Skip to main content
SpringerLink
Log in

Association of residual gastric acid secretion with persistent symptoms in gastroesophageal reflux disease patients receiving standard-dose proton pump inhibitor therapy

  • Original Article
  • Published:
Esophagus Aims and scope Submit manuscript

Abstract

Background

Although a third of gastroesophageal reflux disease (GERD) patients are refractory to proton pump inhibitor (PPI) therapy, the underlying mechanism of the refractoriness remains unclear. We compared the level of gastric acid suppression during PPI treatment between responders and non-responders by directly measuring gastric acid secretion in GERD patients taking PPIs.

Methods

Seventy-five consecutive patients receiving standard-dose PPI therapy for GERD were prospectively recruited, irrespective of persistent GERD symptoms. They were asked about their GERD symptoms using a validated questionnaire, and simultaneously underwent both a routine endoscopic examination and a gastric acid secretory testing using an endoscopic gastrin test. Associations between residual gastric acid secretion during PPI treatment and persistent GERD symptoms were analyzed by a logistic regression analysis.

Results

Overall, 26 of 75 (34.7%) patients were judged to be positive for persistent GERD symptoms. The patients with and without persistent symptoms showed similar gastric acid secretion levels (1.3 [1.3] mEq/10 min vs. 1.4 [2.0] mEq/10 min). Sufficient gastric acid suppression, defined as < 0.6, was not significantly associated with persistent GERD symptoms (odds ratio 1.1, 95% confidence interval 0.40–3.5).

Conclusions

This study provided solid evidence to support that the gastric acid suppression level during PPI treatment does not differ between patients with and without persistent GERD symptoms. The insignificant role of residual gastric acid in the persistent GERD symptoms suggests that the use of medications other than those that enhance gastric acid inhibitory effects would be an essential approach for the management of PPI-refractory GERD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

EGT:

Endoscopic gastrin test

ERD:

Erosive reflux disease

GERD:

Gastroesophageal reflux disease

HH:

Hiatal hernia

NERD:

Non-erosive reflux disease

OR:

Odds ratio

PPI:

Proton pump inhibitor

SD:

Standard deviation

References

  1. Iwakiri K, Kinoshita Y, Habu Y, et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015. J Gastroenterol. 2016;51:751–67.

    Article  Google Scholar 

  2. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther. 2010;32:720–37.

    Article  CAS  Google Scholar 

  3. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61:1340–54.

    Article  CAS  Google Scholar 

  4. Charbel S, Khandwala F, Vaezi MF. The role of esophageal pH monitoring in symptomatic patients on PPI therapy. Am J Gastroenterol. 2005;100:283–9.

    Article  Google Scholar 

  5. Mandaliya R, DiMarino AJ, Cohen S. Survey of findings in patients having persistent heartburn on proton pump inhibitor therapy. Dis Esophagus. 2016;29:27–33.

    Article  CAS  Google Scholar 

  6. Sugimoto M, Nishino M, Kodaira C, et al. Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy. World J Gastroenterol. 2011;17:1858–65.

    Article  CAS  Google Scholar 

  7. Becker V, Bajbouj M, Waller K, et al. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors—a follow-up study of intraluminal-impedance guided therapy. Aliment Pharmacol Ther. 2007;26:1355–60.

    Article  CAS  Google Scholar 

  8. Iwakiri K, Kawami N, Sano H, et al. Acid and non-acid reflux in Japanese patients with non-erosive reflux disease with persistent reflux symptoms, despite taking a double-dose of proton pump inhibitor: a study using combined pH-impedance monitoring. J Gastroenterol. 2009;44:708–12.

    Article  CAS  Google Scholar 

  9. Nakagawa K, Koike T, Iijima K, et al. Characteristics of symptomatic reflux episodes in Japanese proton pump inhibitor-refractory non-erosive reflux disease patients. World J Gastroenterol. 2015;21:13352–9.

    Article  CAS  Google Scholar 

  10. Rohof WO, Bennink RJ, de Jonge H, et al. Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2014;12:1647–55.

    Article  CAS  Google Scholar 

  11. Gasiorowska A, Navarro-Rodriguez T, Wendel C, et al. Comparison of the degree of duodenogastroesophageal reflux and acid reflux between patients who failed to respond and those who were successfully treated with a proton pump inhibitor once daily. Am J Gastroenterol. 2009;104:2005–133.

    Article  CAS  Google Scholar 

  12. Januszewicz W, Hartley J, Waldock W, et al. Endoscopic measurement of gastric pH associates with persistent acid reflux in patients treated with proton-pump inhibitors for gastroesophageal reflux disease. United Eur Gastroenterol J. 2019;7:1389–98.

    Article  CAS  Google Scholar 

  13. Iijima K, Ohara S, Sekine H, et al. A new endoscopic method of gastric acid secretory testing. Am J Gastroenterol. 1998;93:2113–8.

    Article  CAS  Google Scholar 

  14. Iijima K, Ohara S, Sekine H, et al. Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication. Gut. 2000;46:20–6.

    Article  CAS  Google Scholar 

  15. Iijima K, Koike T, Abe Y, et al. Time series analysis of gastric acid secretion over a 20-year period in normal Japanese men. J Gastroenterol. 2015;50:853–61.

    Article  Google Scholar 

  16. Jonasson C, Wernersson B, Hoff DA, et al. Validation of the GerdQ questionnaire for the diagnosis of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2013;37:564–72.

    Article  CAS  Google Scholar 

  17. Iijima K, Sekine H, Koike T, et al. Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria. Aliment Pharmacol Ther. 2004;19:1181–8.

    Article  CAS  Google Scholar 

  18. Iijima K, Koike T, Abe Y, et al. Cutoff serum pepsinogen values for predicting gastric acid secretion status. Tohoku J Exp Med. 2014;232:293–300.

    Article  CAS  Google Scholar 

  19. Bytzer P, van Zanten SV, Mattsson H, et al. Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis—a post hoc analysis of 5796 patients. Aliment Pharmacol Ther. 2012;36:635–43.

    Article  CAS  Google Scholar 

  20. Aziz Q, Fass R, Gyawali CP, et al. Functional esophageal disorders. Gastroenterology. 2016;150(6):1368–79.

    Article  Google Scholar 

  21. Maejima R, Koike T, Nakagawa K, et al. Esomeprazole inhibits the pentagastrin-stimulated secretion of gastric acid in healthy Japanese volunteers. Tohoku J Exp Med. 2015;235:249–53.

    Article  CAS  Google Scholar 

  22. Bell NJ, Burget D, Howden CW, et al. Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion. 1992;51(Suppl 1):59–67.

    Article  Google Scholar 

  23. Olbe L, Lind T, Cederberg C, et al. Effect of omeprazole on gastric acid secretion in man. Scand J Gastroenterol Suppl. 1986;118:105–7.

    Article  CAS  Google Scholar 

  24. Leite LP, Johnston BT, Just RJ, et al. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol. 1996;91:1527–31.

    CAS  PubMed  Google Scholar 

  25. Boeckxstaens GE, Smout A. Systematic review: role of acid, weakly acidic and weakly alkaline reflux in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2010;32:334–43.

    Article  CAS  Google Scholar 

  26. Hoshino S, Kawami N, Takenouchi N, et al. Efficacy of vonoprazan for proton pump inhibitor-resistant reflux esophagitis. Digestion. 2017;95:156–61.

    Article  CAS  Google Scholar 

  27. Hamada S, Ihara E, Ikeda H, et al. Clinical characterization of vonoprazan-refractory gastroesophageal reflux disease. Digestion. 2019;2:1–8. https://doi.org/10.1159/000503340.

    Article  CAS  Google Scholar 

  28. Zerbib F, Duriez A, Roman S, et al. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut. 2008;57:156–60.

    Article  CAS  Google Scholar 

  29. Woodland P, Shen Ooi JL, Grassi F, et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology. 2017;153:1230–9.

    Article  Google Scholar 

  30. Gordon C, Kang JY, Neild PJ, Maxwell JD. The role of the hiatus hernia in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2004;20:719–32.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan

    H. Kikuchi, T. Koike, M. Saito, K. Nakagawa, W. Hatta & A. Masamune

  2. Department of Gastroenterology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Akita, 010-8543, Japan

    S. Fukuda, Y. Shimodaira, K. Watanabe & K. Iijima

Authors
  1. H. Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Koike
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Shimodaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. Hatta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Masamune
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K. Iijima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Iijima.

Ethics declarations

Ethical Statement

The study protocol was approved by the Tohoku University Hospital Ethics Committee (2014-2-136), and all subjects provided their written informed consent prior to enrollment.

Conflict of interest

Masamune A received lecture fees from EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd, and received Commercial research funding from Otsuka Pharmaceutical Co., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd.; Iijima K received lecture fees from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and received Commercial research funding from Otsuka Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kikuchi, H., Fukuda, S., Koike, T. et al. Association of residual gastric acid secretion with persistent symptoms in gastroesophageal reflux disease patients receiving standard-dose proton pump inhibitor therapy. Esophagus 18, 380–387 (2021). https://doi.org/10.1007/s10388-020-00765-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10388-020-00765-2

Keywords

Search

Navigation