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Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn

  • Original Article—Alimentary Tract
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Microscopic esophagitis (ME) is common in patients with non-erosive reflux disease (NERD), and dilation of intercellular spaces (DIS) has been regarded as the potential main mechanism of symptom generation. We aimed to compare these histological abnormalities in healthy volunteers (HVs) and patients with erosive esophagitis (EE), NERD, and functional heartburn (FH).


Consecutive patients with heartburn prospectively underwent upper endoscopy and impedance-pH off-therapy. Twenty EE patients and fifty-seven endoscopy-negative patients (NERD), subclassified as 22 with pH-POS (positive for abnormal acid exposure), 20 with hypersensitive esophagus (HE; normal acid/symptom association probability [SAP]+ or symptom index [SI]+), and 15 with FH (normal acid/SAP-/SI-/ proton pump inhibitor [PPI] test-), were enrolled. Twenty HVs were also included. In each patient/control, multiple specimens (n = 5) were taken from the distal esophagus and histological alterations were evaluated. ME was diagnosed when the global histological score was >0.35.


The prevalence of ME was higher (p < 0.0001) in EE (95 %), pH-POS (77 %), and HE (65 %) NERD patients than in FH patients (13 %) and HVs (15 %). Also, basal cell hyperplasia (p < 0.0023), DIS (p < 0.0001), and papillae elongation (p < 0.0002) showed similar rates of prevalence in the above populations (p < 0.0001). ME, including each histological lesion, had similar low frequencies in FH and HVs (p = 0.9990). Considering the histological abnormalities together, they permitted us to clearly differentiate EE and NERD from FH and HVs (p < 0.0001 and p < 0.0001, respectively).


The lack of ME in the esophageal distal biopsies of FH patients indicates a limited role of these histological abnormalities in symptom generation in them. ME can be considered as an accurate and reliable diagnostic marker for distinguishing FH patients from GERD patients and has the potential to be used to guide the correct therapy.

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Microscopic esophagitis


Dilation of intercellular spaces


Non-erosive reflux disease


Erosive esophagitis


Healthy volunteers


Functional heartburn


Hypersensitive esophagus


Symptom association probability


Symptom index


Proton pump inhibitor


Gastroesophageal reflux disease


Transmission electron microscopy


Light microscopy


Squamocolumnar junction


Basal cell hyperplasia


Papillae elongation


Global score


Acid exposure time


Generalized estimating equations


Lower esophageal sphincter


  1. Dent J. Microscopic esophageal mucosal injury in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2007;5:4–16.

    Article  PubMed  Google Scholar 

  2. Tobey NA, Carson JL, Alkiek RA, Orlando RC. Dilated intercellular spaces: a morphological feature of acid-reflux damaged human esophageal epithelium. Gastroenterology. 1996;111:1200–5.

    Article  PubMed  CAS  Google Scholar 

  3. Calabrese C, Fabbri A, Bortolotti M, Cenacchi G, Areni A, Scialpi C, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-esophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther. 2003;18:525–32.

    Article  PubMed  CAS  Google Scholar 

  4. Caviglia R, Ribolsi M, Maggiano N, Gabbrielli AM, Emerenziani S, Guarino MP, et al. Dilated intercellular spaces of esophageal epithelium in non erosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol. 2005;100:543–8.

    Article  PubMed  Google Scholar 

  5. Villanacci V, Grigolato PG, Cestari R, Missale G, Cengia G, Klersy C, et al. Dilated intercellular spaces as marker of esophageal reflux: histology, semi-quantitative score and morphometry upon light microscopy. Digestion. 2001;64:1–8.

    Article  PubMed  CAS  Google Scholar 

  6. Zentilin P, Savarino V, Mastracci L, Spaggiari P, Dulbecco P, Ceppa P, et al. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol. 2005;100:2299–306.

    Article  PubMed  Google Scholar 

  7. van Malestein H, Farrè R, Sifrim D. Esophageal dilated intercellular spaces (DIS) and nonerosive reflux disease. Am J Gastroenterol. 2007;102:1–8.

    Article  Google Scholar 

  8. Savarino E, Zentilin P, Tutuian R, Pohl D, Casa DD, Frazzoni M, et al. The role of non-acid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol. 2008;103:2685–93.

    Article  PubMed  Google Scholar 

  9. Galmiche JP, Clouse RE, Bàlint A, Cook IJ, Kahrilas PJ, Paterson WG, et al. Functional esophageal disorders. Gastroenterology. 2006;130:1459–65.

    Article  PubMed  Google Scholar 

  10. Frazzoni M, Conigliaro R, Mirante VG, Melotti G. The added value of quantitative analysis of on-therapy impedance-pH parameters in distinguishing refractory non-erosive reflux disease from functional heartburn. Neurogastroenterol Motil. 2011. doi:10.1111/j.1365-2982.2011.01800.x.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Carlsson R, Dent J, Bolling-Sternevald E, Johnsson F, Junghard O, Lauritsen K, et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol. 1998;33:1023–9.

    Article  PubMed  CAS  Google Scholar 

  13. Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–80.

    Article  PubMed  CAS  Google Scholar 

  14. Vakil N, van Zanten SV, Kahrilas P, Dent J. Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.

    Article  PubMed  Google Scholar 

  15. Yerian L, Fiocca R, Mastracci L, et al. Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto Project. Dig Dis Sci. 2011;56(9):2656–65.

    Article  PubMed  Google Scholar 

  16. Fiocca R, Mastracci L, Riddell R, et al. Development of consensus guidelines for the histologic recognition of microscopic esophagitis in patients with gastroesophageal reflux disease: the Esohisto project. Hum Pathol. 2010;41(2):223–31.

    Article  PubMed  Google Scholar 

  17. Mastracci L, Spaggiari P, Grillo F, Zentilin P, Dulbecco P, Ceppa P, et al. Microscopic esophagitis in gastroesophageal reflux disease: individual lesions, biopsy sampling, and clinical correlations. Virchows Arch. 2009;454:31–9.

    Article  PubMed  Google Scholar 

  18. Savarino E, Tutuian R, Zentilin P, Dulbecco P, Pohl D, Marabotto E, 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 

  19. Zentilin P, Iiritano E, Dulbecco P, Bilardi C, Savarino E, De Conca S, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet. Dig Liver Dis. 2006;38:226–32.

    Article  PubMed  CAS  Google Scholar 

  20. Bredenoord AJ, Weusten BL, Smout AJ. Symptom association analysis in ambulatory gastro-oesophageal reflux monitoring. Gut. 2005;54:1810–7.

    Article  PubMed  CAS  Google Scholar 

  21. Vela MF, Camacho-Lobato L, Srinivasan R, Tutuian R, Katz PO, Castell DO. Simultaneous intraesophageal impedance and pH measurement of acid and non-acid gastroesophageal reflux : effect of omeprazole. Gastroenterology. 2001;120:1599–606.

    Article  PubMed  CAS  Google Scholar 

  22. Slaughter JC, Goutte M, Rymer JA, Oranu AC, Schneider JA, Garrett CG, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2011;9(10):868–74.

    Article  PubMed  Google Scholar 

  23. Smout AJPM. Review article: the measurement of non-acid gastro-oesophageal reflux. Aliment Pharmacol Ther. 2007;26(Suppl 2):7–12.

    Article  PubMed  Google Scholar 

  24. Viazis N, Keyoglou A, Kanellopoulos AK, Karamanolis G, Vlachogiannakos J, Triantafyllou K, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol. 2011 (Epub ahead of print).

  25. Savarino E, Marabotto E, Zentilin P, Frazzoni M, Sammito G, Bonfanti D, et al. The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease. Dig Liver Dis. 2011;43(7):542–7.

    Article  PubMed  Google Scholar 

  26. Farré R, Fornari F, Blondeau K, Vieth M, De Vos R, Bisschops R, et al. Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus. Gut. 2010;59:164–9.

    Article  PubMed  Google Scholar 

  27. Farrè R, De Vos R, Geboes K, Vanden Berghe P, Depoortere I, Blondeau K, et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut. 2007;56:1191–7.

    Article  PubMed  Google Scholar 

  28. Fiocca R, Mastracci L, Engström C, Attwood S, Ell C, Galmiche JP, et al. Long-term outcome of microscopic esophagitis in chronic GERD patients treated with esomeprazole or laparoscopic antireflux surgery in the LOTUS trial. Am J Gastroenterol. 2010;105:1015–23.

    Article  PubMed  CAS  Google Scholar 

  29. Vela MF, Craft BM, Sharma N, Freeman J, Hazen-Martin D. Refractory heartburn: comparison of intercellular space diameter in documented GERD vs functional heartburn. Am J Gastroenterol. 2011;106(5):844–50.

    Article  PubMed  Google Scholar 

  30. Savarino E, Zentilin P, Tutuian R, Pohl D, Gemignani L, Malesci A, et al. Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients. J Gastroenterol. 2012;47(2):159–68.

    Article  PubMed  Google Scholar 

  31. Calabrese C, Bortolotti M, Fabbri A, Areni A, Cenacchi G, Scialpi C, et al. Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. Am J Gastroenterol. 2005;100:537–42.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Edoardo Savarino.

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Savarino, E., Zentilin, P., Mastracci, L. et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol 48, 473–482 (2013).

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