Review Article | Open Access
Helicobacter pylori Infection in Gastroesophageal Reflux Disease in the Asian Countries
Helicobacter pylori infection, a common infection in many countries, is related to the clinical course of upper gastrointestinal diseases. Gastroesophageal reflux disease (GERD) is a common esophageal disease in Western countries and its prevalence is increasing in Asian countries. The pathophysiology of GERD is multifactorial. Although no single factor has been isolated as the cause of GERD, a negative association between the prevalence of H. pylori and the severity of GERD, including Barrett’s esophagus, has been demonstrated in epidemiological studies. The high prevalence of H. pylori infection affects the incidence of GERD in Asian countries. In the subjects with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD. The interactions between genetic factors and the virulence of H. pylori infection may be the reason for the low prevalence of GERD in Asian countries. H. pylori eradication is not considered pivotal in GERD exacerbation based on evidence from Western studies. A recent meta-analysis demonstrated that eradication therapy of H. pylori was related to a higher risk of developing de novo GERD in Asian studies. H. pylori infection remains an inconclusive and important issue in GERD in Asian countries.
The prevalence of gastroesophageal reflux disease (GERD) in the general population has been estimated to be 10–20% [1–4]. Conversely, most Asian population-based studies have reported a lower prevalence of less than 10% [3–6]. In epidemiological studies, H. pylori and GERD have been found to be negatively associated and strongly related to cytotoxin-associated gene product- (CagA-) positive strains of H. pylori . However, an increasing prevalence of GERD and decreasing prevalence of H. pylori have been reported in Asian countries , which is in agreement with a previous report of no increase in the prevalence of GERD symptoms with age . GERD markedly reduces patients’ quality of life and imparts a significant economic burden on the healthcare system [9–11]. Therefore, decreasing the prevalence of H. pylori infection is an important issue in GERD, especially in Asian populations. In addition, H. pylori eradication has been presumed to exacerbate GERD due to improvement of gastritis and the recovery of hypochlorhydria; several studies have been conducted to clarify this controversy.
2. Gastric Acidity and H. pylori
Gastric acid plays a key role in the etiology of GERD and is an element of the disease that may be modified by H. pylori infection. Gastric secretion can increase, decrease, or remain steady depending on the pattern of H. pylori-related inflammation . The major components of acid secretion in patients with H. pylori infection include the density of H. pylori colonization, its distribution, and the severity of the mucosal inflammatory response to the infection. Patients with a duodenal ulcer and H. pylori infection have antrum-predominant gastritis, which leads to hypergastrinemia and acid hypersecretion. In contrast, patients with gastric ulcer or gastric cancer present mainly with corpus-predominant gastritis or pangastritis, which is characterized by intense destruction or atrophy of acid-secreting glands. Patients who have corpus-predominant gastritis or pangastritis also show gastric acid hyposecretion [13, 14]. Bacterial virulence and host inflammatory responses are important in determining patterns of acid secretion and gastritis. East Asian CagA-positive strain of H. pylori induces primarily corpus-predominant gastritis or pangastritis with hypochlorhydria. And, East Asian CagA-positive strain is strongly associated with gastric cancer. A Japanese study revealed different sequences of CagA between the regions where gastric cancer is prevalent or not. The authors defined the East Asian CagA-positive strains which showed the specific repeat sequences located in the 3′ region of cagA gene. In the study, most CagA-positive strains in Asian countries were East Asian CagA-positive strains and most CagA-positive strains in Western countries were Western CagA-positive strains . In Asian populations with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD. IL-1B and IL-1RN genetic polymorphisms are inversely associated with the risk of GERD in H. pylori-infected subjects because their specific genotypes are linked to corpus atrophy, gastric cancer, and hypochlorhydria [16–20]. Thus, such specific genotypes, including the IL-1B-511-T, IL-1B-31-C, and IL-1RN-1 alleles, can be considered protective against GERD. In particular, the subjects with IL-1B-511 T allele is accentuated in the presence of H. pylori infection due to high gastric mucosal IL-1β levels [20, 21]. However, other investigators have reported contradictory results that IL-1B-511-T allele was associated with reflux esophagitis . These opposite results suggest ethnic differences regarding IL-1 genetic polymorphisms and levels of gastric mucosal IL-1β. Additionally, several genetic risk factors for GERD, including polymorphisms in G-protein beta 3 subunit gene (GNB3) , IL-10 , CYP2C19 , glutathione S-transferase P1 [26, 27], cyclin D1 , and DNA repair genes , may be involved.
3. Epidemiological Evidence of a Link between H. pylori Infection and GERD
Table 1 shows recent epidemiological reports of an inverse relationship between H. pylori infection and reflux esophagitis or Barrett’s esophagus in the western countries and East Asian countries [30–35]. This negative association was also evident in patients with severe GERD and H. pylori infection with virulent CagA-positive strains in Western countries [36, 37]. The prevalence of H. pylori infection is inversely correlated with the risk and severity of reflux esophagitis; [30, 37, 38] and the prevalence of H. pylori infection suggests a protective role in both Barrett’s esophagus and esophageal adenocarcinoma [7, 34, 35, 37–41].
|GERD: gastroesophageal reflux disease.|
4. Proton Pump Inhibitors (PPIs) in GERD Patients with H. pylori Infection
Long-term maintenance therapy of proton pump inhibitors (PPIs) for GERD induces gastritis and progression of gastric atrophy and intestinal metaplasia to gastric adenocarcinoma in patients with H. pylori infection [46, 47]. These patterns are significantly associated with the CagA-positive strains . Current guidelines, including the Asia-Pacific Consensus for H. pylori infection, recommend H. pylori eradication in GERD patients requiring long-term PPIs . However, there is no evidence that H. pylori eradication reduces the risk of gastric adenocarcinoma in patients with this condition.
5. H. pylori Eradication in GERD
Despite the inverse relationship between H. pylori and GERD in cross-sectional studies, the results are less consistent in prospective studies of H. pylori eradication in patients with GERD. Early studies revealed that H. pylori eradication was positively associated with reflux esophagitis or GERD symptoms in patients with gastric and duodenal ulcer diseases [50, 51]. Hiatal hernia, corpus gastritis, and CagA-positive H. pylori strains have been reported to be risk factors for newly developed reflux esophagitis after H. pylori eradication [51, 52]. However, other studies have shown improvement of reflux symptoms after H. pylori eradication in patients with peptic ulcer disease and nonulcer dyspepsia [53, 54]. The Maastricht IV Consensus Report suggested that H. pylori eradication does not exacerbate preexisting GERD or affect treatment efficacy . A recent meta-analysis demonstrated that eradication therapy of H. pylori was related to a significantly higher risk of developing de novo GERD in Asian studies . In contrast, no such risk has been reported by Western studies [43–45]. Table 2 shows the summaries of the results of meta-analyses. However, this remains an inconclusive issue in Asian countries. For example, two large-scale cohort studies in Korea produced inconsistent results [56, 57]. Thus, the revised version of the Korean guidelines for Helicobacter pylori infection states that H. pylori eradication does not affect the development or clinical course of GERD .
|RCT: randomized controlled trial; GERD: gastroesophageal reflux disease; H. pylori: Helicobacter pylori.|
H. pylori infection and GERD are highly prevalent conditions globally. The prevalence of H. pylori varies geographically and among ethnicities. Many epidemiological studies have shown a negative correlation between H. pylori infection and GERD. A specific virulence factor, such as CagA, and specific host genotypes may affect the diverse prevalence and other aspects of GERD owing to individual differences in acid secretion. A high prevalence of CagA-positive strains has been reported in Asian countries. The diversity of H. pylori infection between Western and Asian countries should be considered when analyzing the results of studies of H. pylori eradication in GERD patients. To date, cohort studies and randomized controlled trials of the effects of H. pylori eradication on GERD are inconclusive. The decreasing prevalence of H. pylori and the recovery of acid secretion capacity after eradication in patients with CagA-positive H. pylori and corpus gastritis are possible causes of the higher prevalence of GERD in Asian countries. These issues necessitate a more detailed study.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Su Jin Hong wrote the paper; Sang Woo Kim revised the paper.
- G. R. Locke III, N. J. Talley, S. L. Fett, A. R. Zinsmeister, and L. J. Melton III, “Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota,” Gastroenterology, vol. 112, no. 5, pp. 1448–1456, 1997.
- J. Y. Kang, “Systematic review: geographical and ethnic differences in gastro-oesophageal reflux disease,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 7, pp. 705–717, 2004.
- J. Dent, H. B. El-Serag, M.-A. Wallander, and S. Johansson, “Epidemiology of gastro-oesophageal reflux disease: a systematic review,” Gut, vol. 54, no. 5, pp. 710–717, 2005.
- A. Becher and J. Dent, “Systematic review: ageing and gastro-oesophageal reflux disease symptoms, oesophageal function and reflux oesophagitis,” Alimentary Pharmacology & Therapeutics, vol. 33, no. 4, pp. 442–454, 2011.
- N. Kim, S. W. Lee, S. I. Cho et al., “The prevalence of and risk factors for erosive oesophagitis and non-erosive reflux disease: a nationwide multicentre prospective study in Korea,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 2, pp. 173–185, 2008.
- W. M. Wong, K. C. Lai, K. F. Lam et al., “Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study,” Alimentary Pharmacology & Therapeutics, vol. 18, no. 6, pp. 595–604, 2003.
- D. A. Corley, A. Kubo, T. R. Levin et al., “Helicobacter pylori and gastroesophageal reflux disease: a case-control study,” Helicobacter, vol. 13, no. 5, pp. 352–360, 2008.
- K. Y. Ho, Y. H. Chan, and J. Y. Kang, “Increasing trend of reflux esophagitis and decreasing trend of Helicobacter pylori infection in patients from a multiethnic Asian country,” The American Journal of Gastroenterology, vol. 100, no. 9, pp. 1923–1928, 2005.
- W. G. Shin, H. U. Kim, S. G. Kim et al., “Work productivity and activity impairment in gastroesophageal reflux disease in Korean full-time employees: a multicentre study,” Digestive and Liver Disease, vol. 44, no. 4, pp. 286–291, 2012.
- E. M. M. Quigley and A. P. S. Hungin, “Review article: quality-of-life issues in gastro-oesophageal reflux disease,” Alimentary Pharmacology & Therapeutics, vol. 22, supplement 1, pp. 41–47, 2005.
- B. B. Dean, J. A. Crawley, C. M. Schmitt, J. Wong, and J. J. Ofman, “The burden of illness of gastro-oesophageal reflux disease: impact on work productivity,” Alimentary Pharmacology and Therapeutics, vol. 17, no. 10, pp. 1309–1317, 2003.
- K. E. L. McColl, E. El-Omar, and D. Gillen, “Interactions between H. pylori infection, gastric acid secretion and anti-secretory therapy,” British Medical Bulletin, vol. 54, no. 1, pp. 121–138, 1998.
- T. Koike, S. Ohara, H. Sekine et al., “Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis,” American Journal of Gastroenterology, vol. 94, no. 12, pp. 3468–3472, 1999.
- T. Koike, S. Ohara, H. Sekine et al., “Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion,” Gut, vol. 49, no. 3, pp. 330–334, 2001.
- T. Azuma, S. Yamazaki, A. Yamakawa et al., “Association between diversity in the Src homology 2 domain—containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer,” Journal of Infectious Diseases, vol. 189, no. 5, pp. 820–827, 2004.
- T. Ando, E. M. El-Omar, Y. Goto et al., “Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy,” Gut, vol. 55, no. 2, pp. 158–164, 2006.
- S. Kato, M. Onda, S. Yamada, N. Matsuda, A. Tokunaga, and N. Matsukura, “Association of the interleukin-1β genetic polymorphism and gastric cancer risk in Japanese,” Journal of Gastroenterology, vol. 36, no. 10, pp. 696–699, 2001.
- T. Furuta, E. M. El-Omar, F. Xiao, N. Shirai, M. Takashima, and H. Sugimura, “Interleukin 1β polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan,” Gastroenterology, vol. 123, pp. 92–105, 2002.
- D. M. M. Queiroz, J. B. Guerra, G. A. Rocha et al., “IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis,” Gastroenterology, vol. 127, no. 1, pp. 73–79, 2004.
- D. Chourasia, B. R. Achyut, S. Tripathi, B. Mittal, R. D. Mittal, and U. C. Ghoshal, “Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL- 1RN*1 (T1) haplotype may protect against the disease,” The American Journal of Gastroenterology, vol. 104, no. 11, pp. 2704–2713, 2009.
- J. J. Kim, N. Kim, S. Hwang et al., “Relationship of interleukin-1β levels and gastroesophageal reflux disease in Korea,” Journal of Gastroenterology and Hepatology, vol. 28, no. 1, pp. 90–98, 2013.
- A. Muramatsu, T. Azuma, T. Okuda et al., “Association between interleukin-1β-511C/T polymorphism and reflux esophagitis in Japan,” Journal of Gastroenterology, vol. 40, no. 9, pp. 873–877, 2005.
- D. R. de Vries, J. J. M. Ter Linde, M. A. van Herwaarden, A. J. P. M. Smout, and M. Samsom, “Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3),” The American Journal of Gastroenterology, vol. 104, no. 2, pp. 281–285, 2009.
- M. D. Gough, R. Ackroyd, A. W. Majeed, and N. C. Bird, “Prediction of malignant potential in reflux disease: are cytokine polymorphisms important?” The American Journal of Gastroenterology, vol. 100, no. 5, pp. 1012–1018, 2005.
- M. Kawamura, S. Ohara, T. Koike et al., “The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19 polymorphism,” Alimentary Pharmacology and Therapeutics, vol. 17, no. 7, pp. 965–973, 2003.
- A. G. Casson, Z. Zheng, G. A. Porter, and D. L. Guernsey, “Genetic polymorphisms of microsomal epoxide hydroxylase and glutathione S-transferases M1, T1 and P1, interactions with smoking, and risk for esophageal (Barrett) adenocarcinoma,” Cancer Detection and Prevention, vol. 30, no. 5, pp. 423–431, 2006.
- B. Liu, Y. J. Fan, M. L. Wang et al., “Genetic polymorphisms in glutathione S-transferases T1, M1 and P1 and susceptibility to reflux esophagitis,” Diseases of the Esophagus, vol. 19, no. 6, pp. 477–481, 2006.
- A. G. Casson, Z. Zheng, S. C. Evans et al., “Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma,” Cancer, vol. 104, no. 4, pp. 730–739, 2005.
- A. G. Casson, Z. Zheng, S. C. Evans, P. J. Veugelers, G. A. Porter, and D. L. Guernsey, “Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma,” Carcinogenesis, vol. 26, no. 9, pp. 1536–1541, 2005.
- S. J. Chung, S. H. Lim, J. Choi 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 5,616 health check-up Koreans,” Journal of Neurogastroenterology and Motility, vol. 17, no. 3, pp. 267–273, 2011.
- T. Gunji, H. Sato, K. Iijima et al., “Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males,” Journal of Gastroenterology, vol. 46, no. 4, pp. 448–455, 2011.
- H. Chiba, T. Gunji, H. Sato et al., “A cross-sectional study on the risk factors for erosive esophagitis in young adults,” Internal Medicine, vol. 51, no. 11, pp. 1293–1299, 2012.
- H. Ashktorab, O. Entezari, M. Nouraie et al., “Helicobacter pylori protection against reflux esophagitis,” Digestive Diseases and Sciences, vol. 57, no. 11, pp. 2924–2928, 2012.
- A. Sonnenberg, R. H. Lash, and R. M. Genta, “A national study of helicobactor pylori infection in gastric biopsy specimens,” Gastroenterology, vol. 139, no. 6, pp. 1894.e2–1901.e2, 2010.
- A. P. Thrift, N. Pandeya, K. J. Smith et al., “Helicobacter pylori infection and the risks of Barrett's oesophagus: a population-based case-control study,” International Journal of Cancer, vol. 130, no. 10, pp. 2407–2416, 2012.
- J. J. Vicari, R. M. Peek, G. W. Falk et al., “The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease,” Gastroenterology, vol. 115, no. 1, pp. 50–57, 1998.
- A. P. Weston, A. S. Badr, M. Topalovski, R. Cherian, A. Dixon, and R. S. Hassanein, “Prospective evaluation of the prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett's esophagus, Barrett's dysplasia, and Barrett's adenocarcinoma,” American Journal of Gastroenterology, vol. 95, no. 2, pp. 387–394, 2000.
- J. Zhang, X.-L. Chen, K.-M. Wang, X.-D. Guo, A.-L. Zuo, and J. Gong, “Relationship of gastric Helicobacter pylori infection to Barrett's esophagus and gastro-esophageal reflux disease in Chinese,” World Journal of Gastroenterology, vol. 10, no. 5, pp. 672–675, 2004.
- Y. Abe, S. Ohara, T. Koike et al., “The prevalence of Helicobacter pylori infection and the status of gastric acid secretion in patients with Barrett's esophagus in Japan,” The American Journal of Gastroenterology, vol. 99, no. 7, pp. 1213–1221, 2004.
- T. Rokkas, D. Pistiolas, P. Sechopoulos, I. Robotis, and G. Margantinis, “Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis,” Clinical Gastroenterology and Hepatology, vol. 5, no. 12, pp. 1413–1417, 2007.
- D. C. Whiteman, P. Parmar, P. Fahey et al., “Association of Helicobacter pylori infection with reduced risk for esophageal cancer is independent of environmental and genetic modifiers,” Gastroenterology, vol. 139, no. 1, pp. 73–83, 2010.
- T. Xie, X. Cui, H. Zheng, D. Chen, L. He, and B. Jiang, “Meta-analysis: eradication of Helicobacter pylori infection is associated with the development of endoscopic gastroesophageal reflux disease,” European Journal of Gastroenterology and Hepatology, vol. 25, no. 10, pp. 1195–1205, 2013.
- M. Yaghoobi, F. Farrokhyar, Y. Yuan, and R. H. Hunt, “Is there an increased risk of GERD after Helicobacter pylori eradication: a meta-analysis,” The American Journal of Gastroenterology, vol. 105, no. 5, pp. 1007–1013, 2010.
- B. Qian, S. Ma, L. Shang, J. Qian, and G. Zhang, “Effects of Helicobacter pylori eradication on gastroesophageal reflux disease,” Helicobacter, vol. 16, no. 4, pp. 255–265, 2011.
- A. M. Saad, A. Choudhary, and M. L. Bechtold, “Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials,” Scandinavian Journal of Gastroenterology, vol. 47, no. 2, pp. 129–135, 2012.
- A. E. Berstad, J. G. Hatlebakk, H. Maartmann-Moe, and P. Brandtzaeg, “Helicobacter pylori gastritis and epithelial cell proliferation in patients with reflux oesophagitis after treatment with lansoprazole,” Gut, vol. 41, no. 6, pp. 740–747, 1997.
- P. Moayyedi, C. Wason, R. Peacock et al., “Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression,” Helicobacter, vol. 5, no. 4, pp. 206–214, 2000.
- S. Gudlaugsdottir, H. Van Dekken, T. Stijnen, and J. H. P. Wilson, “Prolonged use of proton pump inhibitors, CagA status, and the outcome of Helicobacter pylori gastritis,” Journal of Clinical Gastroenterology, vol. 34, no. 5, pp. 536–540, 2002.
- K. M. Fock, P. Katelaris, K. Sugano et al., “Second Asia-Pacific consensus guidelines for Helicobacter pylori infection,” Journal of Gastroenterology and Hepatology, vol. 24, no. 10, pp. 1587–1600, 2009.
- T. Koike, S. Ohara, H. Sekine et al., “Increased gastric acid secretion after Helicobacter pylori eradication may be a factor for developing reflux oesophagitis,” Alimentary Pharmacology and Therapeutics, vol. 15, no. 6, pp. 813–820, 2001.
- H. Hamada, K. Haruma, M. Mihara et al., “High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: impacts of hiatal hernia and corpus gastritis,” Alimentary Pharmacology and Therapeutics, vol. 14, no. 6, pp. 729–735, 2000.
- T. Rokkas, S. D. Ladas, K. Triantafyllou et al., “The association between CagA status and the development of esophagitis after the eradication of Helicobacter pylori,” The American Journal of Medicine, vol. 110, no. 9, pp. 703–707, 2001.
- P. Malfertheiner, J. Dent, L. Zeijlon et al., “Impact of Helicobacter pylori eradication on heartburn in patients with gastric or duodenal ulcer disease—results from a randomized trial programme,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 8, pp. 1431–1442, 2002.
- N. Vakil, N. J. Talley, M. Stolte, M. Sundin, O. Junghard, and E. Bolling-Sternevald, “Patterns of gastritis and the effect of eradicating Helicobacter pylori on gastro-oesophageal reflux disease in Western patients with non-ulcer dyspepsia,” Alimentary Pharmacology & Therapeutics, vol. 24, no. 1, pp. 55–63, 2006.
- P. Malfertheiner, F. Megraud, C. A. O'Morain et al., “Management of Helicobacter pylori infection—the Maastricht IV/ Florence consensus report,” Gut, vol. 61, no. 5, pp. 646–664, 2012.
- S. Y. Nam, I. J. Choi, K. H. Ryu, B. C. Kim, C. G. Kim, and B.-H. Nam, “Effect of Helicobacter pylori infection and its eradication on reflux esophagitis and reflux symptoms,” The American Journal of Gastroenterology, vol. 105, no. 10, pp. 2153–2162, 2010.
- N. Kim, S. W. Lee, J. I. Kim et al., “Effect of Helicobacter pylori eradication on the development of reflux esophagitis and gastroesophageal reflux symptoms: a nationwide multi-center prospective study,” Gut and Liver, vol. 5, no. 4, pp. 437–446, 2011.
- S. G. Kim, H. Jung, H. L. Lee et al., “Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition,” Journal of Gastroenterology and Hepatology, vol. 29, pp. 1371–1386, 2014.
Copyright © 2015 Su Jin Hong and Sang Woo Kim. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.