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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

Background:

The effect of Helicobacter pylori eradication on reflux oesophagitis is unclear.

Aim:

To study the effect of H. pylori eradication on oesophageal acid exposure and disease severity in patients with reflux oesophagitis.

Methods:

Patients with reflux oesophagitis and H. pylori infection were recruited for 24-h oesophageal pH-metry. They were then randomly assigned to receive either treatment for H. pylori eradication (1-week omeprazole-based triple therapy, followed by 7-week omeprazole) or omeprazole alone (8-week omeprazole). Uninfected patients were recruited as controls. Endoscopy, pH monitoring and symptom assessment were repeated at 26 weeks.

Results:

Forty patients (25 H. pylori-positive and 15 uninfected) with erosive oesophagitis were studied. Fourteen were randomized to receive treatment for H. pylori eradication and 11 to receive omeprazole alone. There was no difference in the percentage of time the oesophageal pH < 4 before and 26 weeks after treatment among the three groups. However, the percentage of time the oesophageal pH < 2 (P=0.01) and pH < 3 (P=0.02) was significantly increased in patients receiving treatment for H. pylori eradication. Three (21%) patients in the group receiving treatment for H. pylori eradication had worsening of reflux oesophagitis.

Conclusions:

H. pylori eradication increases oesophageal acid exposure and may adversely affect the clinical course of reflux disease in a subset of patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

In recent years, epidemiological studies have reported a negative association between Helicobacter pylori infection and gastro-oesophageal reflux disease (GERD), implying a protective effect of H. pylori against the condition.1–7 The eradication of H. pylori has been associated with the emergence of reflux oesophagitis in some patients with duodenal ulcer.8 Among patients with GERD, those with H. pylori infection have less severe oesophagitis than those without the infection.1, 5, 6 The protective effect of H. pylori infection can probably be attributed to corpus gastritis, which inhibits gastric acid secretion and hence reduces oesophageal acid exposure.9 It has also been shown that H. pylori augments the acid-suppressive effect of proton pump inhibitors,10, 11 such that GERD patients infected with H. pylori have a higher healing rate of reflux oesophagitis and better symptomatic relief during treatment than uninfected patients.12

Despite the possible protective effect of H. pylori in GERD, it has been reported that long-term proton pump inhibitor treatment accelerates the development of atrophic gastritis in patients with persistent H. pylori infection.13 Therefore, it has been recommended that H. pylori should be eradicated before long-term proton pump inhibitor is initiated for GERD.14 However, whether H. pylori eradication will aggravate the disease activity in GERD patients is still unclear. Follow-up studies on the oesophageal acid exposure and clinical severity in GERD patients receiving H. pylori eradication treatment are sparse. Schwizer et al. has reported, in a randomized controlled trial, that H. pylori eradication helps to prolong the disease-free interval in GERD patients.15

This study aimed to evaluate the changes in oesophageal acid exposure, reflux symptoms and the severity of oesophagitis after eradication of H. pylori in patients with GERD. It was conducted in a population in which a strong negative association existed between GERD and H. pylori.7

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

Patients and endoscopy

From February 1998 to May 1999, consecutive patients presenting with weekly attacks of heartburn or acid regurgitation were screened for the presence of erosive oesophagitis. Patients were excluded if they had a current or past history of peptic ulcer disease, previous gastric surgery, had received anti-Helicobacter therapy, or had received proton pump inhibitor for any duration within 4 weeks before entry into the study. Upper endoscopy (Olympus GIF-100 or XQ-200 endoscope) was performed for all recruited patients to exclude coexisting peptic ulcer and to assess the severity of reflux oesophagitis using a modified Savary–Miller grading system.16 In this study, grade 1 oesophagitis referred to the presence of single or isolated erosion(s) on one mucosal fold, grade 2 to non-circumferential erosions on more than one mucosal fold with or without confluence, grade 3 to circumferential erosions and grade 4 to the presence of stricture or ulcer. The presence of hiatus hernia was also noted. The diagnosis of H. pylori infection was confirmed if both biopsy urease test and histology were positive. Biopsy specimens were obtained from the antrum and corpus for histological assessment. Neutrophil and mononuclear cell infiltration (0–3) and atrophy were scored according to the visual analogue scale of the updated Sydney classification.17 A combined inflammatory score (0–6), which was the sum of the neutrophil and mononuclear cell infiltration scores, was used to assess the severity of gastritis. Histological assessment was performed by a single pathologist. A blood sample was obtained to determine the cagA status by the Western blot technique (Helico Blot 2.0, Genelab, Singapore). Patients with documented endoscopic oesophagitis were then recruited for 24-h ambulatory oesophageal pH monitoring and symptom assessment. Written consent was obtained from all recruited patients.

Oesophageal manometry and pH study

Patients were instructed to stop antisecretory and prokinetic agents for at least 10 days prior to the study, except for the use of antacid. After an overnight fast, oesophageal manometry was performed using an eight-channel, silicone rubber, low-compliance, pneumohydraulic, perfused manometric assembly with sleeve sensor (Dentsleeve, South Australia). The manometric assembly was passed transnasally and the position of the lower oesophageal sphincter was determined using the station pull-through technique on 0.5-cm intervals. After removal of the manometric catheter, a monocrystalline antimony pH catheter (Synectics Medical, Sweden) was then passed transnasally and the electrode was positioned 5 cm above the proximal margin of the lower oesophageal sphincter. Twenty-four-hour ambulatory oesophageal pH monitoring was then carried out. Patients were instructed to take meals and work according to their daily routine, except that coffee, fruit juice and antacids were avoided. Data acquisition was performed using a portable data logger (Microdigitrapper MK III, Medtronic, Denmark). Semi-automated analysis was performed with the aid of commercially available software (EsopHogram, Medtronic, Denmark). Any reflux episode, defined as pH < 4, with a duration of less than 5 s was considered as an artefact. Parameters of oesophageal acid exposure included the DeMeester score and the oesophageal acid exposure time (percentages of time oesophageal pH below 4, 3 and 2). The analysis of oesophageal acid exposure was further categorized into total, supine and 2-h post-prandial periods. All analyses were performed by a single investigator (JCYW) who was blind to the H. pylori status, treatment group and severity of reflux oesophagitis of the patients.

Symptom assessment

The severity of reflux symptoms during the last week before pH recording was evaluated by a validated questionnaire for heartburn and acid regurgitation. The questionnaire was composed of frequency and severity of acid regurgitation and heartburn, respectively. They were rated semi-quantitatively by the patient using a four-point Likert scale system (frequency: 0, asymptomatic; 1, less than one episode per week; 2, one or more episodes per week; 3, one or more episodes per day; severity: 0, asymptomatic; 1, mild; 2, moderate; 3, severe). If there was a discrepancy between the ratings of heartburn and acid regurgitation, the higher score was used. A combined score (0–6) was then obtained from the sum of the frequency and severity scores.

Randomization of treatment

After baseline oesophageal pH recording, H. pylori-infected patients were randomized to receive either H. pylori eradication therapy or omeprazole treatment. Randomization was conducted by the drawing of closed envelopes. In the group treated with H. pylori eradication therapy, patients received a 1-week course of omeprazole, 20 mg, amoxicillin, 1 g, and clarithromycin, 500 mg, twice daily. This was followed by 7 weeks of omeprazole, 20 mg daily, for the treatment of GERD. In the group treated with omeprazole alone, H. pylori-infected GERD patients received one week of omeprazole, 20 mg twice daily, followed by 20 mg daily for 7 weeks. Uninfected GERD patients were recruited as controls. They also received 1 week of omeprazole, 20 mg twice daily, followed by 20 mg daily for 7 weeks. No maintenance acid suppressive drug was given after 8 weeks in all three groups of patients, but they were given alginate-containing antacids on an as-required basis. The reflux symptoms of patients were reviewed 8 and 26 weeks after treatment. Follow-up endoscopic assessment, with biopsy urease test and pH monitoring, was performed at the end of 26 weeks. During follow-up pH monitoring, patients were advised to take similar meals as in the baseline pH studies.

Statistical analysis

The primary outcome measure of this study was the oesophageal acid exposure. The secondary outcome measures included the reflux symptom score and the grading of erosive oesophagitis. The parameters of oesophageal acid exposure, symptom scores and grades of oesophagitis between the three groups before and 26 weeks after treatment were compared by the Kruskal–Wallis H-test. The Wilcoxon signed-rank test was used to detect differences before and 26 weeks after treatment within each group. All values were presented as means (s.d.), and a two-tailed P value of less than 0.05 was regarded as statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

Twenty-five H. pylori-infected GERD patients with weekly reflux symptoms and endoscopic oesophagitis were recruited in this study (Figure 1). Fourteen patients were randomly assigned to receive eradication therapy and 11 received omeprazole only. All 14 patients given eradication therapy had successful eradication of the bacteria as confirmed by both histology and biopsy urease test. Fifteen patients without H. pylori infection were recruited as the control group. The three groups were comparable with respect to age, sex ratio, body mass index, prevalence of hiatus hernia and severity of reflux disease (Table 1). Twenty-one (84%) H. pylori-positive patients were cagA-positive.

image

Figure 1. . Flow chart of management and follow-up assessment. OAC: omeprazole, 20 mg b.d., amoxicillin, 1 g b.d., and clarithromycin, 500 mg b.d.

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Table 1.  . Baseline characteristics of patients Thumbnail image of

Change in oesophageal acid exposure after H. pylori eradication

All three groups of patients showed similar oesophageal acid exposure times and DeMeester scores (Table 2) at baseline. There was no difference in the total percentage of time the oesophageal pH < 4 or the DeMeester scores among the three groups (Table 2, Figure 2) at 26 weeks. However, the total percentages of time the oesophageal pH < 2 and pH < 3 were significantly increased in the eradication therapy group. The increase in oesophageal acid exposure occurred primarily during the upright and post-prandial periods. During the post-prandial period, there was a significantly higher oesophageal acid exposure at pH < 2 (Table 2, Figures 3a,b). The oesophageal acid exposure during the supine period was unaltered after H. pylori eradication.

Table 2.  . Comparison of symptom scores and oesophageal acid exposure time Thumbnail image of
image

Figure 2. . Comparison of DeMeester scores between patients given eradication therapy (HpE) and patients treated with omeprazole alone (Hp+). Mean values are represented as horizontal lines. Patients with worsening of reflux oesophagitis are represented as broken lines. *Comparison of DeMeester scores between week 0 and 26 in HpE group, P=0.29 (Wilcoxon signed-rank test). #Comparison of DeMeester scores between week 0 and 26 in Hp+ group, P=0.36 (Wilcoxon signed-rank test).

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image

Figure 3. . (a) Comparison of percentage time pH < 3 before (left column) and after (right column) Helicobacter pylori eradication. (b) Comparison of percentage time pH < 2 before (left column) and after (right column) H. pylori eradication.

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Change in severity of reflux symptoms and oesophagitis after H. pylori eradication

All three groups of patients showed comparable reflux symptom scores before treatment, and there was no significant change in symptom score in all groups at 26 weeks after treatment (Table 2). There was also no difference in the median grade of reflux oesophagitis among the three groups of patients before and after treatment (Table 3). Three (21%) male patients in the eradication therapy group showed worsening of reflux oesophagitis, accompanied by an increased oesophageal acid exposure and symptom score, whereas none of the patients in the group treated with omeprazole alone or in the H. pylori-negative group showed a deterioration in reflux oesophagitis.

Table 3.  . Comparison of oesophagitis in different groups of patients Thumbnail image of

Change in gastritis after H. pylori eradication

The eradication therapy group and the group treated with omeprazole alone had comparable baseline gastritis scores (Table 4). Eight (57%) and seven (63%) patients had moderate to severe corpus gastritis in the eradication therapy group and the group treated with omeprazole alone, respectively. Patients infected by cagA-positive H. pylori had significantly more severe gastritis than those with cagA-negative infection at both the antrum (median score, 3.5 vs. 2.5; P < 0.01; Mann–Whitney U-test) and the body (median score, 3 vs. 2; P < 0.01; Mann–Whitney U-test). Gastritis scores were significantly reduced at both the antrum and the corpus in patients treated with eradication therapy 26 weeks after treatment (P < 0.01; Wilcoxon signed-rank test; Table 5), but were unaltered in patients treated with omeprazole alone. It should be noted that all three patients with disease exacerbation after eradication therapy had severe antral gastritis at baseline; two also had severe corpus gastritis and one had moderate corpus gastritis. None of the patients was found to have gastric atrophy.

Table 4.  . Baseline gastritis scores of HpE and Hp+ patients before treatment Thumbnail image of
Table 5.  . Gastritis scores of HpE and Hp+ patients at 26 weeks after treatment Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

We set out to evaluate the changes in oesophageal acid exposure, reflux symptoms and the severity of oesophagitis after eradication of H. pylori in patients with GERD. In contrast to previous studies, our results showed that the eradication of H. pylori led to an increase in oesophageal acid exposure and adversely affected the clinical course in a subset of patients with oesophagitis over a period of 6 months.

The impact of antibacterial therapy on the severity of GERD has been a subject of dispute. Tefera et al. monitored the oesophageal acid exposure and clinical events in GERD patients after H. pylori eradication therapy, and found no difference in both the percentage of the total time the oesophageal pH < 4 and the reflux symptom scores at 12 weeks.18 Axon et al. reported that H. pylori eradication had no deleterious effect on symptomatic relapse rate and time to first relapse among GERD patients.19 However, in another intriguing study, Schwizer et al. observed an earlier relapse for GERD patients with persistent H. pylori infection compared to those receiving eradication therapy, although both oesophageal acid exposure and gastric acidity were unaltered with H. pylori eradication.15 They suggested that H. pylori infection might lower the pain threshold in patients without oesophagitis.

Our study design differed from the aforementioned studies in several aspects. Firstly, we used more stringent criteria for GERD. Only patients with erosive oesophagitis and frequent reflux symptoms were recruited. Patients with endoscopy-negative reflux disease were excluded as they were more likely to have `acid-sensitive oesophagus' instead of pathological gastro-oesophageal reflux.20 We used the oesophageal acid exposure instead of symptom relapse as the primary outcome measure because it is the gold standard quantifiable marker of gastro-oesophageal reflux.21, 22 We also arranged follow-up oesophageal pH studies for all patients at 26 weeks so that comparison of oesophageal acid exposure among the three groups was more appropriate. As the spontaneous healing of oesophagitis may occur in a minority of patients, we also recruited an H. pylori-negative control group so that any natural regression of the severity of reflux disease could be observed.

In contrast to previous studies, we observed a modest increase in oesophageal acid exposure after H. pylori eradication. The duration of oesophageal pH ≤ 3 was significantly prolonged after eradication therapy. These changes could be missed by conventional methods of analysis, i.e. the percentage of time pH < 4 and the DeMeester score. Moreover, three patients showed worsening of oesophagitis in addition to increased oesophageal acid exposure, whereas none of the patients in the non-eradicated and uninfected groups showed disease exacerbation. The relatively high incidence of disease exacerbation in our study may be due to the presence of severe gastritis in many patients. Over half of the H. pylori-infected patients had moderate or severe corpus gastritis. There is increasing evidence that the inhibitory effect of H. pylori infection on gastric acid secretion depends on the pattern and extensiveness of gastritis. Patients with severe corpus-predominant gastritis or pangastritis have more profound suppression of gastric acid secretion than those with antrum-predominant gastritis.23 As a result, post-eradication rebound of gastric acid secretion predominantly occurs in patients with severe corpus gastritis. We postulate that a subset of reflux patients with hiatus hernia and corpus gastritis is prone to disease exacerbation after H. pylori eradication. Due to the small number of patients in the study, these observations need to be confirmed by studies with larger sample sizes so that sub-group analysis can be performed.

In this study, H. pylori eradication conferred no benefit on symptom relapse as all three groups showed similar symptom scores at 26 weeks. In conjunction with the finding of Schwizer et al.'s study,15 we suggest that H. pylori infection plays little role in modifying the pain threshold of patients with erosive oesophagitis, in contrast to those with endoscopy-negative reflux disease. In patients with erosive disease, however, H. pylori eradication may aggravate oesophageal acid exposure and result in an exacerbation of oesophagitis.

Lastly, it is noteworthy that H. pylori eradication predominantly increases upright and post-prandial oesophageal acid exposure, whereas oesophageal acid exposure during the supine period is unaffected. There are two possible explanations for this finding. Firstly, H. pylori eradication predominantly causes rebound in meal-stimulated gastric acid secretion with relative sparing of nocturnal basal acid secretion.24 Secondly, H. pylori eradication provokes more frequent acid reflux during transient lower oesophageal sphincter relaxation, which is the major mechanism of upright and post-prandial gastro-oesophageal reflux.25 It would be worthwhile to further evaluate the effect of H. pylori eradication on transient lower oesophageal sphincter relaxation.

In conclusion, H. pylori eradication is associated with an increase in oesophageal acid exposure and may adversely affect the clinical course of reflux disease in a subset of patients.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References

This work was supported by a grant (No. CUHK 4260/98M) from the Research Grant Committee of Hong Kong and the Hong Kong Society of Gastroenterology.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. References
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