Increased gastric acid secretion after Helicobacter pylori eradication may be a factor for developing re ux oesophagitis

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1 Aliment Pharmacol Ther 2001; 15: 813±820. Increased gastric acid secretion after Helicobacter pylori eradication may be a factor for developing re ux oesophagitis T. KOIKE, S. OHARA, H. SEKINE, K. IIJIMA, K. KATO, T. TOYOTA & T. SHIMOSEGAWA Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan Accepted for publication 12 January 2001 SUMMARY Background: The role of acid secretion in re ux oesophagitis which may develop after H. pylori eradication is not well known. Aim: To investigate the participation of altered gastric acid secretion and the presence of hiatal hernia in the development of re ux oesophagitis after eradication therapy for H. pylori. Subjects and Methods: A total of 105 patients with H. pylori infection, but without re ux oesophagitis at the time of eradication therapy, were followed prospectively for 7 months after the clearance of this microorganism. Gastric acid secretion was assessed by endoscopic gastrin test, and the presence of hiatal hernia by endoscopy. Results: Re ux oesophagitis developed in 11 out of 105 (10.5%) patients when examined at 7 months after the eradication therapy. The incidence was correlated signi cantly with the increase in gastric acid secretion after the eradication of H. pylori, and was signi cantly higher in the patients with hiatal hernia (20%) than in those without it (0%). Conclusions: Increased acid secretion after H. pylori eradication is an important risk factor of re ux oesophagitis, especially in patients with hiatal hernia. INTRODUCTION Recent studies have shown that re ux oesophagitis may develop after the successful treatment of Helicobacter pylori infection. 1, 2 We and others have reported previously that H. pylori eradication causes an alteration in gastric acid secretion. 3±8 Although gastric acid secretion has been accepted as a key factor in the pathogenesis of re ux oesophagitis, the relationship between changes in acid secretion and the development of re ux oesophagitis after H. pylori eradication is not well known. 9 Recently, we have developed a convenient method for measuring stimulated gastric acid secretion. The method, named endoscopic gastrin test, can be 1 Correspondence to: Dr T. Koike, Department of Gastroenterology, Tohoku University Graduate School of Medicine, 1±1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980±8574, Japan. tkoike@rd5.so-net.ne.jp performed in a short time concomitantly with the routine endoscopic examination. 10 It has been con rmed in a previous study that the results of the endoscopic gastrin test are highly reproducible and are correlated signi cantly with the peak acid output determined by the conventional gastric acid stimulation test. In the present study, using the endoscopic gastrin test, we investigated whether changes in gastric acid secretion after H. pylori eradication play a role in the development of re ux oesophagitis. In addition, we investigated the in uence of the presence or absence of hiatal hernia, an important pathogenic factor of re ux oesophagitis. 11±13 SUBJECTS AND METHODS Subjects A total of 105 with H. pylori infection in whom re ux oesophagitis had been ruled out endoscopically (76 men and 29 women, mean age 51.5 years) were followed up Ó 2001 Blackwell Science Ltd 813

2 814 T. KOIKE et al. prospectively for 7 months after the eradication therapy for H. pylori. Among the 105 patients, 39 had gastric ulcers (non-prepyloric ulcer), 36 had duodenal ulcers, 11 had atrophic gastritis, and 19 had early gastric cancer which had been treated by endoscopic mucosal resection. None of the patients had taken non-steroidal anti-in ammatory drugs or antibiotics, or proton pump inhibitors within 4 weeks before the beginning of the study or after the eradication therapy. All patients were asked to stop taking H 2 -receptor antagonists at least 48 h before the study entry and subsequently thereafter. The patients in whom the eradication of H. pylori had failed were excluded. On each visit, the patients were inquired about the quality and severity of gastrointestinal symptoms. The present study was performed according to the Declaration of Helsinki and informed consent was obtained from all patients. This study was approved by the Ethics Committee for the Human Research of Tohoku University School of Medicine. H. pylori eradication At entry, each patient underwent upper gastrointestinal endoscopy including endoscopic gastrin test for the evaluation of gastric acid secretion, and mucosal biopsies of the antrum and body of the stomach for histology and rapid urease testing. After this initial assessment, the patients received the following medications for 1 week: omeprazole 20 mg/day, metronidazole 500 mg b.d., and clarithromycin 200 mg b.d. The H. pylori status was reassessed by a combination of histology, rapid urease testing, and 13 C-urea breath testing 7 months later. 14 Gastric acid secretion Detailed procedures of the endoscopic gastrin test have been reported previously. 10 Brie y, after an overnight fast, the subjects received an intramuscular injection of tetragastrin (Gastopsin, Nippon Kayaku, Tokyo, Japan) at a dose of 4 lg/kg and underwent endoscopic examination about 15 min later. After the endoscope was introduced into the stomach, pooled gastric uid was aspirated and discarded. Gastric uid secreted between 20 and 30 min after tetragastrin injection was aspirated and collected under direct visualization, together with routine endoscopic examination of the stomach and duodenal bulb. Finally, biopsy specimens were taken as indicated, and the endoscope was removed. The sample volume collected over the 10-min period was recorded, and the H + concentration was determined by titration. The acid output during the 10 min was calculated by multiplying the volume by the H + concentration, and the endoscopic gastrin test value was expressed as H + meq/10 min. We have shown previously that endoscopic gastrin test values correlated very well with the peak acid output determined by the conventional method of stimulated gastric acid secretion (correlation coef cient 0.92) and that the reproducibility was ne (coef cient of variation 5.6%). In the present study, gastric acid secretion was evaluated by the endoscopic gastrin test before and 7 months after the H. pylori eradication. Changes in endoscopic gastrin test values were classi ed into four groups: markedly increased (increase by more than 2 meq/10 min), increased (increase by between 0.5 and 2 meq/10 min), no change (increase or decrease by less than 0.5 meq/10 min), and decreased (decrease by more than 0.5 meq/10 min). Histology Biopsy specimens taken from the gastric antrum and upper body along the greater curvature were evaluated histologically. Histological assessment was performed by two pathologists (TK and HS) independently and in a blinded manner. Using the Updated Sydney system, the degrees of in ammation and activity were scored from 0to3. 15 The in ammation and activity scores were summed up and expressed as the gastritis score. Hiatal hernia The diagnosis of hiatal hernia was made endoscopically if gastric mucosa was observed circumferentially above the oesophageal hiatus. The assessment was performed by two experienced endoscopists (TK and KI) independently and in a blinded manner. Statistical analysis Results were expressed as the mean s.d. Statistical analysis of data was performed by the Fisher's exact probability test and v 2 -test for independence. In addition, the Mann±Whitney U-test or Wilcoxon rank sum test was used as appropriate. P-values less than 0.05 were considered statistically signi cant.

3 ACID SECRETION AFTER H. PYLORI ERADICATION 815 RESULTS Clinical course In all patients with peptic ulceration, the ulcers were cured by the eradication therapy and did not relapse during the 7-month follow-up period. Endoscopically proven re ux oesophagitis occurred in 11 out of 105 (10.5%) patients at 7 months after the eradication therapy. The grade of re ux oesophagitis was judged to be relatively mild, A or B by the Los Angeles classi cation (Table 1). 16 Re ux oesophagitis developed more frequently in the patients over 50 years of age than in those under 50 years [19.0% (11 out of 58) vs. 0% (0 out of 47); P < 0.01 by Fisher's exact probability test]. In addition, it tended to develop more frequently in men than in women [13.2% (10 out of 76) vs. 3.4% (one out of 29)], although the difference was not statistically signi cant (P ˆ 0.28 by Fisher's exact probability test). Among the 11 patients who developed re ux oesophagitis, seven had a history of gastric ulcer, two had a history of duodenal ulcer, one had a history of atrophic gastritis, and one had a history of early gastric cancer. Although the majority of patients who developed oesophagitis had a history of gastric ulcer, no signi cant difference was found in the incidence of re ux oesophagitis amongst the patients with the respective diseases [gastric ulcer, 17.9% (seven out of 39); duodenal ulcer, 5.6% (two out of 36); atrophic gastritis, 9.1% (one out of 11); early gastric cancer, 5.3% (one out of 19); P ˆ 0.29 by v 2 -test for independence]. Sixty-nine patients had taken H 2 -receptor antagonists before eradication, but their incidence of oesophagitis after the therapy was not signi cantly different from that of the patients who had not taken them before [11.6% (eight out of 69) vs. 8.3% (three out of 36); P ˆ 0.60: v 2 -test for independence]. The incidence of heart burn was 1.9% (two out of 105) before the eradication of H. pylori, and this symptom continued for both patients even after the therapy. At 7 months after the eradication, 14 out of 103 (13.6%) patients complained of new intermittent heartburn. Five patients with re ux oesophagitis were asymptomatic, and six stated mid occasional heartburn which did not require treatment. Changes in acid secretion In most patients who developed re ux oesophagitis, the endoscopic gastrin test values were found to be increased at 7 months after the clearance of H. pylori. Before eradication, there was no signi cant difference in the endoscopic gastrin test value between the patients who developed re ux oesophagitis and those who did not ( vs meq/10min; P ˆ 0.58 by the Mann±Whitney U-test). After eradication, there was a tendency for the mean endoscopic gastrin test value to be higher in the former patients group than in the latter group, although the difference did not reach the signi cant level ( vs meq/10min; P ˆ 0.21 by the Mann± Whitney U-test). The increase in endoscopic gastrin test values was signi cantly greater in the patients who developed re ux oesophagitis than in those who did not ( vs meq/10min; P < 0.05 by the Mann±Whitney U-test; Figure 1). Collectively, re ux oesophagitis developed in 4.3% (one out of 23) of the patients with decreased acid secretion, 0% (zero out of 18) of those with no change in acid secretion, and 6.7% (two out of 30) and 23.5% (eight out of 34) of the patients with increased and markedly increased acid secretion, respectively. The results of the endoscopic gastrin test indicated that the incidence of posteradication re ux oesophagitis correlated signi cantly with the increase in gastric acid secretion (P < 0.01 by the Mann±Whitney U-test; Figure 2). Gastritis score At 7 months after the eradication of H. pylori, the mean gastritis scores of the antrum and body were decreased signi cantly in all subjects (antrum: ± ; body: ± ; P < by the Wilcoxon rank sum test). The gastritis score before eradication therapy tended to be higher, both in the antrum and body, in the patients who developed re ux oesophagitis after the eradication compared with those who did not, although the difference was not statistically signi cant (antrum: vs , P ˆ 0.12; body: vs , P ˆ 0.19 by the Mann±Whitney U-test; Figure 3). Hiatal hernia Re ux oesophagitis developed in 20.0% (11 out of 55) of the patients with hiatal hernia after the eradication of H. pylori, but in none (zero out of 50) of the patients without hiatal hernia (P < 0.01 by Fisher's exact probability test).

4 816 T. KOIKE et al. DISCUSSION Recent studies have shown that re ux oesophagitis may develop after the successful treatment of H. pylori infection. 1, 2 It is assumed that the important predisposing factors of re ux oesophagitis are the presence of hiatal hernia, transient lower oesophageal sphincter Figure 1. Acid secretion in the patients with (d) and without (s) development of re ux oesophagitis after cure of H. pylori infection. Before eradication, there was no signi cant difference in the endoscopic gastrin test value between the patients who developed re ux oesophagitis and those who did not ( vs meq/10 min; P ˆ 0.58 by the Mann±Whitney U-test). After eradication, there was a tendency for the mean endoscopic gastrin test value to be higher in the former patients group than the latter group ( vs meq/10 min; P ˆ 0.21 by the Mann±Whitney U-test). The increase in endoscopic gastrin test value was signi cantly greater in the patients who developed re ux oesophagitis than in those who did not ( vs meq/10 min; P < 0.05 by the Mann±Whitney U-test). Figure 2. Relationship between changes in acid secretion and the incidence of re ux oesophagitis. The development of re ux oesophagitis after H. pylori eradication was correlated signi cantly with the increase in acid secretion. (P < 0.01 by the Mann± Whitney U-test).

5 ACID SECRETION AFTER H. PYLORI ERADICATION 817 Figure 3. Gastritis score of the antrum (A) and body (B) of the patients with (d) and without (s) development of re ux oesophagitis after cure of H. pylori infection. The gastritis score before eradication therapy tended to be higher, both in the antrum and body, in the patients who developed re ux oesophagitis after the eradication, compared with those who did not (antrum: vs , P ˆ 0.12; body: vs , P ˆ 0.19 by the Mann±Whitney U-test). relaxation, and impaired oesophageal clearance of re uxed gastric contents. 11±13, 17±21 Although acidity in the oesophagus may be a key factor for the pathogenesis of re ux oesophagitis, it has also been reported that no differences were found in gastric acid secretion between patients with re ux oesophagitis and matched controls. 9 The nding suggested the importance of inhibitory mechanisms that block the regurgitation of acidic gastric contents. On the other hand, it has also been reported that oesophagitis was found in only one out of 12 patients with a basal acid output of less than 0.1 meq/h, suggesting that profoundly decreased gastric acid secretion prevents the development of re ux oesophagitis. 9 In relation to this issue, we and others have shown previously that gastric acid secretion varies signi cantly after the eradication of H. pylori. 3±8 The mechanism of developing re ux oesophagitis after H. pylori eradication is not well understood, especially concerning the relation to gastric acid secretion. Therefore, the rst aim of this study was to investigate whether changes in gastric acid secretion can explain the development of re ux oesophagitis after H. pylori eradication. The endoscopic gastrin test was employed for the purpose because this new technique has proven to be very useful for evaluating endoscopic ndings and gastric acid secretion simultaneously in a large number of patients. Recently, several studies have demonstrated that gastric acid secretion is decreased in H. pylori-positive patients with stomach body gastritis, and that the clearance of H. pylori rapidly improves acid secretion with the resolution of in ammation. 6±8 The mechanism by which gastritis of the stomach body inhibits gastric acid secretion is not clear, but in ammatory cytokines, such as interleukin-1 or proteins produced by H. pylori, may be responsible. 22±24 Labenz et al. have reported that the patients who developed re ux oesophagitis after the clearance of H. pylori had severe gastritis in the stomach body. They concluded that the most important

6 818 T. KOIKE et al. factor for predicting the development of re ux oesophagitis after eradication therapy is the presence of preceding severe gastritis that caused decreased acid secretion. 1 However, they did not provide direct evidence of decreased acid secretion. In agreement with Labenz et al., we found in the present study that the patients who developed re ux oesophagitis after the eradication of H. pylori tended to have severe gastritis prior to the eradication therapy. In addition, by the endoscopic gastrin test, we have clari ed that the incidence of post-eradication re ux oesophagitis correlated signi cantly with the recovery of gastric acid secretion, suggesting that increased acid secretion may be one important risk factor. In H. pyloripositive patients with gastric hyposecretion due to corpus gastritis, the eradication of H. pylori may improve the acid secretion and promote the occurrence of re ux oesophagitis. This hypothesis may explain why the majority of patients who developed oesophagitis had gastric ulcer, because it is very often associated with corpus gastritis. Although this study did not include a randomized control group which were not treated for H. pylori, the fact that the majority of cases of re ux oesophagitis in Japan do not have H. pylori infection and that the development of re ux oesophagitis usually does not occur in the patients with continuing H. pylori infection, may justify the assumption that the development of re ux oesophagitis in 10.5% of the patients within 7 months after the eradication therapy is an unusually high probability. 25±28 Conversely, according to recent large population-based studies, no evidence was obtained that supports the increased frequency of heartburn symptoms or re ux oesophagitis after the eradication of H. pylori in patients with duodenal ulcer or dyspepsia. 29±31 These results seem to be at variance with those of Labenz et al. and this study. One reason for the discrepancy may be the difference in the evaluation of gastro-oesophageal re ux; this study and that of Labenz et al. evaluated only endoscopically-proven re ux oesophagitis, whereas other contradictory reports evaluated heartburn symptoms. Another reason may be the difference in acid secretion before the clearance of H. pylori in individual subjects, because the effects of H. pylori on acid secretion vary from patient to patient. For example, patients with active duodenal ulcers have high acid secretion, whilst the acid secretion of patients with H. pylori-positive gastric ulcer and atrophic gastritis is low. 10, 32, 33 Among the 105 patients entered into this study, 39 had gastric ulcers, 36 had duodenal ulcers, 11 had atrophic gastritis, and 19 had early gastric cancer. Therefore, the group chosen is not representative of the population of patients referred for endoscopy, most of whom have a normal endoscopy with diagnosis of non-ulcer dyspepsia. Although the reason for the varied acid secretion in patients with H. pylori infection remains unclear, differences in the strain of H. pylori, including the cytotoxin-associated antigen (cag A) phenotype, or differences in the hot response may have an in uence on the acid secretion. 34±38 Therefore, it is important to examine the level of acid secretion before and after the eradication therapy for H. pylori when the development of re ux oesophagitis is investigated. Atrophic gastritis and severe gastritis of the stomach body cause acid hyposecretion. In Japan, the incidence of these pathological conditions due to H. pylori 39, 40 infection is higher than that in Western countries. Therefore, after H. pylori eradication, increased acid secretion may occur more frequently in Japanese people, and some of them may develop re ux oesophagitis. Accordingly, we also investigated another factor of re ux oesophagitis, i.e. hiatal hernia. The results clearly demonstrated that the rate of re ux oesophagitis after H. pylori eradication was signi cantly higher in the patients with hiatal hernia than in those without it. Therefore, in the patients with oesophageal motility disturbances such as hiatal hernia, the eradication of H. pylori may induce the development of re ux oesophagitis. Although there are still few reports concerning the relationship between H. pylori infection and lower oesophageal sphincter dysfunction or hiatal hernia, the predominant opinion so far is that H. pylori infection may not play a major role in the pathogenesis of these phenomena. 41 In contrast, we and others have reported that the incidence of H. pylori infection is low and the degree of atrophic gastritis is mild in Japanese patients with re ux oesophagitis, suggesting that H. pylori infection may be inversely correlated with the incidence of this disease. 25, 26, 28 We consider that the decreased acid secretion by H. pylori infection may inhibit the development of re ux oesophagitis in the patients with lower oesophageal sphincter dysfunction or hiatal hernia, but the recovery of acid secretion after the clearance of H. pylori may thereby cause the development of re ux oesophagitis. In conclusion, increased acid secretion is an important risk factor for re ux oesophagitis after H. pylori

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