Reflux esophagitis triggered after Helicobacter pylori eradication: a noteworthy demerit of eradication therapy among the Japanese?
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
In the February 2013 Revision of Insured Medical Treatment, bacterial eradication for all Helicobacter pylori-positive individuals in Japan was covered under the insurance scheme. However, reflux esophagitis is believed to occur in approximately 10% of Japanese patients who undergo eradication therapy. Hence, the risk of reflux esophagitis among such cases should be carefully considered, particularly in the treatment for H. pylori-positive patients who are otherwise healthy. The eradication of H. pylori in cases of H. pylori-positive gastritis markedly suppresses gastric inflammation, and inhibits gastric mucosal atrophy and its progression to intestinal metaplasia. In a long-term follow-up study (10–20 years), eradication treatment was found to reduce the risk of subsequent gastric cancer. However, the fact that eradication-induced reflux esophagitis could increase the long-term risk of Barrett's esophagus and esophageal adenocarcinoma should also be considered in the Japanese population. Appropriate treatment with proton pump inhibitors should be taken into consideration for patients undergoing eradication therapy in clinical practice.
Eradication of Helicobacter pylori (H. pylori) in cases of H. pylori-positive gastritis markedly suppresses gastric inflammation, and inhibits gastric mucosal atrophy and its progression to intestinal metaplasia. Therefore, eradication therapy has been found to reduce the risk of subsequent gastric cancer not only in high-risk group of patients such as those who have undergone endoscopic resection for early gastric cancer (Fukase et al., 2008) but also in healthy asymptomatic infected individuals (Fuccio et al., 2009; Ma et al., 2012; Ford et al., 2014). Thus far, two meta-analyses consistently indicated that H. pylori eradication significantly reduce the risk of gastric cancer with relative risk (95% CI): 0.65 (0.43–0.98) and 0.66 (0.46–0.95) (Fuccio et al., 2009; Ford et al., 2014), and a single study successfully revealed its significant preventive effect among more than 3000 subjects with long-term follow-up such as 10–20 years with relative risk (95% CI): 0.61 (0.38–0.96) (Ma et al., 2012). Meanwhile, the occurrence of reflux esophagitis after H. pylori eradication was first reported in Europe in 1997 (Labenz et al., 1997). Since then, several conflicting results regarding the causal relationship between eradication therapy and reflux esophagitis have been reported. In this article, we describe the association between H. pylori infection and reflux esophagitis and review the literature on post-eradication reflux esophagitis.
Effect of H. pylori Infection on Gastric Acid Secretion and its Association with Gastroesophageal Reflux Disease
Several meta-analyses have confirmed that H. pylori infection is inversely correlated with the occurrence of a large spectrum of gastroesophageal reflux diseases (GERDs), ranging from erosive esophagitis and Barrett's esophagus (BE) to esophageal adenocarcinoma (Raghunath et al., 2003; Rokkas et al., 2007; Wang et al., 2009; Fischbach et al., 2012; Xie et al., 2013a,b). This association is more pronounced in Asia, although it has also been observed in Western countries (Raghunath et al., 2003; McColl, 2004; Xie et al., 2013a,b). With regard to the mechanism underlying the inhibition of GERD onset by gastric H. pylori infection, the effect of H. pylori on gastric acid secretion and the manner in which the infection modifies GERD manifestation through the reflux of gastric acid into the esophagus are important.
The effect of H. pylori infection on gastric acid secretion is associated with the spread of infection-associated gastritis (Atherton and Blaser, 2009). In some cases, the region involved in gastric acid secretion in the stomach body is largely unaffected by H. pylori infection and the associated gastric inflammation in the gastric antrum; therefore, the secretion of gastric acid is not reduced. In addition, the infection also results in elevated serum gastrin levels. In such cases, the risk of H. pylori infection-associated GERD does not decrease, but is, in fact, believed to increase (Iijima et al., 2000). On the other hand, in cases where gastric inflammation caused by H. pylori infection affects the entire stomach body (region involved in gastric acid secretion), the suppressive effect induced by inflammatory cells on parietal cells reduces gastric acid secretion. Furthermore, prolonged inflammation of the stomach body results in a decrease in the number of parietal cells owing to gastric mucosal atrophy, thus further reducing acid secretion (Iijima et al., 2004a). Therefore, in cases where H. pylori infection suppresses gastric acid secretion, the level of gastric acid produced during gastric reflux decreases; this process is considered to be the main mechanism through which H. pylori infection inhibits the onset of GERD (Koike et al., 2001a; Abe et al., 2004; Inomata et al., 2006).
The extent to which H. pylori infection reduces acid secretion greatly differs according to the patient's race. Although gastric acid secretion levels were found to remain constant in most patients with H. pylori infection from Western countries (Katelaris et al., 1993; Peterson et al., 1993), the majority of Japanese patients with H. pylori infection (mostly elderly individuals) exhibited decreased acid secretion (Iijima et al., 2004b, 2014). Thus, host racial differences in the effect of H. pylori infection on gastric acid secretion could be responsible for the different degree of inhibitory effect of the infection on the manifestation of GERD between Asian and Western countries.
Reflux Esophagitis after H. pylori Eradication
Moreover, no consensus has been reached on whether H. pylori eradication leads to the onset of reflux esophagitis. There have been some meta-analyses regarding effects of H. pylori eradication on the occurrence of GERD (Raghunath et al., 2004; Yaghoobi et al., 2010; Saad et al., 2012; Xie et al., 2013a). Of these, two meta-analyses failed to find any significant association between the two factors (Raghunath et al., 2004; Saad et al., 2012), and one meta-analysis showed that although there was no significant association in overall analysis, H. pylori eradication was significantly associated with the risk of subsequently developing GERD among peptic ulcer patients with relative risk (95% CI): 2.0 (1.1–3.9) (Yaghoobi et al., 2010). Another meta-analysis comprising 12 randomized controlled studies showed that H. pylori eradication led to a higher risk of GERD with relative risk (95% CI): 2.0 (1.2–3.2) (Xie et al., 2013a). The possible reasons underlying the lack of a consensus include geographic differences and differences between the diseases for which eradication was performed. First, the geographic differences could explain the conflicting results as one meta-analysis clearly indicated that the risk was significant in the subgroup analysis of Asian studies while it was not observed in that of Western studies with relative risk (95% CI): 4.5 (1.7–12.4) vs. 1.2 (0.9–1.6) (Xie et al., 2013a). Yet, other meta-analyses included only a few Asian studies, and they did not perform subgroup analysis in different regional areas (Raghunath et al., 2004; Yaghoobi et al., 2010; Saad et al., 2012). As mentioned previously, this regional difference is attributed to the racial differences in the effect of H. pylori infection on gastric acid secretion. In Europeans and Americans, H. pylori infection does not lead to a major change in gastric acid secretion, and a minimal increase is observed after eradication (Katelaris et al., 1993; Peterson et al., 1993). In contrast, in Asians, H. pylori infection is associated with decreased gastric acid secretion in the majority of the cases (Iijima et al., 2004b, 2014); therefore, eradication is believed to result in the recovery of gastric acid secretion (Koike et al., 2001b).
Furthermore, the wide variance in reports concerning the likelihood of reflux esophagitis after eradication may be explained by the difference in the diseases for which eradication is performed. For example, in cases with H. pylori-positive gastric ulcers, reflux esophagitis is known to occur frequently after eradication (Koike et al., 2001b). On the other hand, in cases with duodenal ulcers, the risk of reflux esophagitis is low; in fact, eradication has been reported to improve the previously existing reflux esophagitis in such cases (Ishiki et al., 2004). Therefore, disease-related differences in the acid secretion changes associated with eradication are believed to play a role in the occurrence reflux esophagitis after eradication (Koike et al., 2001a).
On the other hand, increased gastric acid secretion may be a necessary but not a sufficient factor for developing reflux esophagitis after eradication, since a previous study using simultaneous 24 h pH determination in the stomach and esophagus demonstrated that increased gastric acidity after eradication was not accompanied by concomitant increase in gastroesophageal acid reflux (Fukuchi et al., 2005). In addition to increased gastric acid secretion, impairment of anti-reflux mechanism from the stomach into the esophagus such as hiatal hernia may also be important for developing reflux esophagitis after eradication (Hamada et al., 2000; Koike et al., 2001b; Inoue et al., 2004; Kawanishi, 2005). In fact, Koike et al. reported that reflux esophagitis occurred after eradication only in patients with hiatal hernia (Koike et al., 2001b).
A previous study, which examined hospitalized patients with a variety of diseases who underwent eradication in Japan, reported that the frequency of post-eradication reflux esophagitis was 10–18% (Hamada et al., 2000; Koike et al., 2001b; Inoue et al., 2004; Kawanishi, 2005; Take et al., 2009). The post-eradication follow-up examination revealed many cases of patients in whom reflux esophagitis manifested transiently after the eradication and disappeared after several years (Take et al., 2009). In addition, proton pump inhibitors (PPIs) treatment should be effective for curing reflux esophagitis after eradication, although the drugs do not need to be administered to all patients undergoing eradication therapy given that only a sub-group of patients suffer from the disease after eradication. In the future, the course of post-eradication reflux esophagitis (i.e., the percentage of cases in which reflux esophagitis progresses to BE and esophageal adenocarcinoma) should be observed closely with a long-term follow-up (10–20 years).
Post-Eradication Reflux Esophagitis in Healthy Asymptomatic H. pylori-Infected Japanese Individuals
Since February 2013, the Japanese national health insurance has covered eradication therapy for all H. pylori-positive patients with chronic gastritis, with an aim of reducing the risk of the subsequent development of gastric cancer (Asaka, 2013); hence, eradication therapy is more widely administered at present. Therefore, the estimation of the risk of reflux esophagitis after eradication therapy in H. pylori-positive, asymptomatic, healthy individuals is important. A recent large-scale cross-sectional study in healthy Japanese subjects indicated that there was a significant difference in the prevalence of reflux esophagitis between the subjects with chronic H. pylori infection and those who underwent successful eradication (2.3 vs. 8.8%) (Minatsuki et al., 2013). However, thus far, the risk of post-eradication reflux esophagitis in the H. pylori-positive population has not been assessed in a prospective cohort study in Japan. One report on the efficacy of eradication therapy in 841 H. pylori-positive patients in Taiwan, which is in close proximity to Japan, stated that eradication increased the morbidity associated with reflux esophagitis from 13.7 to 27.3% (Lee et al., 2013). In a Korean study involving 421 patients who underwent health check-ups, reflux esophagitis developed in 10.0% of the patients who underwent eradication compared to 4.3% of the patients who did not undergo eradication; thus, the eradication group showed a significantly higher morbidity (Nam et al., 2010). These data indicate that when eradication therapy is administered to the H. pylori-positive population in Asia, the morbidity associated with reflux esophagitis is likely to increase in a sub-group of the subjects.
A potential merit of eradication for patients with peptic ulcers, mucosa-associated lymphoid tissue (MALT) lymphoma, or those who undergo endoscopic resection for early gastric cancer, should obviously outweigh the demerits of the therapy including the de novo development of reflux esophagitis. Hence, eradication therapy should not be avoided for these patients due to the risk of developing GERD. Even if GERD develops after eradication, PPI treatment should be effective for curing such disorder. However, eradication-induced reflux esophagitis could in theory increase the long-term risk of BE and esophageal adenocarcinoma (Abe et al., 2011). Hence, the preventive effect of H. pylori eradication on gastric cancer should be carefully considered at the cost of increasing the risk of reflux esophagitis, in the treatment of healthy asymptomatic individuals with H. pylori infection (Blaser, 2010), particularly in Asian populations. Presence of hiatal hernia (Hamada et al., 2000; Koike et al., 2001b; Inoue et al., 2004; Kawanishi, 2005), body gastritis (Hamada et al., 2000; Koike et al., 2001b), and older age (Koike et al., 2001b; Take et al., 2009) are identified as risk factors for reflux esophagitis after H. pylori eradication in Japan, hence careful attention needs to be taken in treating such patients.
This work was supported in part by a Grant-in-Aid to KI (25460924) from the Ministry of Education, Science, Sports and Culture in Japan.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abe, Y., Koike, T., Iijima, K., Imatani, A., Ishida, K., Yuki, T., et al. (2011). Esophageal Adenocarcinoma Developing after Eradication of Helicobacter pylori. Case Rep. Gastroenterol. 5, 355–360. doi: 10.1159/000329878
Abe, Y., Ohara, S., Koike, T., Sekine, H., Iijima, K., Kawamura, M., et al. (2004). The prevalence of Helicobacter pylori infection and the status of gastric acid secretion in patients with Barrett's esophagus in Japan. Am. J. Gastroenterol. 99, 1213–1221. doi: 10.1111/j.1572-0241.2004.30313.x
Fischbach, L. A., Nordenstedt, H., Kramer, J. R., Gandhi, S., Dick-Onuoha, S., Lewis, A., et al. (2012). The association between Barrett's esophagus and Helicobacter pylori infection: a meta-analysis. Helicobacter 17, 163–175. doi: 10.1111/j.1523-5378.2011.00931.x
Ford, A. C., Forman, D., Hunt, R. H., Yuan, Y., and Moayyedi, P. (2014). Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ 348:g3174. doi: 10.1136/bmj.g3174
Fuccio, L., Zagari, R. M., Eusebi, L. H., Laterza, L., Cennamo, V., Ceroni, L., et al. (2009). Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann. Intern. Med. 151, 121–128. doi: 10.7326/0003-4819-151-2-200907210-00009
Fukase, K., Kato, M., Kikuchi, S., Inoue, K., Uemura, N., Okamoto, S., et al. (2008). Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 372, 392–397. doi: 10.1016/S0140-6736(08)61159-9
Fukuchi, T., Ashida, K., Yamashita, H., Kiyota, N., Tsukamoto, R., Takahashi, H., et al. (2005). Influence of cure of Helicobacter pylori infection on gastric acidity and gastroesophageal reflux: study by 24-h pH monitoring in patients with gastric or duodenal ulcer. J. Gastroenterol. 40, 350–360. doi: 10.1007/s00535-004-1552-1
Hamada, H., Haruma, K., Mihara, M., Kamada, T., Yoshihara, M., Sumii, K., et al. (2000). High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: impacts of hiatal hernia and corpus gastritis. Aliment. Pharmacol. Ther. 14, 729–735. doi: 10.1046/j.1365-2036.2000.00758.x
Iijima, K., Koike, T., Abe, Y., Ohara, S., Nakaya, N., and Shimosegawa, T. (2014). Time series analysis of gastric acid secretion over a 20-year period in normal Japanese men. J. Gastroenterol. doi: 10.1007/s00535-014-1031-2. [Epub ahead of print].
Iijima, K., Ohara, S., Koike, T., Sekine, H., and Shimosegawa, T. (2004b). Gastric acid secretion of normal Japanese subjects in relation to H. pylori infection, aging, and gender. Scand. J. Gastroenterol. 39, 709–716. doi: 10.1080/00365520410005911
Iijima, K., Ohara, S., Sekine, H., Koike, T., Kato, K., Asaki, S., et al. (2000). Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication. Gut 46, 20–26. doi: 10.1136/gut.46.1.20
Iijima, K., Sekine, H., Koike, T., Imatani, A., Ohara, S., and Shimosegawa, T. (2004a). Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria. Aliment. Pharmacol. Ther. 19, 1181–1188. doi: 10.1111/j.1365-2036.2004.01948.x
Inomata, Y., Koike, T., Ohara, S., Abe, Y., Sekine, H., Iijima, K., et al. (2006). Preservation of gastric acid secretion may be important for the development of gastroesophageal junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status. Am. J. Gastroenterol. 101, 926–933. doi: 10.1111/j.1572-0241.2006.00497.x
Inoue, H., Imoto, I., Taguchi, Y., Kuroda, M., Nakamura, M., Horiki, N., et al. (2004). Reflux esophagitis after eradication of Helicobacter pylori is associated with the degree of hiatal hernia. Scand. J. Gastroenterol. 39, 1061–1065. doi: 10.1080/00365520410008006
Ishiki, K., Mizuno, M., Take, S., Nagahara, Y., Yoshida, T., Yamamoto, K., et al. (2004). Helicobacter pylori eradication improves pre-existing reflux esophagitis in patients with duodenal ulcer disease. Clin. Gastroenterol. Hepatol. 2, 474–479. doi: 10.1016/S1542-3565(04)00165-X
Katelaris, P. H., Seow, F., Lin, B. P., Napoli, J., Ngu, M. C., and Jones, D. B. (1993). Effect of age, Helicobacter pylori infection, and gastritis with atrophy on serum gastrin and gastric acid secretion in healthy men. Gut 34, 1032–1037. doi: 10.1136/gut.34.8.1032
Koike, T., Ohara, S., Sekine, H., Iijima, K., Abe, Y., Kato, K., et al. (2001a). Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut. 49, 330–334. doi: 10.1136/gut.49.3.330
Koike, T., Ohara, S., Sekine, H., Iijima, K., Kato, K., Toyota, T., et al. (2001b). Increased gastric acid secretion after Helicobacter pylori eradication may be a factor for developing reflux oesophagitis. Aliment. Pharmacol. Ther. 15, 813–820. doi: 10.1046/j.1365-2036.2001.00988.x
Labenz, J., Blum, A. L., Bayerdörffer, E., Meining, A., Stolte, M., and Börsch, G. (1997). Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 112, 1442–1447. doi: 10.1016/S0016-5085(97)70024-6
Lee, Y. C., Chen, T. H., Chiu, H. M., Shun, C. T., Chiang, H., Liu, T. Y., et al. (2013). The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut 62, 676–682. doi: 10.1136/gutjnl-2012-302240
Ma, J. L., Zhang, L., Brown, L. M., Li, J. Y., Shen, L., Pan, K. F., et al. (2012). Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 104, 488–492. doi: 10.1093/jnci/djs003
McColl, K. E. (2004). Review article: Helicobacter pylori and gastro-oesophageal reflux disease–the European perspective. Aliment. Pharmacol. Ther. 20(Suppl. 8), 36–39. doi: 10.1111/j.1365-2036.2004.02227.x
Minatsuki, C., Yamamichi, N., Shimamoto, T., Kakimoto, H., Takahashi, Y., Fujishiro, M., et al. (2013). Background factors of reflux esophagitis and non-erosive reflux disease: a cross-sectional study of 10,837 subjects in Japan. PLoS ONE 8:e69891. doi: 10.1371/journal.pone.0069891
Nam, S. Y., Choi, I. J., Ryu, K. H., Kim, B. C., Kim, C. G., and Nam, B. H. (2010). Effect of Helicobacter pylori infection and its eradication on reflux esophagitis and reflux symptoms. Am. J. Gastroenterol. 105, 2153–2162. doi: 10.1038/ajg.2010.251
Peterson, W. L., Barnett, C. C., Evans, D. J. Jr., Feldman, M., Carmody, T., Richardson, C., et al. (1993). Acid secretion and serum gastrin in normal subjects and patients with duodenal ulcer: the role of Helicobacter pylori. Am. J. Gastroenterol. 88, 2038–2043.
Raghunath, A., Hungin, A. P., Wooff, D., and Childs, S. (2003). Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 326:737. doi: 10.1136/bmj.326.7392.737
Raghunath, A. S., Hungin, A. P., Wooff, D., and Childs, S. (2004). Systematic review: the effect of Helicobacter pylori and its eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis. Aliment. Pharmacol. Ther. 20, 733–744. doi: 10.1111/j.1365-2036.2004.02172.x
Rokkas, T., Pistiolas, D., Sechopoulos, P., Robotis, I., and Margantinis, G. (2007). Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin. Gastroenterol. Hepatol. 5, 1413–1417. doi: 10.1016/j.cgh.2007.08.010
Saad, A. M., Choudhary, A., and Bechtold, M. L. (2012). Effect of Helicobacter pylori treatment on gastroesophageal reflux disease (GERD): meta-analysis of randomized controlled trials. Scand. J. Gastroenterol. 47, 129–135. doi: 10.3109/00365521.2011.648955
Take, S., Mizuno, M., Ishiki, K., Nagahara, Y., Yoshida, T., Yokota, K., et al. (2009). Helicobacter pylori eradication may induce de novo, but transient and mild, reflux esophagitis: Prospective endoscopic evaluation. J. Gastroenterol. Hepatol. 24, 107–113. doi: 10.1111/j.1440-1746.2008.05606.x
Xie, F. J., Zhang, Y. P., Zheng, Q. Q., Jin, H. C., Wang, F. L., Chen, M., et al. (2013b). Helicobacter pylori infection and esophageal cancer risk: an updated meta-analysis. World J. Gastroenterol. 19, 6098–6107. doi: 10.3748/wjg.v19.i36.6098
Xie, T., Cui, X., Zheng, H., Chen, D., He, L., and Jiang, B. (2013a). Meta-analysis: eradication of Helicobacter pylori infection is associated with the development of endoscopic gastroesophageal reflux disease. Eur. J. Gastroenterol. Hepatol. 25, 1195–1205. doi: 10.1097/meg.0b013e328363e2c7
Keywords: H. pylori, reflux esophagitis, gerd, eradication, gastric acid
Citation: Iijima K, Koike T and Shimosegawa T (2015) Reflux esophagitis triggered after Helicobacter pylori eradication: a noteworthy demerit of eradication therapy among the Japanese? Front. Microbiol. 6:566. doi: 10.3389/fmicb.2015.00566
Received: 08 December 2014; Accepted: 22 May 2015;
Published: 09 June 2015.
Edited by:Yeong Yeh Lee, Universiti Sains Malaysia, Malaysia
Reviewed by:Hridayesh Prakash, University of Hyderabad, India
Ramakrishnan Sitaraman, TERI University, India
Amin Talebi Bezmin Abadi, Tarbiat Modares University, Iran
Copyright © 2015 Iijima, Koike and Shimosegawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Katsunori Iijima, Division of Gastroenterology, Tohoku University Graduate School of Medicine, Seiryo-machi, Aobaku, Sendai 980-8574, Japan, firstname.lastname@example.org