Skip to main content


Log in

Impairment of chemical clearance and mucosal integrity distinguishes hypersensitive esophagus from functional heartburn

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript



Hypersensitive esophagus (HE) is defined by endoscopy-negative heartburn with a normal acid exposure time but positive symptom association probability (SAP) and/or symptom index (SI) on impedance–pH monitoring, and proton pump inhibitor (PPI) responsiveness. Functional heartburn (FH) is distinguished by negative SAP/SI and PPI refractoriness. The clinical value of SAP and SI has been questioned. We aimed to investigate whether impairment of chemical clearance and of mucosal integrity, expressed by the postreflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI), characterize HE independently of SAP and SI.


Impedance–pH tracings from PPI-responsive endoscopy-negative patients, 125 with nonerosive reflux disease and 108 with HE, distinguished by an abnormal and a normal acid exposure time, and from 70 patients with FH were retrospectively selected and blindly reviewed.


The mean PSPW index and MNBI were significantly lower in nonerosive reflux disease (30 %, 1378 Ω) than in HE (51 %; 2274 Ω) and in both of them as compared with FH (76 %; 3445 Ω) (P = 0.0001). Both the PSPW index (adjusted odds ratio 0.863, P = 0.001) and the MNBI (adjusted odds ratio 0.998, P = 0.001) were independent predictors of HE; with their combined assessment, the area under the curve on receiver operating characteristic analysis was 0.957. SAP and/or SI was positive in 67 of the 108 HE patients (62 %), whereas the PSPW index and/or MNBI was abnormal in 99 of the 108 HE patients (92 %; P < 0.0001).


HE is characterized by impairment of chemical clearance and mucosal integrity, which explains the increased reflux perception. When SAP and SI afford uncertain results, the PSPW index and MNBI should be analyzed.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others


  1. Galmiche JP, Clouse RE, Balint A, et al. Functional esophageal disorders. Gastroenterology. 2006;130:1459–65.

    Article  PubMed  Google Scholar 

  2. Katz P, Gerson L, Vela M. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308–28.

    Article  PubMed  Google Scholar 

  3. Zerbib F, Sifrim D, Tutuian R, et al. Modern medical and surgical management of difficult-to-treat GORD. United Eur Gastroenterol J. 2013;1:21–31.

    Article  Google Scholar 

  4. Savarino E, Zentilin P, Savarino V. NERD: an umbrella term including heterogeneous subpopulations. Nat Rev Gastroenterol Hepatol. 2013;10:371–80.

    Article  CAS  PubMed  Google Scholar 

  5. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2011;9:868–74.

    Article  PubMed  Google Scholar 

  6. Vaezi MF. Ambulatory monitoring for gastroesophageal reflux disease: where do we stand? Clin Gastroenterol Hepatol. 2015;13:892–4.

    Article  PubMed  Google Scholar 

  7. Conchillo J, Smout A. Review article: intra-oesophageal impedance monitoring for the assessment of bolus transit and gastro-oesophageal reflux. Aliment Pharmacol Ther. 2008;29:3–14.

    Article  PubMed  Google Scholar 

  8. Woodley FW, Fernandez F, Mousa H. Diurnal variation in the chemical clearance of acid gastroesophageal reflux in infants. Clin Gastroenterol Hepatol. 2007;5:37–43.

    Article  PubMed  Google Scholar 

  9. Frazzoni M, Manta R, Mirante VG, et al. Esophageal chemical clearance is impaired in gastro-oesophageal reflux disease—a 24 h impedance-pH monitoring assessment. Neurogastroenterol Motil. 2013;25:399–406.

    Article  CAS  PubMed  Google Scholar 

  10. Kessing BF, Bredenoord AJ, Weijenborg PW, et al. Esophageal acid exposure decreases intraluminal baseline impedance. Am J Gastroenterol. 2011;106:2093–7.

    Article  CAS  PubMed  Google Scholar 

  11. Farrè R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut. 2011;60:885–92.

    Article  PubMed  Google Scholar 

  12. Woodland P, Al-Zinaty M, Yazaki E, et al. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut. 2013;62:1256–61.

    Article  PubMed  Google Scholar 

  13. Farrè R. Pathophysiology of gastro-esophageal reflux disease: a role for mucosa integrity? Neurogastroenterol Motil. 2013;25:783–99.

    PubMed  Google Scholar 

  14. Martinucci I, De Bortoli N, Savarino E, et al. Esophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn. Neurogastroenterol Motil. 2014;26:546–55.

    Article  CAS  PubMed  Google Scholar 

  15. De Bortoli N, Martinucci I, Savarino E, et al. Association between baseline impedance values and response proton pump inhibitors in patients with heartburn. Clin Gastroenterol Hepatol. 2015;13:1082–8.

    Article  PubMed  Google Scholar 

  16. Frazzoni M, Savarino E, De Bortoli N, et al. Analyses of the post-reflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of patients with reflux disease. Clin Gastroenterol Hepatol. 2016;14:40–6.

    Article  PubMed  Google Scholar 

  17. Savarino E, Pohl D, Zentilin P, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut. 2009;58:1185–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Frazzoni M, Conigliaro R, Manta R, et al. Reflux parameters as modified by EsophyX or laparoscopic fundoplication in refractory GERD. Aliment Pharmacol Ther. 2011;34:67–75.

    Article  CAS  PubMed  Google Scholar 

  19. Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy. Am J Gastroenterol. 2010;105:1053–61.

    Article  PubMed  Google Scholar 

  20. Penagini R, Sweis R, Mauro A, et al. Inconsistency in the diagnosis of functional heartburn: usefulness of prolonged wireless pH monitoring in patients with proton pump inhibitor refractory gastroesophageal reflux disease. J Neurogastroenterol Motil. 2015;21:265–72.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zerbib F, Roman S, Alpert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101:1956–63.

    Article  PubMed  Google Scholar 

  22. Savarino E, Zentilin P, Mastracci L, et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol. 2013;48:473–82.

    Article  PubMed  Google Scholar 

  23. Bredenoord AJ, Smout AJPM. Association between reflux and symptoms during ambulatory reflux monitoring: pros and cons of existing methods. Neurogastroenterol Motil. 2013;25:633–7.

    Article  CAS  PubMed  Google Scholar 

  24. Cheng F-K, Albert D, Maydonovitch C, et al. Categorization of patients with reflux symptoms referred for pH and impedance testing while off therapy. Clin Gastroenterol Hepatol. 2015;13:867–73.

    Article  PubMed  Google Scholar 

  25. Patel A, Sayuk GS, Gyawali P. Parameters on esophageal pH-impedance monitoring that predict outcomes of patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2015;13:884–91.

    Article  PubMed  Google Scholar 

  26. Patel A, Sayuk G, Kushnir V, et al. GERD phenotypes from pH-impedance monitoring predict symptomatic outcomes on prospective evaluation. Neurogastroenterol Motil. 2016;28:513–21.

    Article  CAS  PubMed  Google Scholar 

  27. Pritchett JM, Aslam M, Slaughter JC, et al. Efficacy of esophageal impedance/pH monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy. Clin Gastroenterol Hepatol. 2009;7:743–8.

    Article  PubMed  Google Scholar 

  28. Frazzoni M, Conigliaro R, Melotti G. Reflux parameters as modified by laparoscopic fundoplication in 40 patients with heartburn/regurgitation persisting despite PPI therapy. A study using impedance-pH monitoring. Dig Dis Sci. 2011;56:1099–106.

    Article  PubMed  Google Scholar 

  29. Frazzoni M, Conigliaro R, Mirante VG, et al. The added value of quantitative analysis of on-therapy impedance-pH parameters in distinguishing refractory non-erosive reflux disease from functional heartburn. Neurogastroenterol Motil. 2012;24:141–7.

    Article  CAS  PubMed  Google Scholar 

  30. Frazzoni M, Piccoli M, Conigliaro R, et al. Refractory gastroesophageal reflux disease as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. Surg Endosc. 2013;27:2940–6.

    Article  PubMed  Google Scholar 

  31. De Bortoli N, Martinucci I, Savarino E, et al. Manually calculated oesophageal bolus clearance time increases in parallel with reflux severity at impedance-pH monitoring. Dig Liver Dis. 2015;47:1027–32.

    Article  PubMed  Google Scholar 

  32. Frazzoni M, Conigliaro R, Melotti G. Weakly acidic refluxes have a major role in the pathogenesis of proton pump inhibitor-resistant reflux oesophagitis. Aliment Pharmacol Ther. 2011;33:601–6.

    Article  CAS  PubMed  Google Scholar 

  33. Ribolsi M, Savarino E, De Bortoli N, et al. Reflux pattern and role of impedance-pH variables in predicting PPI response in patients with suspected GERD-related chronic cough. Aliment Pharmacol Ther. 2014;40:966–73.

    Article  CAS  PubMed  Google Scholar 

  34. Gyawali CP. Redeeming clinical value of esophageal pH impedance monitoring. Clin Gastroenterol Hepatol. 2016;14:47–9.

    Article  PubMed  Google Scholar 

  35. Numans M, Lau J, de Wit N, et al. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease—a meta-analysis of diagnostic test characteristics. Ann Intern Med. 2004;140:518–27.

    Article  CAS  PubMed  Google Scholar 

  36. Frazzoni M, Bertani H, Manta R, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis. 2014;46:596–612.

    Article  CAS  PubMed  Google Scholar 

  37. Frazzoni M, Bertani H, Conigliaro R, et al. Neoplastic progression in short-segment Barrett’s oesophagus is associated with impairment of chemical clearance, but not inadequate acid suppression by proton pump inhibitor therapy. Aliment Pharmacol Ther. 2014;40:835–42.

    Article  CAS  PubMed  Google Scholar 

  38. Zerbib F, Roman S, Des Varannes SB, et al. Normal values of pharyngeal and esophageal 24 h pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol. 2013;11:366–72.

    Article  PubMed  Google Scholar 

  39. Broeders JA, Draaisma WA, Bredenoord AJ, et al. Oesophageal acid hypersensitivity is not a contraindication to Nissen fundoplication. Br J Surg. 2009;96:1023–30.

    Article  CAS  PubMed  Google Scholar 

  40. Desjardin M, Luc G, Collet D, et al. 24 h pH-impedance monitoring on therapy to select patients with refractory reflux symptoms for antireflux surgery. A single center retrospective study. Neurogastroenterol Motil. 2016;28:146–52.

    Article  CAS  PubMed  Google Scholar 

  41. Roman S, Bruley Des Varannes S, Pouderoux P, et al. Ambulatory 24 h oesophageal impedance–pH recordings: reliability of automatic analysis for gastro-oesophageal reflux assessment. Neurogastroenterol Motil. 2006;18:978–86.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Marzio Frazzoni.

Ethics declarations

Conflict of interest

The study was conducted without any financial support. The authors have no conflict of interest to declare.

Additional information

Selected in abstract form for a lecture in the Distinguished Abstract Plenary Session during Digestive Disease Week, May 24, 2016, held in San Diego, CA, USA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frazzoni, M., de Bortoli, N., Frazzoni, L. et al. Impairment of chemical clearance and mucosal integrity distinguishes hypersensitive esophagus from functional heartburn. J Gastroenterol 52, 444–451 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: