Correspondence to: Dr U. C. Nzeako, Gastroenterology and Hepatology (E19A), Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: Nzeako.Ugochukwu@mayo.edu
Background : Some patients with gastro-oesophageal reflux disease continue to experience symptoms despite therapy with proton pump inhibitors. One recently proposed cause is the occurrence of nocturnal acid breakthrough.
Aim : To investigate the relationship between acid breakthrough occurrence (nocturnal and daytime) and refractory symptoms among patients with gastro-oesophageal reflux disease on proton pump inhibitors.
Methods : Fifty-two consecutive patients with persistent symptoms of gastro-oesophageal reflux disease despite proton pump inhibitor therapy underwent 24-h pH study at the Mayo Clinic between January 1 and November 10, 1999. Relevant data were extracted and analysed.
Results : Fifty-two patients, 18 males and 34 females, were eligible for the study. The mean age was 53 ± 2.2 years. Thirty-seven patients (71%) had nocturnal acid breakthrough, and 36 (69%) had daytime acid breakthrough. Sixty per cent of patients experienced both nocturnal and daytime acid breakthrough, whereas 19% had neither. Among those with nocturnal and daytime acid breakthrough, only 36% and 33% of symptoms, respectively, were associated with gastro-oesophageal reflux episodes. The proportion of patients with symptoms and the mean symptom scores were not significantly different between those with and without acid breakthrough.
Conclusions : Gastric acid breakthrough occurs nocturnally and during the daytime in patients on proton pump inhibitor therapy. With less than 36% of refractory symptoms associated with gastro-oesophageal reflux, gastric acid breakthrough cannot explain symptom refractoriness to proton pump inhibitor therapy in a significant majority of patients evaluated by 24-h pH study.
Over 95 million Americans experience heartburn annually. In most, this is a transient or intermittent phenomenon, and this sub-group of individuals does not seek medical attention for their symptoms. Others suffer frequent bouts of bothersome heartburn for which they seek medical treatment. Therapy for gastro-oesophageal reflux disease (GERD) and reflux oesophagitis, the commonest causes of heartburn in these individuals, has been greatly improved by the introduction of proton pump inhibitors. By suppressing gastric acid production, proton pump inhibitors reduce or eliminate oesophageal injury during reflux episodes, resulting in the healing and relief of symptoms. However, some patients continue to experience symptoms despite therapy with proton pump inhibitors, prompting further studies to elucidate the potential causes of refractoriness to therapy in this group. One recently proposed cause is the occurrence of nocturnal acid breakthrough (NAB) while on proton pump inhibitor therapy.1,2
Recent studies have reported that up to 73% of individuals on proton pump inhibitors experience NAB.1–3 Among those receiving twice-daily dosing of omeprazole, 20 mg, or lansoprazole, 30 mg, NAB occurred approximately 5–11 h after the evening dose of proton pump inhibitor, usually between 01.00 and 02.00 h.1,2 Furthermore, it has previously been shown that, among GERD patients with symptoms refractory to proton pump inhibitors, the percentage of time that the gastric pH is less than four during the daytime does not differ significantly from that during the nocturnal period.4 However, no study has specifically examined the clinical impact of acid breakthrough occurring during the daytime on patient symptoms which persist despite proton pump inhibitor therapy.
Our study examines the clinical implications of NAB, particularly with regard to refractory patient symptoms. It also evaluates the clinical role of daytime acid breakthrough (DAB) and its relationship with patient symptoms.
Materials and methods
Fifty-seven consecutive patients with persistent GERD symptoms while on proton pump inhibitor therapy underwent 24-h pH study while on therapy between January 1 and November 10, 1999 at our institution. Data from 52 consenting patients were analysed. Symptoms included typical and atypical GERD symptoms, namely heartburn, dyspepsia, chest pain and cough. All patients had experienced symptoms for at least 5 months.
In all cases, the oesophageal sensor was located in the distal oesophagus, 5 cm proximal to the lower oesophageal sphincter, whilst the gastric sensor of the pH probe was located in the stomach, 15 cm below the oesophageal sensor. The pH studies were recorded using a digital recorder and computer-based system (Biostar pH, Sandhill Scientific, Denver, CO, USA).
Symptom diaries kept during the pH study and 24-h pH tracings were carefully reviewed and the following information extracted.
(a) The total number of symptom events reported by the patient during the 24-h pH study.
(b) The total number of reflux episodes recorded by the oesophageal sensor.
(c) The number of symptom events associated with (± 2 min) reflux episodes.
(d) The presence of acid breakthrough, with NAB defined as a gastric pH of less than four for any 1-h period between 22.00 and 08.00 h, 1 and DAB defined as a gastric pH of less than four for any 1-h period between 08.00 and 22.00 h.
(e) The names and dosages of any other acid-modulating medications (antacids, H2-blockers, etc.) being used concomitantly.
(f) Symptoms not occurring during acid breakthrough events. These were divided into those occurring between 22.00 and 08.00 h (among patients with or without NAB), and those occurring between 08.00 and 22.00 h (among those with or without DAB). Data from these patients were then further subdivided into those who had experienced NAB or DAB, and those who had not.
By calculating the average number of symptoms reported by each patient group, a ‘mean symptom score’ was obtained as a summary measure of symptom burden in each of these groups.
In order to evaluate the relationship between proton pump inhibitor dose and the occurrence of NAB or DAB, we combined patient data into three efficacy groups based on the daily dose of either omeprazole or lansoprazole (Table 1). In general, the doses of omeprazole and lansoprazole in each group have been shown to have similar efficacy in previous studies. Patients taking a total daily dose of omeprazole, 20 mg, or lansoprazole, 30 mg, were assigned to group 1. Patients taking a total daily dose of omeprazole, 40 mg, or lansoprazole, 60 mg, were assigned to group 2. Patients taking a total daily dose of omeprazole, 80 mg, or lansoprazole, 120 mg, were assigned to group 3.
Table 1. Daily doses of proton pump inhibitors (PPI) taken by patients during the study *
No. of cases†
No. with DAB‡
No. with NAB§
PPI efficacy group
Numbers in parentheses are percentages.
Total number of cases.
Number with daytime acid breakthrough (DAB).
Number with nocturnal acid breakthrough (NAB).
20 mg daily
20 mg b.d.
40 mg daily
40 mg b.d.
30 mg daily
30 mg b.d.
60 mg b.d.
Because gastric acid breakthrough was the event being studied, we defined an ‘event-related symptom’ as one occurring in association with an episode of acid breakthrough and, conversely, a ‘non-event-related symptom’ as one occurring during the period being studied (i.e. either between 08.00 and 22.00 h, or between 22.00 and 08.00 h), but not during an acid breakthrough episode.
Patient histories were reviewed for results of previous upper endoscopic biopsies and serologies for Helicobacter pylori status. Where possible, results were correlated with the occurrence of NAB, DAB and symptom burden.
Descriptive statistics were calculated for each group. Differences between groups of discrete or continuous data were computed using the t-test for unpaired observations or the Wilcoxon rank sum test. The chi-squared test or Fisher's exact test, where appropriate, was used to test proportional differences between categories. To estimate the relationship between any two groups of discrete data, Spearman's correlation coefficients were computed. Means are reported plus or minus the standard error. Two-tailed P values of less than 0.05 were considered to be significant. Logistic regression was performed to assess whether the patient age or number of symptom events could predict the occurrence of either NAB or DAB.
The study was approved by the Mayo Clinic Institutional Review Board.
Data from 52 patients were analysed. All patients were taking a proton pump inhibitor at the time of the 24-h pH study. The doses and types of proton pump inhibitor being used by the patients during the study are shown in Table 1.
Refractory symptoms included heartburn only (39 cases), heartburn and non-cardiac chest pain (nine cases) and cough, nausea and dysphagia (four cases).
The mean and median ages were 52.7 ± 2.2 years and 50 years, respectively (range, 17–86 years). There were 18 males and 34 females. Thirty-four patients had a history of hiatal hernia.
Five patients who had a history of Barrett's oesophagus all experienced NAB during their 24-h pH study; however, only one experienced symptoms in association with NAB.
Overall symptom–reflux correlation
Of a total of 519 symptom episodes reported by patients in this study, only 152 (29.3%) were associated with oesophageal reflux of acidic gastric contents, as recorded by the oesophageal sensor of the pH probe (Figure 1a).
Group analysis of GERD symptoms during NAB
The mean ages of those with (52.9 ± 2.3 years) and without (52.1 ± 5.0 years) NAB were not significantly different. The female to male ratio was 1 : 2 (Figure 1b).
A total of 209 reflux episodes were recorded during the 24-h pH recordings of those with NAB; 299 symptom episodes were also reported by these patients during the recording period, only 107 (35.8%) of which were associated with reflux episodes (Figure 1a).
Thirty-seven patients (71.1%) had NAB, whereas 15 did not. Of those with NAB, 17 (45.9%) had event-related symptoms, whereas 20 did not. Two of these 20 patients (10%) without event-related symptoms experienced non-event-related symptoms (Table 2). Thus, a total of 19 patients (51.3%) with NAB experienced symptoms at some point between 22.00 and 08.00 h (Table 3). Of the 17 patients who had event-related symptoms, nine also experienced non-event-related symptoms. In other words, a significant proportion (P=0.01) of NAB patients who had symptoms occurring in relation to gastric acid breakthrough experienced the same symptoms at times when no gastric acid breakthrough was occurring (Table 2).
Table 2. Relationship between occurrence of event-related and non-event-related symptoms among patients with nocturnal acid breakthrough (NAB) *
Event- related symptoms present
Event- related symptoms absent
Presence of event-related symptoms associated with significantly more non-event-related symptoms ( P =0.01).
Table 3. Occurrence of symptoms in patients with and without nocturnal acid breakthrough (NAB)
No significant association of symptoms between those with and without nocturnal acid breakthrough ( P < 0.89).
Eight of the 15 patients without NAB (53.3%) had symptoms during the same time period during which NAB, by definition, would usually occur (i.e. between 22.00 and 08.00 h). Thus, in this study of patients with GERD symptoms refractory to proton pump inhibitor therapy, the proportion of symptomatic patients did not differ significantly between the groups with and without NAB.
There was no significant gender difference between symptomatic and asymptomatic patients with NAB.
The mean symptom scores were 9.3 ± 2.8 episodes per 24-h period for the group with NAB and 11.6 ± 3.5 episodes per 24-h period for those without NAB, i.e. not significantly different (P < 0.64) (Figure 2a).
Efficacy analysis of the proton pump inhibitors, using the three pre-defined efficacy groups, showed a significant reduction in the proportion of patients with NAB as the proton pump inhibitor dose was increased (P=0.003) (Table 1; Figure 3). By logistic regression, neither the number of symptom events nor the patient age predicted the occurrence of NAB.
Acid breakthrough in the heartburn-only group
Thirty-nine patients, all on continuous proton pump inhibitor therapy, with a mean age of 50 ± 2 years, continued to have heartburn as their sole symptom. Twenty-five were female. We analysed data from this group to obtain information regarding the role of NAB in typical, but refractory, GERD symptoms.
A total of 226 reflux episodes were recorded during the 24-h pH recordings in this group. During the same period, 361 symptom episodes were reported, 114 (31.6%) of which were associated with a reflux episode.
Twenty-nine patients (74%) had NAB, of which 19 (65%) were female. Their mean symptom score was 10.8 ± 1.7, greater than that of those without NAB (4.8 ± 1.7; P=0.09), but this difference did not reach statistical significance. The mean symptom scores among patients known to have hiatal hernia, who are theoretically more likely to experience reflux, were also not significantly different between those with and without NAB (P=0.31).
Of those with NAB, 14 (48.3%) had event-related symptoms, whereas 15 did not. However, eight of these 15 patients (53.3%) experienced heartburn between 22.00 and 08.00 h, but at a time when no acid breakthrough was occurring (non-event-related symptom). Seven of the 14 NAB patients with event-related symptoms also experienced non-event-related symptoms during the pH study period.
Five of the 10 patients (50%) without NAB had symptoms between 22.00 and 08.00 h (i.e. the same time period during which NAB, by definition, would usually occur). This was not significantly different from the proportion of symptomatic patients in the NAB group.
H. pyloristatus and acid breakthrough
Information on the H. pylori status was available for 20 patients, only three (15%) of whom were H. pylori-positive. This probably reflects the known prevalence of H. pylori infection among patients presenting to the institution at which this study was performed (≈ 10%). Of the 17 H. pylori-negative patients, 14 (82.3%) had NAB and 13 (76.5%) had DAB. All H. pylori-negative patients with NAB and 11 patients (84.6%) with DAB experienced heartburn as their only complaint. One of the three H. pylori-positive patients had NAB, whereas two had DAB.
Acid breakthrough during the daytime (DAB)
Thirty-six patients experienced DAB. The average ages of those with (53.0 ± 2.4 years) and without (51.9 ± 4.6 years) DAB were not significantly different. A total of 282 reflux episodes were recorded during the 24-h pH recordings of patients with DAB; 384 symptom episodes were reported by this group of patients, 126 (32.8%) of which were associated with reflux episodes (Figure 1a).
Twenty-five patients with DAB (69.4%) experienced event-related symptoms, whereas 11 did not. Eighteen (72%) of those with event-related symptoms also had non-event-related symptoms. Of the 11 DAB patients who did not experience any event-related symptoms, eight (72.7%) had non-event-related symptoms, and three had no symptoms whatsoever during the pH study. Based on these observations (and unlike those with NAB), patients with DAB who had event-related symptoms were not more likely to experience further symptoms at times when no gastric acid breakthrough was occurring, than those with non-event-related symptoms.
Of the 16 patients without DAB, 50% experienced symptoms between 08.00 and 22.00 h. The proportion of patients who experienced symptoms was therefore not significantly different between those with and without DAB.
The mean symptom score for those with DAB (10.7 ± 4.2) was not significantly different from that of those without DAB (8.4 ± 4.4; P=0.63) (Figure 2a). Although more patients with DAB had event-related symptoms, the overall proportions of patients with or without DAB who experienced symptoms were not significantly different (P=0.30). No significant difference in the proportion of males and females was found between the groups with and without DAB (Figure 1b). Neither the number of symptom events nor the patient age predicted the occurrence of DAB.
Overall gastric acid breakthrough burden
Of the 52 patients studied, significantly more had both NAB and DAB (31 patients; 59.6%) than neither (10 patients; 19.2%) (Figure 2b). The mean symptom score for patients who had both NAB and DAB during the pH recording period (11.1 ± 3.21) was not significantly different from that for those with neither (13.2 ± 5.05; P < 0.70).
This study confirms the observation that gastric acid breakthrough on proton pump inhibitors is the norm rather than the exception.1–3 An important question arising from the description of NAB in patients on proton pump inhibitors is: what role does this physiological phenomenon play in the clinical setting? Our study attempts to provide some insights into the clinical impact and importance of NAB and, in particular, the symptoms associated with this breakthrough.
Our results show that, among patients complaining of persistent GERD symptoms refractory to proton pump inhibitor therapy, gastric acid breakthrough, be it nocturnal or daytime, is not temporally associated with significantly more symptoms. Furthermore, as a group, patients with gastric acid breakthrough are no more likely to exhibit these refractory symptoms than those without acid breakthrough. These findings suggest that gastric acid breakthrough per se does not account for the ‘refractory’ symptoms among patients who remain symptomatic on proton pump inhibitor therapy. Furthermore, regardless of the timing of gastric acid breakthrough (be it nocturnal or daytime), only 29.3–35.8% of refractory symptoms correlate temporally with the occurrence of oesophageal reflux in these patients (Figure 1a).
Previous studies have shown significantly greater oesophageal acid reflux episodes among patients with GERD and Barrett's oesophagus when compared with normal controls. However, there is little evidence to support the notion that the occurrence of gastric acid breakthrough invariably results in significantly more frequent oesophageal acid exposure in patients with these diseases, or that gastric acid breakthrough by itself results in symptom refractoriness to proton pump inhibitor therapy. In fact, a recent study showed no significant difference in the percentages of patients with GERD, Barrett's oesophagus and normal controls experiencing NAB while on proton pump inhibitor therapy (70%, 80% and 67%, respectively).1
Patients in our study who experienced symptoms during episodes of NAB (event-related symptoms) were significantly more likely to complain of further symptoms when no acid breakthrough was present. The reasons for these findings are unclear; however, a possible explanation could be that NAB associated with significant reflux may be more damaging because of the absence of gravity in the supine or lateral recumbent positions, and may be associated with greater contact time between the noxious refluxate and the oesophageal mucosa. Such damaged and inflamed oesophageal mucosa may then be sensitive to non-acidic refluxate occurring at other times. However, this explanation is made less plausible by our finding that patients with symptoms were no more likely to have NAB, nor did more symptoms occur during periods of NAB. Thus, another possible explanation may be that the presence of ‘refractory’ symptoms while on proton pump inhibitors identifies a subset of patients in whom visceral hyperalgesia may play a role. Other aetiologies may also play a role in the causation of these symptoms. For instance, duodeno-gastro-oesophageal reflux has recently received more attention as a possible factor in the symptomatology of GERD, and synergism between the duodenal refluxate (conjugated bile acids) and the gastric refluxate (acid/pepsin) in symptom causation has been the topic of some discussion. Interestingly, it has been reported that, in humans, duodeno-gastro-oesophageal reflux under certain circumstances can result in symptoms of GERD without oesophageal mucosal injury.5 Non-erosive reflux disease, of which symptomatic duodeno-gastro-oesophageal reflux may be a component, is an area of increasing interest among researchers. Functional heartburn may also explain some of these symptoms.6 Certainly, more studies are needed to clarify findings such as these.
Some recent articles have attributed refractory and recurrent symptoms among patients on proton pump inhibitor therapy to NAB.7,8 Other studies have shown that the administration of a bedtime H2-receptor antagonist decreases the occurrence of NAB.3,9,10 Although a few anecdotal reports and patient marketing surveys have suggested that patients with symptoms refractory to proton pump inhibitors obtain symptomatic relief by additionally using over-the-counter H2-receptor antagonist preparations, such as Zantac 75 and Pepcid AC,7,9 no well-designed study has investigated the efficacy of this approach in the management of refractory symptoms, particularly as it relates to the elimination of gastric acid breakthrough by these H2-receptor antagonists. In fact, a review of the data from one of these studies9 shows that despite being symptomatic with typical heartburn symptoms at the time of enrolment, none of the patients studied manifested significant nocturnal oesophageal acid reflux during the baseline 24-h ambulatory pH study. Thus, the reported efficacy of the addition of an H2-receptor blocker to proton pump inhibitor therapy may be true and proven for the reduction of breakthrough gastric acidity, but remains unvalidated in terms of benefit for symptomatic oesophageal disease. Furthermore, data reported in that study9 showed that the vast majority of acidic oesophageal reflux occurred in the upright position, presumably during the daytime, in all the treatment groups studied, suggesting that significant oesophageal irritation or damage by acid might be occurring during the daytime as well.
The findings in our study provide the first critical examination of these issues. Because gastric acid breakthrough was only temporally correlated with refractory symptoms in about one-third (29.3–35.8%) of cases, these would be the only ones likely to derive possible benefit from further acid reduction with H2-receptor antagonists. This further suggests that the majority of patients with symptoms refractory to proton pump inhibitors (based on our data, at least 64.2% of cases) are unlikely to benefit from additional H2-receptor antagonist therapy. Because the occurrence of acid breakthrough did not correlate with symptom refractoriness, any observed symptom improvement noticed among patients given H2-blockers in addition to proton pump inhibitor therapy may not be directly related to the effect of H2-receptor antagonists in reducing acid breakthrough. Placebo-controlled studies may be necessary to evaluate the true effects of this approach to therapy.
Only five patients in our study had a history of Barrett's oesophagus, and four of these experienced both types of acid breakthrough. All five patients were symptomatic and therefore the presence of Barrett's oesophagus, with its associated decrease in oesophageal sensitivity to acid reflux,11,12 was not considered a source of bias for our study results.
Although the majority of H. pylori-negative study patients experienced gastric acid breakthrough (82.3% NAB, 76.5% DAB), as expected from previously published reports,13 symptom frequency did not appear to be significantly different between those with and without H. pylori infection. However, the sample sizes were too small for firm conclusions to be drawn from our data.
Interestingly, our study showed that 59.6% of patients with refractory symptoms had both NAB and DAB, whereas only about 19% had neither (Figure 2b). Symptom scores were not significantly different between these two groups. Thus, other, as yet undescribed, phenomena appear to be responsible for refractory symptoms in the majority of GERD patients on proton pump inhibitors.
Two recent studies have examined the association between reflux symptoms and reflux events for acid and non-acid reflux using combined multichannel intraluminal impedance and pH monitoring.14,15 In one of these,14 of a total of 148 symptom events reported by study patients, 75 were associated with reflux, and 73 were reported by patients when no reflux event (whether acid or non-acid) was occurring. This study also showed that, whilst heartburn was significantly more common in association with acid reflux (64%), it also occurred in 27% of instances in association with non-acid reflux. These findings lend direct support to those in our study by showing that: (i) symptoms occur due to non-acidic refluxate, as may take place in patients on proton pump inhibitors; and (ii) patients with GERD symptoms may experience some of these at times when no reflux is occurring, thus implying that the administration of additional acid-blocking agents (either proton pump inhibitors or additional H2-receptor antagonists in those already on proton pump inhibitors) may not yield symptomatic benefit based on any efficacy in eliminating acid breakthrough. Similar results have been reported in a more recently published study,15 and are in complete agreement with our findings.
Because our study is based on 24-h pH recordings, which represent an attempt to obtain a snapshot in time of the usual daily gastro-oesophageal events, it has inherent limitations. Therefore, based on the current study, we cannot exclude the potential additive role of acid breakthrough with other, more important, but as yet undiscovered, factors in causing symptom refractoriness. However, until mechanisms are available to monitor the internal gastric and oesophageal milieu for several consecutive days, findings based on 24-h pH studies remain the best available way to evaluate the effects of the luminal milieu on disease manifestations in these organs.
In conclusion, gastric acid breakthrough is a phenomenon that occurs in the majority of patients on proton pump inhibitor therapy. In patients with refractory symptoms while on proton pump inhibitor therapy, various symptom indices studied were no different between those with and without acid breakthrough, and the occurrence of acid breakthrough did not predict those in whom symptoms were found during 24-h pH recording. Among those with acid breakthrough on proton pump inhibitor therapy, refractory symptoms were related to reflux events in only 29.3–35.8% of instances, suggesting that other, as yet undetermined, factors were also at play in the majority of these patients. An increased proton pump inhibitor dose resulted in a decrease in the occurrence of gastric acid breakthrough. Our findings imply that, although the addition of H2-receptor blockers to proton pump inhibitor therapy has been shown to reduce or eliminate acid breakthrough, it cannot be assumed that this will yield symptomatic relief, nor that symptomatic relief is consistently related to the additional acid-suppressing action by these agents. Well-designed placebo-controlled studies are needed to evaluate patients who report symptom relief with additional H2-receptor antagonist therapy while on proton pump inhibitors, in order to confirm that this relief is in fact due to the further control of gastric acid resulting from the additional medication.
The authors thank all Mayo Clinic gastroenterology assistants for their contribution in the performance of the 24-h pH studies.