, EE or NERD had similar amounts of daytime reflux, but the nocturnal (supine) reflux was more common in the patients with more severe disease (Figure 1).13

image

Figure 1. pH findings in 220 patients with GERD. There was a statistical relationship (P < 0.05 to P < 0.001) between levels of damage and total acid contact time (ACT) and with supine ACT, but there was no relationship in upright ACT. Figure adapted from Frazzoni et al.13

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Symptoms do not distinguish EE from NERD

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

In a study of nearly 1000 patients presenting with typical reflux symptoms, 32% had EE.14 More importantly, neither physician evaluation nor a validated questionnaire that segregated patients into mild, moderate, or severe symptoms were predictive of EE. Likewise, in one of the studies validating the Los Angeles Scale for oesophagitis grading, patients with normal endoscopies were not distinguished from the various grades of oesophagitis by a validated questionnaire.3 On the other hand, there may be some phenotypic clues as to whether a patient might have NERD. It is clear that older patients are more likely to have EE and oesophagitis, while NERD is more common in younger patient groups.15 There is a trend towards more NERD in women compared with men, as well as more psychologic comorbidity in patients with NERD.16 The effect on quality of life, related to symptoms, is similar in patients with NERD and those with EE.17

Response of NERD symptoms to GERD therapy

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

The most common parameter for judging the efficacy of a GERD therapy is its ability to heal EE. This healing can be expected in up to 90% of patients treated with a once-daily proton pump inhibitor (PPI) for 4–8 weeks.18, 19 Higher grades of oesophagitis are more difficult to heal, but once healed can be maintained in remission with medical or surgical therapy.20, 21 Even in EE, where the association between symptoms and mucosal damage seems more intact, resolution of oesophagitis is not always predicted by symptoms. For example, a study that compared rabeprazole 20 mg daily to omeprazole 20 mg daily found an 8-week healing of oesophagitis in more than 90% of patients, but only 73–76% had improvement and 31–38% resolution of symptoms.22 As noted above, patients with EE have more acid exposure than those with NERD, so it would seem that symptoms in NERD patients would be easier to control. Actually, the opposite is true. In a study of patients with and without EE, treated with omeprazole 20 mg daily for 4 weeks, complete symptom relief was achieved in 48% of the EE patients and only 29% of the NERD patients.17 A recent report looked at the ability of esomeprazole to control heartburn over 2 weeks in patients with varying degrees of oesophageal damage and acid exposure.23 They used an end point of ‘total control of heartburn’ defined as a day without heartburn for 24 h. Although this was a 4-week trial, the proportion of days free of heartburn stabilized after about 4 days. Esomeprazole was more likely to result in total control of heartburn in patients with EE (71–80%) compared with NERD (52–67%). Interestingly, patients with a positive pH test had total control in 65–73%, and those with a negative test also had good levels of total control (51–58%). Many NERD patients have various other symptoms that they associate with GERD, and even when heartburn, regurgitation, or both respond, the other symptoms often persist.24

There have been several additional studies reporting the results of PPI therapy in patients with NERD. Bate et al. reported a placebo-controlled trial of omeprazole 20 mg daily in patients with reflux symptoms and a negative endoscopy.25 After 4 weeks of therapy, daytime heartburn was more likely absent in patients on omeprazole (81% vs. 46%). Rabeprazole daily was found to be superior to placebo for the relief of symptoms in NERD patients in two separate studies. The first reported satisfactory relief of symptoms in 57% of patients treated with either 10 or 20 mg daily of rabeprazole, compared with 32% of patients on placebo.26 There was no difference between the two doses of rabeprazole. In another similar study, daytime heartburn was more likely to be controlled with rabeprazole 20 mg daily compared with placebo (79.5% vs. 59.2%) as was nighttime heartburn (80.3% vs. 68.3%).27 An Asian study comparing rabeprazole 10 mg to esomeprazole 20 mg daily in patients with NERD reported statistically identical, satisfactory symptom control with the two medications (rabeprazole 98%; esomeprazole 81%).28

Lind et al. reported an important study that enrolled patients with heartburn and a negative endoscopy.29 They performed 24-h pH testing, but the data were not used to select patients for the trial. Patients were then randomized to omeprazole 10 or 20 mg daily or placebo for 4 weeks. Omeprazole 20 mg daily resulted in resolution of symptoms in 61%, omeprazole 10 mg in 49%, and placebo in 24%. The pH data were then used to evaluate response to therapy in these patients by dividing patients’ initial acid exposure into 4 groups (<4.0%, 4.0–5.9%, 6.0–9.9% and >10%). The two doses of omeprazole were equal in the patients with the least (normal) level of acid exposure, but were each better than placebo (Figure 2). In patients with pathologic amounts of acid exposure, there was a better dose–response curve with the full (20-mg dose) compared to lower-dose omeprazole, which likewise outperformed placebo. Perhaps the most interesting finding in the study was that the highest rate of symptom control was obtained in patients with the greatest (>10%) acid exposure. In another study with pH data, Richter et al., actually used an abnormal pH test (pH <4.0 for >5% of 24 h) as an entry criteria for another study of 2 doses of omeprazole (10 mg and 20 mg daily) vs. placebo.30 In that study, acid regurgitation was absent at the end of 4 weeks of therapy in 68% (20 mg), 60% (10 mg), and 43% (placebo). In a large study of esomeprazole 40 mg daily in patients with NERD, heartburn-free days were more common on drug treatment (63–66%) compared to placebo (36–46%) (P < 0.001).31 Despite the statistical difference, the small therapeutic gain of esomeprazole over placebo was somewhat disappointing. A systematic review was recently published that combined data from 7 trials and found pooled response rates at 4 weeks of 56% in EE and 37% in NERD (P < 0.0001).32 Just as in EE, PPI therapy is superior to histamine2-receptor antagonist (H2RA) therapy in treating NERD. For example, both 15 mg and 30 mg daily of lansoprazole were superior to 150-mg twice-daily ranitidine in patients with NERD.33

image

Figure 2. Proportion of patients with sufficient control of heartburn after 4 weeks of therapy segregated by pretreatment oesophageal acid exposure. Statistics from these data were not presented in the paper, but it is clear that the response to placebo was stable, regardless of acid exposure. The response to PPI was greatest in patients with the most oesophageal acid exposure. Figure adapted from Lind et al.29

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The lower response rate in NERD could be due to one of several factors. It is possible that the symptoms in these patients have nothing to do with GERD and are related to other factors. An alternative, interesting hypothesis was presented in a report suggesting that postprandial gastric acid secretion was actually more difficult to control in NERD compared to EE.34 The basis for this finding is currently unknown and fairly surprising, as patients with NERD at baseline have less oesophageal acid exposure than patients with EE.35 Patients with reflux symptoms, a normal endoscopy, and normal overall acid exposure may still respond to PPI therapy. In a small study of patients with typical symptoms and normal testing, 11 of 18 improved on PPI therapy.36 This improvement was much more likely if there was a positive symptom index and quite unusual in patients with a negative symptom index. A larger version of this trial is needed to help sort this out further, but the data suggest that patients with normal acid exposure and a negative symptom index benefit little from PPI therapy.

Much of our understanding of the long-term maintenance of GERD stems from trials in patients who initially had EE. Those trials indicate that most patients require chronic therapy and that daily PPI therapy is the preferred treatment.3, 17 There are some new data that may indicate a different course for NERD. In a European trial of over 700 patients with heartburn and normal or nearly normal endoscopies, patients were treated with omeprazole or ranitidine to bring their symptoms under control and then managed with intermittent courses of therapy.37 Many patients (47%) were able to be continued on intermittent therapy for a year with most being off therapy for at least 6 of the 12 months. Omeprazole therapy was superior to ranitidine in the initial control of symptoms, but equal numbers of patients on each drug were able to complete the year of intermittent therapy. In another study, patients with NERD had their symptoms controlled with PPI therapy and then were randomized to esomeprazole 20 mg, 40 mg, or placebo at most once daily. Patients were much more likely to complete the trial on either dose of esomeprazole (20 mg: 92%; 40 mg: 89%) compared with placebo (58%). The average intake of esomeprazole was about one dose every 3 days.38 Similar results were reported in a trial of rabeprazole 20 mg daily used on an as needed basis.39 The authors used a 100-point visual analogue scale and found satisfaction at the end of 6 months in both patients with NERD (mean = 97, range 50–100) and mild EE (mean = 90, range 10–100). They also found that patients averaged a dose of medication about every third day. Even a lower dose of rabeprazole (10 mg) was found to keep the majority of NERD patients in satisfactory control when given on an on-demand basis.40

Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

Traditionally, GERD has been considered excluded in patients who have completely negative testing, including endoscopy and pH testing (acid exposure and symptom index). Is this necessarily true? Using pH testing to exclude GERD has become the subject of considerable concern. Reasons for this concern include the finding of normal acid exposure in up to 29% of patients with documented oesophagitis and differences found in the simultaneous acid exposure recorded by two attached probes.41, 42 When ambulatory pH testing was compared in a 2-week course of omeprazole in patients with and without oesophagitis, some patients with normal pH tests responded to the medication, but more importantly, some patients with well-documented EE had a negative pH test.43 In addition, a recent report repeated pH testing on patients who had an initial negative test.44 If the patient's symptoms had been typical or worse than typical during their first pH test, 22% of second tests were positive, while 55% of studies were abnormal if the patients said their day was ‘better than typical’ during the first test. Whether impedance testing,45, 46 and more prolonged testing using the radiotelemetry (Bravo) system,47 will improve the ability of ambulatory reflux testing to exclude GERD remains to be seen.

Based on many of the studies discussed above, it seems that patients with a negative pH test and endoscopy, who have convincing symptoms that respond to a trial of PPI, probably do have GERD. This is actually a relatively unusual patient, when considering the typical reflux symptoms of heartburn and regurgitation. Atypical GERD symptoms are more of a problem, especially given preliminary data from recent placebo controlled trials finding similar improvement with b.d. PPIs and placebo in ear, nose and throat symptoms and with asthma that is presumed to be reflux related.48, 49

Conclusion

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References

Many, perhaps most, patients with GERD symptoms will have neither EE nor Barrett's oesophagus on endoscopy, and hence are potentially classified as NERD. Symptoms do not reliably predict which patients have oesophagitis, and reflux may be confirmed in this patient group with ambulatory reflux testing, response to therapy (PPI test) or both. Symptoms in patients with NERD are just as severe as in EE and are often more difficult to control. PPI therapy is the treatment of choice for patients with GERD, regardless of the state of their oesophageal mucosa. It is clear that symptom control in NERD is often inferior to symptom control in EE. Finally, the concept of functional heartburn is not fully defined. Undoubtedly, there are patients who have reflux symptoms that respond to PPI, yet have normal mucosa and normal acid exposure. It is reasonable to suppress these patients’ symptoms with PPI therapy, regardless of their underlying (or lack of underlying) pathophysiology.

References

  1. Top of page
  2. Summary
  3. Pathophysiology of non-erosive reflux disease
  4. Symptoms do not distinguish EE from NERD
  5. Response of NERD symptoms to GERD therapy
  6. Can a patient with a negative endoscopy, pH test, and symptom index still have GERD?
  7. Conclusion
  8. References
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