Overlap Between GERD and Functional Esophageal Disorders—a Pivotal Mechanism for Treatment Failure

  • Ofer Z. Fass
  • Ronnie FassEmail author
Invited Commentary


ᅟRefractory GERD is very common, and while many different underlying mechanisms have been identified, the main focus has remained on residual reflux (acidic or non-acidic). Recently, Rome IV introduced two new concepts with important impact on patients with refractory GERD. They include the introduction of the reflux hypersensitivity group and the proposal that GERD can overlap with a functional esophageal disorder. Recent studies have demonstrated that the latter affects approximately three quarters of the GERD patients who failed PPI once daily.


GERD Reflux hypersensitivity Functional heartburn PPI Heartburn Esophagus 


Compliance with ethical standards

Conflict of interest

Ofer Fass declares that he has no conflict of interest. Ronnie Fass declares that he is an advisor for Ironwood, Mecleri Therapeutics, Takeda and Chinoin, speaker for Ostrazeneca, Takeda, Cadilla and Diversitek and receive research money from Ironwood.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


  1. 1.
    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, the Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101(8):1900–20.CrossRefGoogle Scholar
  2. 2.
    Dent J, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005;54(5):710–7.CrossRefGoogle Scholar
  3. 3.
    El-Serag HB, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871–80.CrossRefGoogle Scholar
  4. 4.
    Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308–28; quiz 329.CrossRefGoogle Scholar
  5. 5.
    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(6):720–37.CrossRefGoogle Scholar
  6. 6.
    Fass R. Therapeutic options for refractory gastroesophageal reflux disease. J Gastroenterol Hepatol. 2012;27(s3):3–7.CrossRefGoogle Scholar
  7. 7.
    Fass R, et al. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease--where next? Aliment Pharmacol Ther. 2005;22(2):79–94.CrossRefGoogle Scholar
  8. 8.
    Tutuian R, Vela MF, Hill EG, Mainie I, Agrawal A, Castell DO. Characteristics of symptomatic reflux episodes on acid suppressive therapy. Am J Gastroenterol. 2008;103:1090–6.CrossRefGoogle Scholar
  9. 9.
    Mainie I, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55(10):1398–402.CrossRefGoogle Scholar
  10. 10.
    Hillman L, et al. A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease. Dis Esophagus. 2017;30(9):1–15.Google Scholar
  11. 11.
    Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003;17(2):243–51.CrossRefGoogle Scholar
  12. 12.
    Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedance–pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. BJS. 2006;93(12):1483–7.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    Jenkinson AD, Kadirkamanathan SS, Scott SM, Yazaki E, Evans DF. Relationship between symptom response and oesophageal acid exposure after medical and surgical treatment for gastro-oesophageal reflux disease. BJS. 2004;91(11):1460–5.CrossRefGoogle Scholar
  15. 15.
    Kahrilas PJ, Keefer L, Pandolfino JE. Patients with refractory reflux symptoms: what do they have and how should they be managed? Neurogastroenterol Motil. 2015;27(9):1195–201.CrossRefGoogle Scholar
  16. 16.
    Gasiorowska A, Navarro-Rodriguez T, Wendel C, Krupinski E, Perry ZH, Koenig K, 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;104:2005–13.CrossRefGoogle Scholar
  17. 17.
    Rohof WO, Bennink RJ, de Jonge H, Boeckxstaens GE. 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(10):1647–55.CrossRefGoogle Scholar
  18. 18.
    Abdallah, J., et al. Most patients with gastroesophageal reflux disease who failed proton pump inhibitor therapy also have functional esophageal disorders. Clin Gastroenterol Hepatol. 2018.
  19. 19.
    Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Esophageal disorders. Gastroenterology. 2016;150(6):1368–79.CrossRefGoogle Scholar
  20. 20.
    Yamasaki T, Fass R. Reflux hypersensitivity: a new functional esophageal disorder. J Neurogastroenterol Motil. 2017;23(4):495–503.CrossRefGoogle Scholar
  21. 21.
    Gyawali CP, Fass R. Management of gastroesophageal reflux disease. Gastroenterology. 2018;154(2):302–18.CrossRefGoogle Scholar
  22. 22.
    Roman S, Keefer L, Imam H, Korrapati P, Mogni B, Eident K, et al. Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux. Neurogastroenterol Motil. 2015;27(11):1667–74.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineNew York University Langone HealthNew YorkUSA
  2. 2.Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical CenterCase Western Reserve University School of MedicineClevelandUSA

Personalised recommendations