REVIEW URRENT C OPINION
Helicobacter pylori and gastroesophageal reflux disease Arne Kandulski and Peter Malfertheiner
Purpose of review The purpose of the review is to discuss key studies conducted on the intriguing relationship between Helicobacter pylori and gastroesophageal reflux disease. Recent findings Epidemiological studies have repeatedly described a negative association between H. pylori infection and erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma, but not between H. pylori and gastroesophageal reflux disease symptoms. Especially, infection with CagA-positive strains appears to protect the distal esophagus by causing fundic gland atrophy and impaired gastric acid secretion. Although earlier reports suggested the development of erosive esophagitis after H. pylori eradication, more recent studies discuss that H. pylori eradication usually does not have an important clinical impact on gastroesophageal reflux disease. Summary Gastric atrophy is the most widely accepted mechanism by which the distal esophagus is protected from abnormal acid exposure in patients with H. pylori infection. The clinical impact of H. pylori infection on the prevalence of erosive esophagitis and Barrett’s esophagus remains a matter of debate. In areas with a high prevalence of H. pylori-induced atrophic gastritis, the protection that this infection may afford against gastroesophageal reflux disease is not comparable to the risk that H. pylori poses for the development of gastric cancer. Keywords Barrett’s esophagus, eradication, gastroesophageal reflux disease, Helicobacter pylori
INTRODUCTION Helicobacter pylori colonizes the human gastric epithelium and causes chronic inflammation of the gastric mucosa, but does not infect intestinal or squamous type epithelium. H. pylori, therefore, has never been reported to harm the esophagus directly in spite of the direct gastroesophageal connection. Early epidemiologic studies and therapeutic trials led to the initial claim that H. pylori protects against esophageal pathologies [1]. The notion that H. pylori infection plays a protective role for the esophagus remains widespread despite the fact that many studies have not confirmed any such association. The Maastricht-IV–Florence consensus report, which was formulated to guide the management of H. pylori infection, included a careful assessment of all the collected scientific evidence on the relationship between H. pylori and gastroesophageal reflux disease (GERD). This report concluded that there is no association between H. pylori and www.co-gastroenterology.com
symptom severity, recurrence or treatment efficacy in symptomatic GERD, and that H. pylori eradication does not exacerbate preexisting reflux disease. However, it has also been concluded that erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma (EAC) are inversely correlated with H. pylori infection, and in particular with CagAþ strains [2]. This review discusses key studies conducted on the intriguing relationship between H. pylori and GERD.
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany Correspondence to Peter Malfertheiner, MD, Professor, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-vonGuericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. Tel: +49 391 6713100; fax: +49 391 6713105; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:402–407 DOI:10.1097/MOG.0000000000000085 Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner
KEY POINTS H. pylori infection is not associated with symptoms of GERD. H. pylori eradication does not lead to the development of GERD symptoms and does not appear to exacerbate preexisting GERD. H. pylori infection has no apparent impact on the frequency of transient lower esophageal sphincter relaxations, esophageal acid exposure, or motility of the esophageal body. The inverse correlations between H. pylori with erosive esophagitis and Barrett’s esophagus might be caused by gastric atrophy, which can be functionally assessed by serum measurements of pepsinogen I and II.
significant at 0.97 (95% CI: 0.75–1.27). A European population-based case–control study that included 65 363 patients found that H. pylori infection alone was not associated with a decreased risk of GERD symptoms, but the investigators did find a negative association for GERD symptoms in patients who had reduced pepsinogen levels and gastric atrophy (OR: 0.2; 95% CI: 0.8–1.5) [12]. As the prevalence of gastric atrophy in only 2% of the study population was low, but comparable to that reported in the European general population, this negative association is probably not of clinical importance for Europe. A recent study from the United States presented similar data. As in the European studies, GERD symptoms were not associated with H. pylori infection, irrespective of the CagA status. For erosive esophagitis, however, there was a negative association with H. pylori, in particular with CagA-positive strains (OR: 0.47; 95% CI: 0.21–1.03) [13 ]. More than 5000 patients were included in a Korean case–control study in which study individuals had serological assessment of H. pylori prevalence. The authors demonstrated an inverse correlation of H. pylori seroprevalence with the risk and severity of erosive esophagitis (OR: 0.44; 95% CI: 0.39–0.49) [14]. A large cross-sectional survey from Japan that included more than 10 000 individuals found no association for NERD and H. pylori infection, but did find a negative correlation for erosive reflux disease and H. pylori prevalence. A significant association with lower pepsinogen I/II ratio as a functional parameter for fundic gland atrophy supported a protective effective for atrophic gastritis in GERD [15 ]. Table 1 summarizes the recent publications on H. pylori, GERD symptoms, erosive esophagitis, and the prevalence of Barrett’s esophagus. &
EPIDEMIOLOGICAL STUDIES GERD is one of the most frequent diagnoses made by general practitioners in the United States, with enormous burden for the healthcare system [3,4].
Gastroesophageal reflux disease symptoms, erosive esophagitis, and Helicobacter pylori In epidemiological studies, the diagnosis of GERD usually has been based on typical symptoms (e.g. heartburn and regurgitation), or on an endoscopy revealing esophageal erosions or Barrett’s metaplasia [5,6]. Nonerosive reflux disease (NERD) has been diagnosed when there are typical reflux symptoms in the absence of mucosal lesions on endoscopy [5,6]. The definition of NERD has varied among clinical trials, and this variation might explain the poor response to proton pump inhibitor (PPI) treatment of NERD patients in some studies. Abnormal acid exposure on 24 h esophageal pH monitoring has been required in very few studies, but patients with NERD who have abnormal esophageal acid exposure have a higher response rate to PPI treatment [7–10]. Furthermore, GERD symptoms and erosive esophagitis should be considered separately since the correlation between symptoms and esophagitis can be poor. In a meta-analysis from 2003, Raghunath et al. [11] reported a pooled odds ratio (OR) of 0.76 (0.61– 0.96) for the relationship between H. pylori infection and GERD in European studies. This analysis included only studies in which GERD was defined by erosive esophagitis or by abnormal results of esophageal pH monitoring. However, after exclusion of one outlier study that seemed to dominate the analysis, the OR indicating a lower prevalence of GERD in patients with H. pylori was no longer
&&
Barrett’s esophagus, esophageal adenocarcinoma, and Helicobacter pylori H. pylori infection consistently has been reported to be negatively associated with Barrett’s esophagus and EAC. However, there is substantial heterogeneity in study designs and methodological aspects among the published reports. In 2012, Fischbach et al. [16] addressed this heterogeneity. Among 49 studies that initially were included in their metaanalysis, the investigators finally selected only four methodologically comparable studies that were appropriate for final analysis and reported a relative risk of 0.46 (95% CI: 0.35–0.60) for the development of Barrett’s esophagus in patients with H. pylori infection. A subgroup analysis of seven studies showed that this effect was stronger for infection with CagA-positive strains (0.38; 95% CI: 0.19–0.78)
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
403
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Esophagus Table 1. Association of Helicobacter pylori with GERD symptoms, erosive esophagitis, and Barrett’s esophagus – selection of the largest cohort studies Author
Year, study
GERD symptoms OR (95% CI)
Nordenstedt et al. [12]
2007, population based (n ¼ 944)
GERD symptoms: 1.1 (0.8–1.6)
Esophagitis OR (95% CI)
Barrett’s esophagus OR (95% CI) NA
Gastric atrophy (PGI): 0.2 (0.0–0.6) Chung et al. [14] Rubenstein et al. [13 ] &
2011, case-controlled study (n ¼ 5616) 2013, prospective study (n ¼ 533)
NA
0.44 (0.39–0.49)
NA
0.95 (0.55–1.64)
0.63 (0.37–1.08)
0.53 (0.29–0.97)
Symptoms onlya 1.0 (0.94–1.17)
0.58 (0.51–0.65) PGI/II ratio: 0.61 (0.50–0.72)
NA
CagA: 0.36 (0.14–0.90) Minatsuki et al. [15 ] &&
2013, cross-sectional study (n ¼ 10 837)
CagA, studies investigating CagA seropositivity; CI, confidence interval; GERD, gastroesophageal reflux disease; IgG, immunoglobulin G antibody; OR, odds ratio; PGI, pepsinogen I; PGII, pepsinogen II. a Patients with erosive esophagitis were excluded.
[16]. In another systematic review, Rokkas and colleagues [17] reported a lower H. pylori prevalence in patients with Barrett’s esophagus, especially for infection with CagA-positive strains. This meta-analysis also included 10 studies with EAC and found a negative association for this cancer with H. pylori prevalence and CagA seropositivity (OR: 0.51; 95% CI: 0.31–0.82). The authors suggested that H. pylori
Non-atrophic, antrum-predominant gastritis
&
LES pressure
–
Corpus-predominant gastritis with atrophy
infection protects against the development of Barrett’s esophagus and EAC [17]. A recent, prospective case–control study from the United States also demonstrated a negative association between Barrett’s esophagus and H. pylori (OR: 0.53; 95% CI: 0.29–0.97), especially with CagA-positive strains (OR: 0.36; 95% CI: 0.14–0.90) [13 ] (Fig. 1). Although a negative correlation between H. pylori infection
Ammonia nitric oxide
+
Acid
Gastrin –
LES pressure
Acid Ammonia nitric oxide
Gastrin
FIGURE 1. Putative mechanisms of H. pylori gastritis phenotype operative in gastroesophageal reflux disease pathophysiology. Gastrin regulated in both ways depending on amount of residual acid production in chronic atrophic or corpus predominant gastritis. 404
www.co-gastroenterology.com
Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner
and Barrett’s esophagus has been observed consistently when Barrett’s esophagus patients are compared to an ‘endoscopically’ normal control group, this negative association has not been observed in studies that used healthy blood donors as controls [18]. Esophageal exposure to gastric acid and bile acids arising from duodenogastroesophageal reflux is the presumed mechanism for the pathogenesis of Barrett’s esophagus [19]. H. pylori infection that causes gastritis with gastric atrophy might reduce esophageal acid exposure and thereby protect against Barrett’s esophagus. Prospectively, Anderson et al. [20] investigated serum levels of pepsinogen I and II as markers for fundic gland atrophy in association with Barrett’s esophagus. In addition to finding a negative association between H. pylori and Barrett’s esophagus and EAC, the authors found a reduced risk for the development of Barrett’s esophagus even in the presence of only mild gastric atrophy (pepsinogen I/II < 7) [20]. On the basis of these findings, the development of Barrett’s esophagus and EAC appears to occur mostly in patients with a nonatrophic gastric mucosa that is capable of producing the acid required for the pathogenesis of Barrett’s esophagus [21].
EFFECTS OF HELICOBACTER PYLORI INFECTION ON GASTRIC ACID SECRETION, ESOPHAGEAL ACID EXPOSURE, AND MECHANISMS OF GASTROESOPHAGEAL REFLUX There have not been numerous publications on pathophysiological interactions between H. pylori infection and the factors underlying GERD in recent years. Gastric acid secretion can be increased in patients who have an antrum-predominant form of H. pylori gastritis. Although such patients might be expected to have an increased prevalence of GERD, there is no evidence for abnormal acid exposure of the distal esophagus in H. pylori-positive patients as long as the antireflux barrier is healthy and functions normally [22]. In western countries, antrum-predominant gastritis is frequent in patients with GERD [23–27] (Fig. 1), and only a small subset of infected patients with GERD have corpus-predominant gastritis or gastric atrophy with impaired acid secretion. Patients with atrophic gastritis have impaired gastric acid secretion [27], which has been proposed as a protective mechanism against GERD. In Asia and Japan, where corpus-predominant and atrophic gastritis associated acid hyposecretion is more prevalent (Fig. 1), it appears that H. pylori eradication followed by recovery of the corpus mucosa and acid secretion may predispose a small
subset of patients to develop GERD [28,29]. In patients with established GERD, no differences in esophageal acid exposure have been observed between H. pylori-positive and H. pylori-negative patients [30,31]. One report described increased duodenogastric reflux in H. pylori-positive patients by scintigraphic studies, but found no difference between H. pylori-positive and H. pylori-negative patients in gastroesophageal reflux [32]. Similar results were described in a study using the Bilitec technique to evaluate duodenogastric reflux [33].
Helicobacter pylori and potential effects on esophageal motility The lower esophageal sphincter (LES) is an important component of the gastroesophageal antireflux barrier, and LES relaxation can result from exposure to nitric oxide and ammonium. Both of these nitrate compounds are increased in the gastric juice of H. pylori-infected patients, but it is unlikely that they reach concentrations sufficient to affect esophageal small muscle cells and lower LES pressure. It is more likely that increased serum gastrin levels in antrum-predominant H. pylori gastritis may increase LES pressure, as shown in pathophysiological models (Fig. 1) [34,35]. The frequency of transient relaxation of the LES (transient lower esophageal sphincter relaxations), a common mechanism for gastroesophageal reflux, was not found to differ significantly between H. pylori-infected and noninfected patients [36]. In a recent study that included 64 adolescents and young adults with GERD symptoms and pathologic acid exposure on esophageal pH monitoring, again no differences were observed between H. pylori-positive and H. pylori-negative patients regarding the severity of esophageal acid exposure and frequency of esophageal motility abnormalities. Furthermore, H. pylori eradication had no impact on acid exposure or esophageal motility [37 ]. Similar results were described in earlier reports [38,39]. Overall, existing data do not support any effects of H. pylori on esophageal motility. &
HELICOBACTER PYLORI ERADICATION AND GASTROESOPHAGEAL REFLUX DISEASE H. pylori eradication has been reported to favor the development of GERD and, as a consequence, it has been proposed that H. pylori protects against the development of erosive esophagitis [1,40,41]. In contrast, however, other studies have described no effect on GERD development, with some even reporting a decrease in GERD symptoms after
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
405
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Esophagus
H. pylori eradication [42]. In a post-hoc analysis of eight randomized trials, H. pylori eradication did not have a significant effect on the development of erosive esophagitis, new onset of GERD symptoms, or worsening of preexisting symptoms [43]. In 2011, a prospective trial showed no significant differences between patients with or without successful H. pylori eradication in their rates of developing reflux symptoms and erosive esophagitis [44]. A meta-analysis including 10 randomized controlled trials found no difference in the incidence of reflux symptoms (OR: 0.81; 95% CI: 0.56–1.17) and reflux esophagitis (OR: 1.13; 95% CI: 0.72–1.78) between patients who received eradication therapy or placebo [45]. Further meta-analyses reported in 2010 and 2011 came to the same conclusions [46,47]. A subgroup analysis showed a significant improvement of GERD symptoms after successful eradication when compared to persisting H. pylori infection [45]. An improvement of GERD symptomrelated quality of life has also been demonstrated 1 year after eradication therapy [48]. In contrast, one study of H. pylori eradication for gastric cancer prevention in a large population in Taiwan found a significant increase in the incidence of erosive esophagitis when the infection was eradicated. Interestingly, in this area with a high prevalence of H. pylori-associated gastric atrophy (60% before eradication), the authors found a significant reduction of gastric atrophy after 5 years that correlated with the increased incidence of erosive esophagitis [49 ]. &
CONCLUSION Epidemiological studies have found no significant association between H. pylori infection and GERD symptoms. In contrast, H. pylori infection in general, with CagA-positive strains in particular, has consistently been found to be negatively associated with erosive reflux disease, Barrett’s esophagus, and EAC. Recent publications have supported these associations, but they have not provided any additional insights into the causality for these findings. H. pylori-induced gastric atrophy, investigated by serum levels of pepsinogen I and II in several studies, is the most advocated mechanism for how H. pylori infection protects the distal esophagus from abnormal acid exposure. In most interventional studies on H. pylori eradication, there was no increase in GERD. In Asian countries and other areas with a high prevalence of H. pylori-associated atrophic gastritis, where this is not the case, the benefits for H. pylori eradication would anyhow outweigh by far the prevention of gastric cancer as compared to the risk for GERD development. 406
www.co-gastroenterology.com
Acknowledgements None. Conflicts of interest Peter Malfertheiner received speakers fees from Aptalis, Falk, Reckitt-Benckiser, and Takeda. Arne Kandulski has no conflicts of interests.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Labenz J, Blum AL, Bayerdorffer E, et al. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112:1442–1447. 2. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection – the Maastricht IV/Florence consensus report. Gut 2012; 61:646–664. 3. Irvine EJ. Quality of life assessment in gastro-oesophageal reflux disease. Gut 2004; 53 (Suppl 4):iv35–iv39. 4. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012; 143:1179–1187. 5. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. 6. Dent J, Brun J, Fennerty MB, et al. An evidence-based appraisal of reflux disease management – the Genval Workshop Report. Gut 1999; 44 (Suppl 2):S1–S16. 7. Kandulski A, Peitz U, Monkemuller K, et al. GERD assessment including pH metry predicts a high response rate to PPI standard therapy. BMC Gastroenterol 2013; 13:12. 8. Weigt J, Monkemuller K, Peitz U, Malfertheiner P. Multichannel intraluminal impedance and pH-metry for investigation of symptomatic gastroesophageal reflux disease. Dig Dis 2007; 25:179–182. 9. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013; 108:308– 328. 10. Weijenborg PW, Cremonini F, Smout AJ, Bredenoord AJ. PPI therapy is equally effective in well defined nonerosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil 2012; 24:747–757. 11. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003; 326:737. 12. Nordenstedt H, Nilsson M, Johnsen R, et al. Helicobacter pylori infection and gastroesophageal reflux in a population-based study (The HUNT Study). Helicobacter 2007; 12:16–22. 13. Rubenstein JH, Inadomi JM, Scheiman J, et al. Association between Helico& bacter pylori and Barrett’s esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 2013; 12:239– 245. Recent epidemiologic investigation demonstrating the inverse association of H. pylori with erosive esophagitis and Barrett’s esophagus in the United States. 14. Chung SJ, Lim SH, Choi J, et al. Helicobacter pylori serology inversely correlated with the risk and severity of reflux esophagitis in Helicobacter pylori endemic area: a matched case–control study of 5616 health check-up Koreans. J Neurogastroenterol Motil 2011; 17:267–273. 15. Minatsuki C, Yamamichi N, Shimamoto T, et al. Background factors of reflux && esophagitis and nonerosive reflux disease: a cross-sectional study of 10 837 subjects in Japan. PLoS One 2013; 8:e69891. The authors conducted a prospective, cross-sectional survey including more than 10 000 patients from Japan demonstrating a negative association between H. pylori and erosive esophagitis, with a significant association with low pepsinogen I/II ratios as a functional parameter for fundic gland atrophy. 16. Fischbach LA, Nordenstedt H, Kramer JR, et al. The association between Barrett’s esophagus and Helicobacter pylori infection: a meta-analysis. Helicobacter 2012; 17:163–175. 17. Rokkas T, Pistiolas D, Sechopoulos P, et al. Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin Gastroenterol Hepatol 2007; 5:1413–1417; 1417. 18. Wang C, Yuan Y, Hunt RH. Helicobacter pylori infection and Barrett’s esophagus: a systematic review and meta-analysis. Am J Gastroenterol 2009; 104:492–500. 19. Fitzgerald RC. Molecular basis of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 2006; 55:1810–1820.
Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner 20. Anderson LA, Murphy SJ, Johnston BT, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case–control study. Gut 2008; 57:734–739. 21. McColl KE, Going JJ. Aetiology and classification of adenocarcinoma of the gastro-oesophageal junction/cardia. Gut 2010; 59:282–284. 22. Sarnelli G, Ierardi E, Grasso R, et al. Acid exposure and altered acid clearance in GERD patients treated for Helicobacter pylori infection. Dig Liver Dis 2003; 35:151–156. 23. McColl KE, El-Omar EM, Gillen D. Alterations in gastric physiology in Helicobacter pylori infection: causes of different diseases or all epiphenomena? Ital J Gastroenterol Hepatol 1997; 29:459–464. 24. Leodolter A, Wolle K, Peitz U, et al. Helicobacter pylori genotypes and expression of gastritis in erosive gastro-oesophageal reflux disease. Scand J Gastroenterol 2003; 38:498–502. 25. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet 2009; 374:1449–1461. 26. Leodolter A, Ebert MP, Peitz U, et al. Prevalence of H. pylori associated ‘high risk gastritis’ for development of gastric cancer in patients with normal endoscopic findings. World J Gastroenterol 2006; 12:5509–5512. 27. El-Omar EM, Oien K, El-Nujumi A, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997; 113:15–24. 28. Naylor GM, Gotoda T, Dixon M, et al. Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients. Gut 2006; 55:1545–1552. 29. Haruma K. Review article: influence of Helicobacter pylori on gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther 2004; 20 (Suppl 8): 40–44. 30. Fallone CA, Barkun AN, Mayrand S, et al. There is no difference in the disease severity of gastro-oesophageal reflux disease between patients infected and not infected with Helicobacter pylori. Aliment Pharmacol Ther 2004; 20:761–768. 31. Grande M, Cadeddu F, Villa M, et al. Helicobacter pylori and gastroesophageal reflux disease. World J Surg Oncol 2008; 6:74. 32. Artiko VM, Chebib HY, Ugljesic MB, et al. Relationship between enterogastric reflux estimated by scintigraphy and the presence of Helicobacter pylori. Hepatogastroenterology 1999; 46:1234–1237. 33. Manifold DK, Anggiansah A, Rowe I, et al. Gastro-oesophageal reflux and duodenogastric reflux before and after eradication in Helicobacter pylori gastritis. Eur J Gastroenterol Hepatol 2001; 13:535–539. 34. Beales I, Blaser MJ, Srinivasan S, et al. Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells. Gastroenterology 1997; 113:465–471. 35. Calam J, Gibbons A, Healey ZV, et al. How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 1997; 113 (6 Suppl):S43–S49.
36. Zerbib F, Bicheler V, Leray V, et al. H. pylori and transient lower esophageal sphincter relaxations induced by gastric distension in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001; 281:G350–G356. 37. Xinias I, Maris T, Mavroudi A, et al. Helicobacter pylori infection has no impact & on manometric and pH-metric findings in adolescents and young adults with gastroesophageal reflux and antral gastritis: eradication results to no significant clinical improvement. Pediatr Rep 2013; 5:e3. H. pylori and H. pylori eradication had no significant effects on esophageal acid exposure or esophageal motility. 38. Verma S, Jackson W, Floum S, Giaffer MH. Gastroesophageal reflux before and after Helicobacter pylori eradication. A prospective study using ambulatory 24-h esophageal pH monitoring. Dis Esophagus 2003; 16:273–278. 39. Guliter S, Kandilci U. The effect of Helicobacter pylori eradication on gastroesophageal reflux disease. J Clin Gastroenterol 2004; 38:750–755. 40. Lee JM, O’Morain CA. Different management for Helicobacter pylori positive and negative patients with gastro-oesophageal reflux disease? Gut 1998; 43 (Suppl 1):S14–S20. 41. Sacca N, De MA, Rodino S, et al. Reflux esophagitis: a complication of Helicobacter pylori eradication therapy? Endoscopy 1997; 29:224. 42. Vaira D, Vakil N, Rugge M, et al. Effect of Helicobacter pylori eradication on development of dyspeptic and reflux disease in healthy asymptomatic subjects. Gut 2003; 52:1543–1547. 43. Laine L, Sugg J. Effect of Helicobacter pylori eradication on development of erosive esophagitis and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double blind prospective studies. Am J Gastroenterol 2002; 97:2992–2997. 44. Kim N, Lee SW, Kim JI, et al. Effect of Helicobacter pylori eradication on the development of reflux esophagitis and gastroesophageal reflux symptoms: a nationwide multi-center prospective study. Gut Liver 2011; 5:437–446. 45. Saad AM, Choudhary A, Bechtold ML. Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials. Scand J Gastroenterol 2012; 47:129–135. 46. Qian B, Ma S, Shang L, et al. Effects of Helicobacter pylori eradication on gastroesophageal reflux disease. Helicobacter 2011; 16:255–265. 47. Yaghoobi M, Farrokhyar F, Yuan Y, Hunt RH. Is there an increased risk of GERD after Helicobacter pylori eradication?: a meta-analysis. Am J Gastroenterol 2010; 105:1007–1013. 48. Hirata K, Suzuki H, Matsuzaki J, et al. Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy. J Clin Biochem Nutr 2013; 52:172–178. 49. Lee YC, Chen TH, Chiu HM, et al. The benefit of mass eradication of & Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut 2013; 62:676–682. H. pylori eradication for gastric cancer prevention in Taiwan resulted in a significant increase in the incidence of erosive esophagus that was associated with a significant reduction in the frequency of gastric atrophy after 5 years.
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
407
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Arne Kandulski and Peter Malfertheiner
Purpose of review The purpose of the review is to discuss key studies conducted on the intriguing relationship between Helicobacter pylori and gastroesophageal reflux disease. Recent findings Epidemiological studies have repeatedly described a negative association between H. pylori infection and erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma, but not between H. pylori and gastroesophageal reflux disease symptoms. Especially, infection with CagA-positive strains appears to protect the distal esophagus by causing fundic gland atrophy and impaired gastric acid secretion. Although earlier reports suggested the development of erosive esophagitis after H. pylori eradication, more recent studies discuss that H. pylori eradication usually does not have an important clinical impact on gastroesophageal reflux disease. Summary Gastric atrophy is the most widely accepted mechanism by which the distal esophagus is protected from abnormal acid exposure in patients with H. pylori infection. The clinical impact of H. pylori infection on the prevalence of erosive esophagitis and Barrett’s esophagus remains a matter of debate. In areas with a high prevalence of H. pylori-induced atrophic gastritis, the protection that this infection may afford against gastroesophageal reflux disease is not comparable to the risk that H. pylori poses for the development of gastric cancer. Keywords Barrett’s esophagus, eradication, gastroesophageal reflux disease, Helicobacter pylori
INTRODUCTION Helicobacter pylori colonizes the human gastric epithelium and causes chronic inflammation of the gastric mucosa, but does not infect intestinal or squamous type epithelium. H. pylori, therefore, has never been reported to harm the esophagus directly in spite of the direct gastroesophageal connection. Early epidemiologic studies and therapeutic trials led to the initial claim that H. pylori protects against esophageal pathologies [1]. The notion that H. pylori infection plays a protective role for the esophagus remains widespread despite the fact that many studies have not confirmed any such association. The Maastricht-IV–Florence consensus report, which was formulated to guide the management of H. pylori infection, included a careful assessment of all the collected scientific evidence on the relationship between H. pylori and gastroesophageal reflux disease (GERD). This report concluded that there is no association between H. pylori and www.co-gastroenterology.com
symptom severity, recurrence or treatment efficacy in symptomatic GERD, and that H. pylori eradication does not exacerbate preexisting reflux disease. However, it has also been concluded that erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma (EAC) are inversely correlated with H. pylori infection, and in particular with CagAþ strains [2]. This review discusses key studies conducted on the intriguing relationship between H. pylori and GERD.
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany Correspondence to Peter Malfertheiner, MD, Professor, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-vonGuericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. Tel: +49 391 6713100; fax: +49 391 6713105; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:402–407 DOI:10.1097/MOG.0000000000000085 Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner
KEY POINTS H. pylori infection is not associated with symptoms of GERD. H. pylori eradication does not lead to the development of GERD symptoms and does not appear to exacerbate preexisting GERD. H. pylori infection has no apparent impact on the frequency of transient lower esophageal sphincter relaxations, esophageal acid exposure, or motility of the esophageal body. The inverse correlations between H. pylori with erosive esophagitis and Barrett’s esophagus might be caused by gastric atrophy, which can be functionally assessed by serum measurements of pepsinogen I and II.
significant at 0.97 (95% CI: 0.75–1.27). A European population-based case–control study that included 65 363 patients found that H. pylori infection alone was not associated with a decreased risk of GERD symptoms, but the investigators did find a negative association for GERD symptoms in patients who had reduced pepsinogen levels and gastric atrophy (OR: 0.2; 95% CI: 0.8–1.5) [12]. As the prevalence of gastric atrophy in only 2% of the study population was low, but comparable to that reported in the European general population, this negative association is probably not of clinical importance for Europe. A recent study from the United States presented similar data. As in the European studies, GERD symptoms were not associated with H. pylori infection, irrespective of the CagA status. For erosive esophagitis, however, there was a negative association with H. pylori, in particular with CagA-positive strains (OR: 0.47; 95% CI: 0.21–1.03) [13 ]. More than 5000 patients were included in a Korean case–control study in which study individuals had serological assessment of H. pylori prevalence. The authors demonstrated an inverse correlation of H. pylori seroprevalence with the risk and severity of erosive esophagitis (OR: 0.44; 95% CI: 0.39–0.49) [14]. A large cross-sectional survey from Japan that included more than 10 000 individuals found no association for NERD and H. pylori infection, but did find a negative correlation for erosive reflux disease and H. pylori prevalence. A significant association with lower pepsinogen I/II ratio as a functional parameter for fundic gland atrophy supported a protective effective for atrophic gastritis in GERD [15 ]. Table 1 summarizes the recent publications on H. pylori, GERD symptoms, erosive esophagitis, and the prevalence of Barrett’s esophagus. &
EPIDEMIOLOGICAL STUDIES GERD is one of the most frequent diagnoses made by general practitioners in the United States, with enormous burden for the healthcare system [3,4].
Gastroesophageal reflux disease symptoms, erosive esophagitis, and Helicobacter pylori In epidemiological studies, the diagnosis of GERD usually has been based on typical symptoms (e.g. heartburn and regurgitation), or on an endoscopy revealing esophageal erosions or Barrett’s metaplasia [5,6]. Nonerosive reflux disease (NERD) has been diagnosed when there are typical reflux symptoms in the absence of mucosal lesions on endoscopy [5,6]. The definition of NERD has varied among clinical trials, and this variation might explain the poor response to proton pump inhibitor (PPI) treatment of NERD patients in some studies. Abnormal acid exposure on 24 h esophageal pH monitoring has been required in very few studies, but patients with NERD who have abnormal esophageal acid exposure have a higher response rate to PPI treatment [7–10]. Furthermore, GERD symptoms and erosive esophagitis should be considered separately since the correlation between symptoms and esophagitis can be poor. In a meta-analysis from 2003, Raghunath et al. [11] reported a pooled odds ratio (OR) of 0.76 (0.61– 0.96) for the relationship between H. pylori infection and GERD in European studies. This analysis included only studies in which GERD was defined by erosive esophagitis or by abnormal results of esophageal pH monitoring. However, after exclusion of one outlier study that seemed to dominate the analysis, the OR indicating a lower prevalence of GERD in patients with H. pylori was no longer
&&
Barrett’s esophagus, esophageal adenocarcinoma, and Helicobacter pylori H. pylori infection consistently has been reported to be negatively associated with Barrett’s esophagus and EAC. However, there is substantial heterogeneity in study designs and methodological aspects among the published reports. In 2012, Fischbach et al. [16] addressed this heterogeneity. Among 49 studies that initially were included in their metaanalysis, the investigators finally selected only four methodologically comparable studies that were appropriate for final analysis and reported a relative risk of 0.46 (95% CI: 0.35–0.60) for the development of Barrett’s esophagus in patients with H. pylori infection. A subgroup analysis of seven studies showed that this effect was stronger for infection with CagA-positive strains (0.38; 95% CI: 0.19–0.78)
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
403
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Esophagus Table 1. Association of Helicobacter pylori with GERD symptoms, erosive esophagitis, and Barrett’s esophagus – selection of the largest cohort studies Author
Year, study
GERD symptoms OR (95% CI)
Nordenstedt et al. [12]
2007, population based (n ¼ 944)
GERD symptoms: 1.1 (0.8–1.6)
Esophagitis OR (95% CI)
Barrett’s esophagus OR (95% CI) NA
Gastric atrophy (PGI): 0.2 (0.0–0.6) Chung et al. [14] Rubenstein et al. [13 ] &
2011, case-controlled study (n ¼ 5616) 2013, prospective study (n ¼ 533)
NA
0.44 (0.39–0.49)
NA
0.95 (0.55–1.64)
0.63 (0.37–1.08)
0.53 (0.29–0.97)
Symptoms onlya 1.0 (0.94–1.17)
0.58 (0.51–0.65) PGI/II ratio: 0.61 (0.50–0.72)
NA
CagA: 0.36 (0.14–0.90) Minatsuki et al. [15 ] &&
2013, cross-sectional study (n ¼ 10 837)
CagA, studies investigating CagA seropositivity; CI, confidence interval; GERD, gastroesophageal reflux disease; IgG, immunoglobulin G antibody; OR, odds ratio; PGI, pepsinogen I; PGII, pepsinogen II. a Patients with erosive esophagitis were excluded.
[16]. In another systematic review, Rokkas and colleagues [17] reported a lower H. pylori prevalence in patients with Barrett’s esophagus, especially for infection with CagA-positive strains. This meta-analysis also included 10 studies with EAC and found a negative association for this cancer with H. pylori prevalence and CagA seropositivity (OR: 0.51; 95% CI: 0.31–0.82). The authors suggested that H. pylori
Non-atrophic, antrum-predominant gastritis
&
LES pressure
–
Corpus-predominant gastritis with atrophy
infection protects against the development of Barrett’s esophagus and EAC [17]. A recent, prospective case–control study from the United States also demonstrated a negative association between Barrett’s esophagus and H. pylori (OR: 0.53; 95% CI: 0.29–0.97), especially with CagA-positive strains (OR: 0.36; 95% CI: 0.14–0.90) [13 ] (Fig. 1). Although a negative correlation between H. pylori infection
Ammonia nitric oxide
+
Acid
Gastrin –
LES pressure
Acid Ammonia nitric oxide
Gastrin
FIGURE 1. Putative mechanisms of H. pylori gastritis phenotype operative in gastroesophageal reflux disease pathophysiology. Gastrin regulated in both ways depending on amount of residual acid production in chronic atrophic or corpus predominant gastritis. 404
www.co-gastroenterology.com
Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner
and Barrett’s esophagus has been observed consistently when Barrett’s esophagus patients are compared to an ‘endoscopically’ normal control group, this negative association has not been observed in studies that used healthy blood donors as controls [18]. Esophageal exposure to gastric acid and bile acids arising from duodenogastroesophageal reflux is the presumed mechanism for the pathogenesis of Barrett’s esophagus [19]. H. pylori infection that causes gastritis with gastric atrophy might reduce esophageal acid exposure and thereby protect against Barrett’s esophagus. Prospectively, Anderson et al. [20] investigated serum levels of pepsinogen I and II as markers for fundic gland atrophy in association with Barrett’s esophagus. In addition to finding a negative association between H. pylori and Barrett’s esophagus and EAC, the authors found a reduced risk for the development of Barrett’s esophagus even in the presence of only mild gastric atrophy (pepsinogen I/II < 7) [20]. On the basis of these findings, the development of Barrett’s esophagus and EAC appears to occur mostly in patients with a nonatrophic gastric mucosa that is capable of producing the acid required for the pathogenesis of Barrett’s esophagus [21].
EFFECTS OF HELICOBACTER PYLORI INFECTION ON GASTRIC ACID SECRETION, ESOPHAGEAL ACID EXPOSURE, AND MECHANISMS OF GASTROESOPHAGEAL REFLUX There have not been numerous publications on pathophysiological interactions between H. pylori infection and the factors underlying GERD in recent years. Gastric acid secretion can be increased in patients who have an antrum-predominant form of H. pylori gastritis. Although such patients might be expected to have an increased prevalence of GERD, there is no evidence for abnormal acid exposure of the distal esophagus in H. pylori-positive patients as long as the antireflux barrier is healthy and functions normally [22]. In western countries, antrum-predominant gastritis is frequent in patients with GERD [23–27] (Fig. 1), and only a small subset of infected patients with GERD have corpus-predominant gastritis or gastric atrophy with impaired acid secretion. Patients with atrophic gastritis have impaired gastric acid secretion [27], which has been proposed as a protective mechanism against GERD. In Asia and Japan, where corpus-predominant and atrophic gastritis associated acid hyposecretion is more prevalent (Fig. 1), it appears that H. pylori eradication followed by recovery of the corpus mucosa and acid secretion may predispose a small
subset of patients to develop GERD [28,29]. In patients with established GERD, no differences in esophageal acid exposure have been observed between H. pylori-positive and H. pylori-negative patients [30,31]. One report described increased duodenogastric reflux in H. pylori-positive patients by scintigraphic studies, but found no difference between H. pylori-positive and H. pylori-negative patients in gastroesophageal reflux [32]. Similar results were described in a study using the Bilitec technique to evaluate duodenogastric reflux [33].
Helicobacter pylori and potential effects on esophageal motility The lower esophageal sphincter (LES) is an important component of the gastroesophageal antireflux barrier, and LES relaxation can result from exposure to nitric oxide and ammonium. Both of these nitrate compounds are increased in the gastric juice of H. pylori-infected patients, but it is unlikely that they reach concentrations sufficient to affect esophageal small muscle cells and lower LES pressure. It is more likely that increased serum gastrin levels in antrum-predominant H. pylori gastritis may increase LES pressure, as shown in pathophysiological models (Fig. 1) [34,35]. The frequency of transient relaxation of the LES (transient lower esophageal sphincter relaxations), a common mechanism for gastroesophageal reflux, was not found to differ significantly between H. pylori-infected and noninfected patients [36]. In a recent study that included 64 adolescents and young adults with GERD symptoms and pathologic acid exposure on esophageal pH monitoring, again no differences were observed between H. pylori-positive and H. pylori-negative patients regarding the severity of esophageal acid exposure and frequency of esophageal motility abnormalities. Furthermore, H. pylori eradication had no impact on acid exposure or esophageal motility [37 ]. Similar results were described in earlier reports [38,39]. Overall, existing data do not support any effects of H. pylori on esophageal motility. &
HELICOBACTER PYLORI ERADICATION AND GASTROESOPHAGEAL REFLUX DISEASE H. pylori eradication has been reported to favor the development of GERD and, as a consequence, it has been proposed that H. pylori protects against the development of erosive esophagitis [1,40,41]. In contrast, however, other studies have described no effect on GERD development, with some even reporting a decrease in GERD symptoms after
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
405
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Esophagus
H. pylori eradication [42]. In a post-hoc analysis of eight randomized trials, H. pylori eradication did not have a significant effect on the development of erosive esophagitis, new onset of GERD symptoms, or worsening of preexisting symptoms [43]. In 2011, a prospective trial showed no significant differences between patients with or without successful H. pylori eradication in their rates of developing reflux symptoms and erosive esophagitis [44]. A meta-analysis including 10 randomized controlled trials found no difference in the incidence of reflux symptoms (OR: 0.81; 95% CI: 0.56–1.17) and reflux esophagitis (OR: 1.13; 95% CI: 0.72–1.78) between patients who received eradication therapy or placebo [45]. Further meta-analyses reported in 2010 and 2011 came to the same conclusions [46,47]. A subgroup analysis showed a significant improvement of GERD symptoms after successful eradication when compared to persisting H. pylori infection [45]. An improvement of GERD symptomrelated quality of life has also been demonstrated 1 year after eradication therapy [48]. In contrast, one study of H. pylori eradication for gastric cancer prevention in a large population in Taiwan found a significant increase in the incidence of erosive esophagitis when the infection was eradicated. Interestingly, in this area with a high prevalence of H. pylori-associated gastric atrophy (60% before eradication), the authors found a significant reduction of gastric atrophy after 5 years that correlated with the increased incidence of erosive esophagitis [49 ]. &
CONCLUSION Epidemiological studies have found no significant association between H. pylori infection and GERD symptoms. In contrast, H. pylori infection in general, with CagA-positive strains in particular, has consistently been found to be negatively associated with erosive reflux disease, Barrett’s esophagus, and EAC. Recent publications have supported these associations, but they have not provided any additional insights into the causality for these findings. H. pylori-induced gastric atrophy, investigated by serum levels of pepsinogen I and II in several studies, is the most advocated mechanism for how H. pylori infection protects the distal esophagus from abnormal acid exposure. In most interventional studies on H. pylori eradication, there was no increase in GERD. In Asian countries and other areas with a high prevalence of H. pylori-associated atrophic gastritis, where this is not the case, the benefits for H. pylori eradication would anyhow outweigh by far the prevention of gastric cancer as compared to the risk for GERD development. 406
www.co-gastroenterology.com
Acknowledgements None. Conflicts of interest Peter Malfertheiner received speakers fees from Aptalis, Falk, Reckitt-Benckiser, and Takeda. Arne Kandulski has no conflicts of interests.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Labenz J, Blum AL, Bayerdorffer E, et al. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112:1442–1447. 2. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection – the Maastricht IV/Florence consensus report. Gut 2012; 61:646–664. 3. Irvine EJ. Quality of life assessment in gastro-oesophageal reflux disease. Gut 2004; 53 (Suppl 4):iv35–iv39. 4. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012; 143:1179–1187. 5. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. 6. Dent J, Brun J, Fennerty MB, et al. An evidence-based appraisal of reflux disease management – the Genval Workshop Report. Gut 1999; 44 (Suppl 2):S1–S16. 7. Kandulski A, Peitz U, Monkemuller K, et al. GERD assessment including pH metry predicts a high response rate to PPI standard therapy. BMC Gastroenterol 2013; 13:12. 8. Weigt J, Monkemuller K, Peitz U, Malfertheiner P. Multichannel intraluminal impedance and pH-metry for investigation of symptomatic gastroesophageal reflux disease. Dig Dis 2007; 25:179–182. 9. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013; 108:308– 328. 10. Weijenborg PW, Cremonini F, Smout AJ, Bredenoord AJ. PPI therapy is equally effective in well defined nonerosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil 2012; 24:747–757. 11. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003; 326:737. 12. Nordenstedt H, Nilsson M, Johnsen R, et al. Helicobacter pylori infection and gastroesophageal reflux in a population-based study (The HUNT Study). Helicobacter 2007; 12:16–22. 13. Rubenstein JH, Inadomi JM, Scheiman J, et al. Association between Helico& bacter pylori and Barrett’s esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 2013; 12:239– 245. Recent epidemiologic investigation demonstrating the inverse association of H. pylori with erosive esophagitis and Barrett’s esophagus in the United States. 14. Chung SJ, Lim SH, Choi J, et al. Helicobacter pylori serology inversely correlated with the risk and severity of reflux esophagitis in Helicobacter pylori endemic area: a matched case–control study of 5616 health check-up Koreans. J Neurogastroenterol Motil 2011; 17:267–273. 15. Minatsuki C, Yamamichi N, Shimamoto T, et al. Background factors of reflux && esophagitis and nonerosive reflux disease: a cross-sectional study of 10 837 subjects in Japan. PLoS One 2013; 8:e69891. The authors conducted a prospective, cross-sectional survey including more than 10 000 patients from Japan demonstrating a negative association between H. pylori and erosive esophagitis, with a significant association with low pepsinogen I/II ratios as a functional parameter for fundic gland atrophy. 16. Fischbach LA, Nordenstedt H, Kramer JR, et al. The association between Barrett’s esophagus and Helicobacter pylori infection: a meta-analysis. Helicobacter 2012; 17:163–175. 17. Rokkas T, Pistiolas D, Sechopoulos P, et al. Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin Gastroenterol Hepatol 2007; 5:1413–1417; 1417. 18. Wang C, Yuan Y, Hunt RH. Helicobacter pylori infection and Barrett’s esophagus: a systematic review and meta-analysis. Am J Gastroenterol 2009; 104:492–500. 19. Fitzgerald RC. Molecular basis of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 2006; 55:1810–1820.
Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Helicobacter pylori and gastroesophageal reflux disease Kandulski and Malfertheiner 20. Anderson LA, Murphy SJ, Johnston BT, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case–control study. Gut 2008; 57:734–739. 21. McColl KE, Going JJ. Aetiology and classification of adenocarcinoma of the gastro-oesophageal junction/cardia. Gut 2010; 59:282–284. 22. Sarnelli G, Ierardi E, Grasso R, et al. Acid exposure and altered acid clearance in GERD patients treated for Helicobacter pylori infection. Dig Liver Dis 2003; 35:151–156. 23. McColl KE, El-Omar EM, Gillen D. Alterations in gastric physiology in Helicobacter pylori infection: causes of different diseases or all epiphenomena? Ital J Gastroenterol Hepatol 1997; 29:459–464. 24. Leodolter A, Wolle K, Peitz U, et al. Helicobacter pylori genotypes and expression of gastritis in erosive gastro-oesophageal reflux disease. Scand J Gastroenterol 2003; 38:498–502. 25. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet 2009; 374:1449–1461. 26. Leodolter A, Ebert MP, Peitz U, et al. Prevalence of H. pylori associated ‘high risk gastritis’ for development of gastric cancer in patients with normal endoscopic findings. World J Gastroenterol 2006; 12:5509–5512. 27. El-Omar EM, Oien K, El-Nujumi A, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997; 113:15–24. 28. Naylor GM, Gotoda T, Dixon M, et al. Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients. Gut 2006; 55:1545–1552. 29. Haruma K. Review article: influence of Helicobacter pylori on gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther 2004; 20 (Suppl 8): 40–44. 30. Fallone CA, Barkun AN, Mayrand S, et al. There is no difference in the disease severity of gastro-oesophageal reflux disease between patients infected and not infected with Helicobacter pylori. Aliment Pharmacol Ther 2004; 20:761–768. 31. Grande M, Cadeddu F, Villa M, et al. Helicobacter pylori and gastroesophageal reflux disease. World J Surg Oncol 2008; 6:74. 32. Artiko VM, Chebib HY, Ugljesic MB, et al. Relationship between enterogastric reflux estimated by scintigraphy and the presence of Helicobacter pylori. Hepatogastroenterology 1999; 46:1234–1237. 33. Manifold DK, Anggiansah A, Rowe I, et al. Gastro-oesophageal reflux and duodenogastric reflux before and after eradication in Helicobacter pylori gastritis. Eur J Gastroenterol Hepatol 2001; 13:535–539. 34. Beales I, Blaser MJ, Srinivasan S, et al. Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells. Gastroenterology 1997; 113:465–471. 35. Calam J, Gibbons A, Healey ZV, et al. How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 1997; 113 (6 Suppl):S43–S49.
36. Zerbib F, Bicheler V, Leray V, et al. H. pylori and transient lower esophageal sphincter relaxations induced by gastric distension in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001; 281:G350–G356. 37. Xinias I, Maris T, Mavroudi A, et al. Helicobacter pylori infection has no impact & on manometric and pH-metric findings in adolescents and young adults with gastroesophageal reflux and antral gastritis: eradication results to no significant clinical improvement. Pediatr Rep 2013; 5:e3. H. pylori and H. pylori eradication had no significant effects on esophageal acid exposure or esophageal motility. 38. Verma S, Jackson W, Floum S, Giaffer MH. Gastroesophageal reflux before and after Helicobacter pylori eradication. A prospective study using ambulatory 24-h esophageal pH monitoring. Dis Esophagus 2003; 16:273–278. 39. Guliter S, Kandilci U. The effect of Helicobacter pylori eradication on gastroesophageal reflux disease. J Clin Gastroenterol 2004; 38:750–755. 40. Lee JM, O’Morain CA. Different management for Helicobacter pylori positive and negative patients with gastro-oesophageal reflux disease? Gut 1998; 43 (Suppl 1):S14–S20. 41. Sacca N, De MA, Rodino S, et al. Reflux esophagitis: a complication of Helicobacter pylori eradication therapy? Endoscopy 1997; 29:224. 42. Vaira D, Vakil N, Rugge M, et al. Effect of Helicobacter pylori eradication on development of dyspeptic and reflux disease in healthy asymptomatic subjects. Gut 2003; 52:1543–1547. 43. Laine L, Sugg J. Effect of Helicobacter pylori eradication on development of erosive esophagitis and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double blind prospective studies. Am J Gastroenterol 2002; 97:2992–2997. 44. Kim N, Lee SW, Kim JI, et al. Effect of Helicobacter pylori eradication on the development of reflux esophagitis and gastroesophageal reflux symptoms: a nationwide multi-center prospective study. Gut Liver 2011; 5:437–446. 45. Saad AM, Choudhary A, Bechtold ML. Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials. Scand J Gastroenterol 2012; 47:129–135. 46. Qian B, Ma S, Shang L, et al. Effects of Helicobacter pylori eradication on gastroesophageal reflux disease. Helicobacter 2011; 16:255–265. 47. Yaghoobi M, Farrokhyar F, Yuan Y, Hunt RH. Is there an increased risk of GERD after Helicobacter pylori eradication?: a meta-analysis. Am J Gastroenterol 2010; 105:1007–1013. 48. Hirata K, Suzuki H, Matsuzaki J, et al. Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy. J Clin Biochem Nutr 2013; 52:172–178. 49. Lee YC, Chen TH, Chiu HM, et al. The benefit of mass eradication of & Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut 2013; 62:676–682. H. pylori eradication for gastric cancer prevention in Taiwan resulted in a significant increase in the incidence of erosive esophagus that was associated with a significant reduction in the frequency of gastric atrophy after 5 years.
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
407
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
