Skip to main content

Advertisement

SpringerLink
Log in

Non-acid Reflux: When It Matters and Approach to Management

  • Esophagus (J Clarke and N Ahuja, Section Editors)
  • Published:
Current Gastroenterology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This narrative review focuses on the presentation, contributing factors, diagnosis, and treatment of non-acid reflux. We also propose algorithms for diagnosis and treatment.

Recent Findings

There is a paucity of recent data regarding non-acid reflux. The recent Porto and Lyon consensus statements do not fully address non-acid reflux or give guidance on classification. However, recent developments in the lung transplantation field, as well as older data in the general population, argue for the importance of non-acid reflux.

Summary

Extrapolating from the Porto and Lyon consensus, we generally classify pathologic non-acid reflux as impedance events > 80, acid exposure time < 4%, and positive symptom correlation on a standard 24-h pH/impedance test. Other groups not meeting this criteria also deserve consideration depending on the clinical situation. Potential treatments include lifestyle modification, increased acid suppression, alginates, treatment of esophageal hypersensitivity, baclofen, buspirone, prokinetics, and anti-reflux surgery in highly selected individuals. More research is needed to clarify appropriate classification, with subsequent focus on targeted treatments.

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
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871–80.

    PubMed  Google Scholar 

  2. Hachem C, Shaheen NJ. Diagnosis and management of functional heartburn. Am J Gastroenterol. 2016;111(1):53–61 quiz 2.

    PubMed  Google Scholar 

  3. Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17):1640–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut. 2004;53(7):1024–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Mainie I, Tutuian R, Shay S, Vela M, Zhang X, Sifrim D, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shay S, Tutuian R, Sifrim D, Vela M, Wise J, Balaji N, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99(6):1037–43.

    PubMed  Google Scholar 

  7. Zerbib F, des Varannes SB, Roman S, Pouderoux P, Artigue F, Chaput U, et al. Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects. Aliment Pharmacol Ther. 2005;22(10):1011–21.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  9. Zerbib F, Roman S, Ropert A, des Varannes SB, Pouderoux P, Chaput U, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101(9):1956–63.

    PubMed  Google Scholar 

  10. Roman S, Serraj I, Damon H, Mion F. Correlation between gastric pH and gastro-oesophageal reflux contents: ambulatory pH-impedance monitoring results. Neurogastroenterol Motil. 2007;19(7):562–8.

    CAS  PubMed  Google Scholar 

  11. Ishii S, Fukahori S, Asagiri K, Tanaka Y, Saikusa N, Hashizume N, et al. Severe delayed gastric emptying induces non-acid reflux up to proximal esophagus in neurologically impaired patients. J Neurogastroenterol Motil. 2017;23(4):533–40.

    PubMed  PubMed Central  Google Scholar 

  12. Tavakkoli A, Sayed BA, Talley NJ, Moshiree B. Acid and non-acid reflux in patients refractory to proton pump inhibitor therapy: is gastroparesis a factor? World J Gastroenterol. 2013;19(37):6193–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kawami N, Takenouchi N, Umezawa M, Hoshino S, Hanada Y, Hoshikawa Y, et al. Pathogenesis of double-dose proton pump inhibitor-resistant non-erosive reflux disease, and mechanism of reflux symptoms and gastric acid secretion-suppressive effect in the presence or absence of helicobacter pylori infection. Digestion. 2017;95(2):140–5.

    CAS  PubMed  Google Scholar 

  14. Tenca A, Massironi S, Pugliese D, Consonni D, Mauro A, Cavalcoli F, et al. Gastro-esophageal reflux and antisecretory drugs use among patients with chronic autoimmune atrophic gastritis: a study with pH-impedance monitoring. Neurogastroenterol Motil. 2016;28(2):274–80.

    CAS  PubMed  Google Scholar 

  15. Pace F, Sangaletti O, Pallotta S, Molteni P, Porro GB. Biliary reflux and non-acid reflux are two distinct phenomena: a comparison between 24-hour multichannel intraesophageal impedance and bilirubin monitoring. Scand J Gastroenterol. 2007;42(9):1031–9.

    CAS  PubMed  Google Scholar 

  16. Savarino E, Bredenoord AJ, Fox M, Pandolfino JE, Roman S, Gyawali CP, et al. Expert consensus document: advances in the physiological assessment and diagnosis of GERD. Nat Rev Gastroenterol Hepatol. 2017;14(11):665–76.

    PubMed  Google Scholar 

  17. Frazzoni M, de Bortoli N, Frazzoni L, Tolone S, Savarino V, Savarino E. Impedance-pH monitoring for diagnosis of reflux disease: new perspectives. Dig Dis Sci. 2017;62(8):1881–9.

    CAS  PubMed  Google Scholar 

  18. Chae S, Richter JE. Wireless 24, 48, and 96 hour or impedance or oropharyngeal prolonged pH monitoring: which test, when, and why for GERD? Curr Gastroenterol Rep. 2018;20(11):52.

    PubMed  Google Scholar 

  19. Lechien JR, Akst LM, Hamdan AL, Schindler A, Karkos PD, Barillari MR, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160(5):762–82.

    PubMed  Google Scholar 

  20. Hirano I, Richter JE. Practice Parameters Committee of the American College of G. ACG practice guidelines: esophageal reflux testing. Am J Gastroenterol. 2007;102(3):668–85.

    PubMed  Google Scholar 

  21. Ciecierega T, Gordon BL, Aronova A, Crawford CV, Zarnegar R. More art than science: impedance analysis prone to interpretation error. J Gastrointest Surg. 2015;19(6):987–92.

    PubMed  Google Scholar 

  22. Ravi K, DeVault KR, Murray JA, Bouras EP, Francis DL. Inter-observer agreement for multichannel intraluminal impedance-pH testing. Dis Esophagus. 2010;23(7):540–4.

    CAS  PubMed  Google Scholar 

  23. 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(4):226–32.

    CAS  PubMed  Google Scholar 

  24. Committee AT, Wang A, Pleskow DK, Banerjee S, Barth BA, Bhat YM, et al. Esophageal function testing. Gastrointest Endosc. 2012;76(2):231–43.

    Google Scholar 

  25. •• Roman S, Gyawali CP, Savarino E, Yadlapati R, Zerbib F, Wu J, et al. Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29(10):1–15 A very important document that covers the current consensus regarding the diagnosis of GERD. It is from this statement that we extrapolate to define clinically relevant non-acid reflux populations.

    CAS  PubMed  Google Scholar 

  26. •• Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout A, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67(7):1351–62 A very important document that covers the current consensus regarding the diagnosis of GERD. It is from this statement that we extrapolate to define clinically relevant non-acid reflux populations.

    PubMed  Google Scholar 

  27. Kohata Y, Fujiwara Y, Yamagami H, Tanigawa T, Shiba M, Watanabe K, et al. Usefulness of baseline impedance in patients with proton pump inhibitor-refractory nonerosive reflux disease. J Gastroenterol Hepatol. 2015;30(Suppl 1):36–40.

    CAS  PubMed  Google Scholar 

  28. Frazzoni M, Manta R, Mirante VG, Conigliaro R, Frazzoni L, Melotti G. Esophageal chemical clearance is impaired in gastro-esophageal reflux disease—a 24-h impedance-pH monitoring assessment. Neurogastroenterol Motil. 2013;25(5):399–406 e295.

    CAS  PubMed  Google Scholar 

  29. 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 29.

    PubMed  Google Scholar 

  30. Xiao Y, Liang M, Peng S, Zhang N, Chen M. Tailored therapy for the refractory GERD patients by combined multichannel intraluminal impedance-pH monitoring. J Gastroenterol Hepatol. 2016;31(2):350–4.

    CAS  PubMed  Google Scholar 

  31. Strugala V, Avis J, Jolliffe IG, Johnstone LM, Dettmar PW. The role of an alginate suspension on pepsin and bile acids—key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease? J Pharm Pharmacol. 2009;61(8):1021–8.

    CAS  PubMed  Google Scholar 

  32. Ranaldo N, Losurdo G, Iannone A, Principi M, Barone M, De Carne M, et al. Tailored therapy guided by multichannel intraluminal impedance pH monitoring for refractory non-erosive reflux disease. Cell Death Dis. 2017;8(9):e3040.

    PubMed  PubMed Central  Google Scholar 

  33. Savarino E, de Bortoli N, Zentilin P, Martinucci I, Bruzzone L, Furnari M, et al. Alginate controls heartburn in patients with erosive and nonerosive reflux disease. World J Gastroenterol. 2012;18(32):4371–8.

    PubMed  PubMed Central  Google Scholar 

  34. De Ruigh A, Roman S, Chen J, Pandolfino JE, Kahrilas PJ. Gaviscon Double Action Liquid (antacid & alginate) is more effective than antacid in controlling post-prandial oesophageal acid exposure in GERD patients: a double-blind crossover study. Aliment Pharmacol Ther. 2014;40(5):531–7.

    PubMed  PubMed Central  Google Scholar 

  35. Farré R, Blondeau K, Clement D, Vicario M, Cardozo L, Vieth M, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut. 2011;60(7):885–92.

    PubMed  Google Scholar 

  36. 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(2):164–9.

    PubMed  Google Scholar 

  37. Farré R, De Vos R, Geboes K, Verbecke K, Vanden Berghe P, Depoortere I, et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut. 2007;56(9):1191–7.

    PubMed  PubMed Central  Google Scholar 

  38. Woodland P, Shen Ooi JL, Grassi F, Nikaki K, Lee C, Evans JA, et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology. 2017;153(5):1230–9.

    PubMed  Google Scholar 

  39. George N, Abdallah J, Maradey-Romero C, Gerson L, Fass R. Review article: the current treatment of non-cardiac chest pain. Aliment Pharmacol Ther. 2016;43(2):213–39.

    CAS  PubMed  Google Scholar 

  40. Rao SS, Mudipalli RS, Remes-Troche JM, Utech CL, Zimmerman B. Theophylline improves esophageal chest pain—a randomized, placebo-controlled study. Am J Gastroenterol. 2007;102(5):930–8.

    CAS  PubMed  Google Scholar 

  41. Dickman R, Schiff E, Holland A, Wright C, Sarela SR, Han B, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther. 2007;26(10):1333–44.

    CAS  PubMed  Google Scholar 

  42. Jarvenpaa P, Arkkila P, Aaltonen LM. Globus pharyngeus: a review of etiology, diagnostics, and treatment. Eur Arch Otorhinolaryngol. 2018;275(8):1945–53.

    PubMed  Google Scholar 

  43. 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. 2012;107(11):1662–7.

    CAS  PubMed  Google Scholar 

  44. Clarke JO, Fernandez-Becker NQ, Regalia KA, Triadafilopoulos G. Baclofen and gastroesophageal reflux disease: seeing the forest through the trees. Clin Transl Gastroenterol. 2018;9(3):137.

    PubMed  PubMed Central  Google Scholar 

  45. • Li S, Shi S, Chen F, Lin J. The effects of baclofen for the treatment of gastroesophageal reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract. 2014;2014:307805 An important meta-analysis arguing for the efficacy of baclofen in the treatment of GERD. Given lack of other options, we often utilize baclofen to treat problematic non-acid reflux.

    PubMed  PubMed Central  Google Scholar 

  46. 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.

    CAS  PubMed  Google Scholar 

  47. Beaumont H, Boeckxstaens GE. Does the presence of a hiatal hernia affect the efficacy of the reflux inhibitor baclofen during add-on therapy? Am J Gastroenterol. 2009;104(7):1764–71.

    CAS  PubMed  Google Scholar 

  48. Pauwels A, Broers C, Van Houtte B, Rommel N, Vanuytsel T, Tack J. A randomized double-blind, placebo-controlled, cross-over study using baclofen in the treatment of rumination syndrome. Am J Gastroenterol. 2018;113(1):97–104.

    CAS  PubMed  Google Scholar 

  49. Lee YC, Jung AR, Kwon OE, Kang JW, Huh JH, Eun YG. The effect of baclofen combined with a proton pump inhibitor in patients with refractory laryngopharyngeal reflux: a prospective, open-label study in thirty-two patients. Clin Otolaryngol. 2019;44(3):431–4.

    PubMed  Google Scholar 

  50. Dong R, Xu X, Yu L, Ding H, Pan J, Yu Y, et al. Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough. Aliment Pharmacol Ther. 2019;49(6):714–22.

    CAS  PubMed  Google Scholar 

  51. Tack J, Janssen P, Masaoka T, Farré R, Van Oudenhove L. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol. 2012;10(11):1239–45.

    CAS  PubMed  Google Scholar 

  52. Karamanolis GP, Panopoulos S, Denaxas K, Karlaftis A, Zorbala A, Kamberoglou D, et al. The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial. Arthritis Res Ther. 2016;18:195.

    PubMed  PubMed Central  Google Scholar 

  53. Di Stefano M, Papathanasopoulos A, Blondeau K, Vos R, Boecxstaens V, Farre R, et al. Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers. Dis Esophagus. 2012;25(5):470–6.

    PubMed  Google Scholar 

  54. Aggarwal N, Thota PN, Lopez R, Gabbard S. A randomized double-blind placebo-controlled crossover-style trial of buspirone in functional dysphagia and ineffective esophageal motility. Neurogastroenterol Motil. 2018;30(2).

  55. Blonski W, Vela MF, Freeman J, Sharma N, Castell DO. The effect of oral buspirone, pyridostigmine, and bethanechol on esophageal function evaluated with combined multichannel esophageal impedance-manometry in healthy volunteers. J Clin Gastroenterol. 2009;43(3):253–60.

    CAS  PubMed  Google Scholar 

  56. Agrawal A, Hila A, Tutuian R, Mainie I, Castell DO. Bethanechol improves smooth muscle function in patients with severe ineffective esophageal motility. J Clin Gastroenterol. 2007;41(4):366–70.

    CAS  PubMed  Google Scholar 

  57. • Ren LH, Chen WX, Qian LJ, Li S, Gu M, Shi RH. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: a meta-analysis. World J Gastroenterol. 2014;20(9):2412–9 An important meta-analysis regarding the efficacy of prokinetics in GERD. Based on this analysis, we generally avoid prokinetics in non-acid reflux except for highly selected patients.

    PubMed  PubMed Central  Google Scholar 

  58. Gawron AJ, Bell R, Abu Dayyeh BK, Buckley FP, Chang K, Dunst CM, et al. Surgical and endoscopic management options for patients with GERD based on proton pump inhibitor symptom response: recommendations from an expert U.S. panel. Gastrointest Endosc. 2020;92(1):78–87.e2.

  59. Broeders JA, Bredenoord AJ, Hazebroek EJ, Broeders IA, Gooszen HG, Smout AJ. Effects of anti-reflux surgery on weakly acidic reflux and belching. Gut. 2011;60(4):435–41.

    CAS  PubMed  Google Scholar 

  60. 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. Br J Surg. 2006;93(12):1483–7.

    CAS  PubMed  Google Scholar 

  61. Sidwa F, Moore AL, Alligood E, Fisichella PM. Surgical treatment of extraesophageal manifestations of gastroesophageal reflux disease. World J Surg. 2017;41(10):2566–71.

    PubMed  Google Scholar 

  62. Desjardin M, Luc G, Collet D, Zerbib F. 24-hour pH-impedance monitoring on therapy to select patients with refractory reflux symptoms for antireflux surgery. A single center retrospective study. Neurogastroenterol Motil. 2016;28(1):146–52.

    CAS  PubMed  Google Scholar 

  63. Savarino E, Marabotto E, Salvador R, De Cassan C, Furnari M, Zentilin P, et al. Mo1117 patients with non-acid reflux disease and those with erosive and non-erosive reflux disease have similar response to anti-reflux surgical therapy. Gastroenterology. 2015;148(4):S-611.

    Google Scholar 

  64. Xu Y, Zhang C. Letter to the editor: acid reflux or non-acid reflux? Dig Dis Sci. 2018;63(12):3518–9.

    PubMed  Google Scholar 

  65. Hathorn KE, Chan WW, Lo WK. Role of gastroesophageal reflux disease in lung transplantation. World J Transplant. 2017;7(2):103–16.

    PubMed  PubMed Central  Google Scholar 

  66. Hoppo T, Jarido V, Pennathur A, Morrell M, Crespo M, Shigemura N, et al. Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg. 2011;146(9):1041–7.

    PubMed  Google Scholar 

  67. Lo WK, Goldberg HJ, Wee J, Fisichella PM, Chan WW. Both pre-transplant and early post-transplant antireflux surgery prevent development of early allograft injury after lung transplantation. J Gastrointest Surg. 2016;20(1):111–8 discussion 8.

    PubMed  Google Scholar 

  68. Biswas Roy S, Elnahas S, Serrone R, Haworth C, Olson MT, Kang P, et al. Early fundoplication is associated with slower decline in lung function after lung transplantation in patients with gastroesophageal reflux disease. J Thorac Cardiovasc Surg. 2018;155(6):2762–71 e1.

    PubMed  Google Scholar 

  69. Uno K, Iijima K, Hatta W, Koike T, Abe Y, Asano N, et al. Direct measurement of gastroesophageal reflux episodes in patients with squamous cell carcinoma by 24-h pH-impedance monitoring. Am J Gastroenterol. 2011;106(11):1923–9.

    CAS  PubMed  Google Scholar 

  70. Kgomo M, Mokoena TR, Ker JA. Non-acid gastro-oesophageal reflux is associated with squamous cell carcinoma of the oesophagus. BMJ Open Gastroenterol. 2017;4(1):e000180.

    PubMed  PubMed Central  Google Scholar 

  71. Cook MB. Non-acid reflux: the missing link between gastric atrophy and esophageal squamous cell carcinoma? Am J Gastroenterol. 2011;106(11):1930–2.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE), Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 430 Broadway Street, Pavilion C, 3rd Floor, GI suite, Redwood City, CA, 94063, USA

    Thomas A. Zikos & John O. Clarke

Authors
  1. Thomas A. Zikos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John O. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas A. Zikos.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

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.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Esophagus

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zikos, T.A., Clarke, J.O. Non-acid Reflux: When It Matters and Approach to Management. Curr Gastroenterol Rep 22, 43 (2020). https://doi.org/10.1007/s11894-020-00780-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11894-020-00780-4

Keywords

Search

Navigation