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Reflux Hypersensitivity: How to Approach Diagnosis and Management

  • Esophagus (J Clarke and N Ahuja, Section Editors)
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Abstract

Purpose of Review

This paper aims to review the definition and diagnostic criteria for reflux hypersensitivity and comment on the present and future management of this condition.

Recent Findings

In 2016, the Rome IV criteria redefined reflux hypersensitivity as characterized by typical reflux symptoms, absence of endoscopic mucosal disease, absence of pathologic gastroesophageal reflux, and positive symptom correlation between reflux and heartburn episodes. Though uncertain, TPRV1 receptors have been implicated in the pathophysiology of reflux hypersensitivity. Recent studies have shown neuromodulators like SSRIs, SNRIs, and TCAs may be the future of managing this condition.

Summary

With the release of the Rome IV criteria and availability of continuous pH monitoring, the diagnosis of reflux hypersensitivity has become more streamlined. Though there is no definitive therapy for reflux hypersensitivity, several anti-secretory agents and neuromodulators have shown some efficacy in therapeutic trials. The lack of large-scale, randomized controlled trials, however, reinforces the need for further research into the pharmacotherapy of reflux hypersensitivity.

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References

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

  1. Badillo R, Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther. 2014;5:105–12. https://doi.org/10.4292/wjgpt.v5.i3.105.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20. https://doi.org/10.1111/j.1572-0241.2006.00630.x.

    Article  PubMed  Google Scholar 

  3. Schmulson MJ, Drossman DA. What is new in Rome IV. Journal of neurogastroenterology and motility. 2017;23:151–63. https://doi.org/10.5056/jnm16214.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Drossman DA, Hasler WL. Rome IV-functional GI disorders: disorders of gut-brain interaction. Gastroenterology. 2016;150:1257–61. https://doi.org/10.1053/j.gastro.2016.03.035.

    Article  PubMed  Google Scholar 

  5. Corazziari E. Definition and epidemiology of functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2004;18:613–31. https://doi.org/10.1016/j.bpg.2004.04.012.

    Article  PubMed  Google Scholar 

  6. Mearin F, Malfertheiner P. Functional gastrointestinal disorders: complex treatments for complex pathophysiological mechanisms. Dig Dis. 2017;35(Suppl 1):1–4. https://doi.org/10.1159/000485407.

    Article  PubMed  Google Scholar 

  7. Talley NJ. Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil. 2008;20:121–9. https://doi.org/10.1111/j.1365-2982.2008.01097.x.

    Article  PubMed  Google Scholar 

  8. Rubenstein JH, Chen JW. Epidemiology of gastroesophageal reflux disease. Gastroenterol Clin N Am. 2014;43:1–14. https://doi.org/10.1016/j.gtc.2013.11.006.

    Article  Google Scholar 

  9. Yamasaki T, Fass R. Reflux hypersensitivity: a new functional esophageal disorder. Neurogastroenterol Motil. 2017;23:495–503. https://doi.org/10.5056/jnm17097.

    Article  Google Scholar 

  10. Drossman DA. Rome II: The functional gastrointestinal disorders. 2nd ed. Degnon Associates Inc; 2000.

  11. Savarino E, Marabotto E, Bodini G, Pellegatta G, Coppo C, Giambruno E, et al. Epidemiology and natural history of gastroesophageal reflux disease. Minerva Gastroenterol Dietol. 2017;63:175–83. https://doi.org/10.23736/S1121-421X.17.02383-2.

    Article  PubMed  Google Scholar 

  12. Drossman DA. Rome III: The functional gastrointestinal disorders.Degnon Associates; 2006.

  13. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Esophageal disorders. Gastroenterology. 2016;150:1368–79. https://doi.org/10.1053/j.gastro.2016.02.012.

    Article  Google Scholar 

  14. Dent J, Vakil N, Jones R, Bytzer P, Schoning U, Halling K, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the diamond study. Gut. 2010;59:714–21. https://doi.org/10.1136/gut.2009.200063.

    Article  PubMed  Google Scholar 

  15. Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJPM, et al. Modern diagnosis of GERD: the Lyon consensus. Gut. 2018;67:1351–62. https://doi.org/10.1136/gutjnl-2017-314722.

    Article  PubMed  Google Scholar 

  16. 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. https://doi.org/10.1038/ajg.2009.670.

    Article  PubMed  Google Scholar 

  17. Vaezi MF. Use of symptom indices in the management of GERD. Gastroenterol Hepatol. 2012;8:185–7.

    Google Scholar 

  18. Aanen MC, Bredenoord AJ, Numans ME, Samson M, Smout AJ. Reproducibility of symptom association analysis in ambulatory reflux monitoring. Am J Gastroenterol. 2008;103:2200–8. https://doi.org/10.1111/j.1572-0241.2008.02067.x.

    Article  PubMed  Google Scholar 

  19. Savarino E, Savarino E, Zentilin P, Zentilin P, Tutuian R, Tutuian R, et al. Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients. J Gastroenterol. 2012;47:159–68. https://doi.org/10.1007/s00535-011-0480-0.

    Article  PubMed  Google Scholar 

  20. 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;43:542–7. https://doi.org/10.1016/j.dld.2011.01.016.

    Article  PubMed  Google Scholar 

  21. de Bortoli N, Martinucci I, Savarino E, Tutuian R, Frazzoni M, Piaggi P, et al. Association between baseline impedance values and response proton pump inhibitors in patients with heartburn. Clin Gastroenterol Hepatol. 2015;13:1082–8.e1. https://doi.org/10.1016/j.cgh.2014.11.035.

    Article  CAS  PubMed  Google Scholar 

  22. 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;55:1398–402. https://doi.org/10.1136/gut.2005.087668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schmulson M. How to use Rome IV criteria in the evaluation of esophageal disorders. Curr Opin Gastroenterol. 2018;34:258–65. https://doi.org/10.1097/MOG.0000000000000443.

    Article  PubMed  Google Scholar 

  24. 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. https://doi.org/10.1111/j.1365-2036.2010.04406.x.

    Article  CAS  PubMed  Google Scholar 

  25. Sharma N, Agrawal A, Freeman J, Vela MF, Castell D. An analysis of persistent symptoms in acid-suppressed patients undergoing impedance-pH monitoring. Clin Gastroenterol Hepatol. 2008;6:521–4. https://doi.org/10.1016/j.cgh.2008.01.006.

    Article  PubMed  Google Scholar 

  26. Trimble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut. 1995;37:7–12. https://doi.org/10.1136/gut.37.1.7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Du Q, Liao Q, Chen C, Yang X, Xie R, Xu J. The role of transient receptor potential vanilloid 1 in common diseases of the digestive tract and the cardiovascular and respiratory system. Front Physiol. 2019;10:1064. https://doi.org/10.3389/fphys.2019.01064.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yang SC, Chen CL, Yi CH, Liu TT, Shieh KR. Changes in gene expression patterns of circadian-clock, transient receptor potential vanilloid-1 and nerve growth factor in inflamed human esophagus. Sci Rep. 2015;5:13602. https://doi.org/10.1038/srep13602.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Knowles CH, Aziz Q. Visceral hypersensitivity in non-erosive reflux disease. Gut. 2008;57:674–83. https://doi.org/10.1136/gut.2007.127886.

    Article  CAS  PubMed  Google Scholar 

  30. Rinsma NF, Farre R, Troost FJ, Elizalde M, Keszthelyi D, Helyes Z, et al. Exploration of the esophageal mucosal barrier in non-erosive reflux disease. Int J Mol Sci. 2017;18:1091. https://doi.org/10.3390/ijms18051091.

    Article  CAS  PubMed Central  Google Scholar 

  31. Tamura Y, Funaki Y, Izawa S, Iida A, Yamaguchi Y, Adachi K, et al. Pathophysiology of functional heartburn based on Rome III criteria in Japanese patients. World J Gastroenterol. 2015;21:5009–16. https://doi.org/10.3748/wjg.v21.i16.5009.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Weijenborg PW, Smout AJ, Bredenoord AJ. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn. Neurogastroenterol Motil. 2016;28:1649–54. https://doi.org/10.1111/nmo.12864.

    Article  CAS  PubMed  Google Scholar 

  33. Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the microbiota–gut–brain axis in visceral pain: relevance to irritable bowel syndrome. CNS Neurosci Ther. 2016;22:102–17. https://doi.org/10.1111/cns.12490.

    Article  PubMed  Google Scholar 

  34. Hu WHC, Wong W, Lam CLK, Lam KF, Hui WM, Lai KC, et al. Anxiety but not depression determines health care-seeking behaviour in Chinese patients with dyspepsia and irritable bowel syndrome: a population-based study. Aliment Pharmacol Ther 2002 : 16 : 2081–2088. Doi: https://doi.org/10.1046/j.1365-2036.2002.01377.x.

  35. Van Oudenhove L, Vandenberghe J, Geeraerts B, Vos R, Persoons P, Fischler B, et al. Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation? Gut. 2008;57:1666–73. https://doi.org/10.1136/gut.2008.158162.

    Article  PubMed  Google Scholar 

  36. Aro P, Talley NJ, Ronkainen J, Storskrubb T, Vieth M, Johansson S, et al. Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study. Gastroenterology. 2009;137:94–100. https://doi.org/10.1053/j.gastro.2009.03.039.

    Article  PubMed  Google Scholar 

  37. Fass R, Naliboff BD, Fass SS, Peleg N, Wendel C, Malagon IB, et al. The effect of auditory stress on perception of intraesophageal acid in patients with gastroesophageal reflux disease. Gastroenterology. 2008;134:696–705. https://doi.org/10.1053/j.gastro.2007.12.010.

    Article  PubMed  Google Scholar 

  38. Taché Y, Kiank C, Stengel A. A role for corticotropin-releasing factor in functional gastrointestinal disorders. Curr Gastroenterol Rep. 2009;11:270–7. https://doi.org/10.1007/s11894-009-0040-4.

    Article  PubMed  Google Scholar 

  39. Schey R, Dickman R, Parthasarathy S, Quan SF, Wendel C, Merchant J, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology. 2007;133:1787–95. https://doi.org/10.1053/j.gastro.2007.09.039.

    Article  PubMed  Google Scholar 

  40. Broers C, Melchior C, Van Oudenhove L, Vanuytsel T, Van Houtte B, Scheerens C, et al. The effect of intravenous corticotropin-releasing hormone administration on esophageal sensitivity and motility in health. Am J Physiol Gastrointest Liver Physiol. 2017;312:G526–34. https://doi.org/10.1152/ajpgi.00437.2016.

    Article  PubMed  Google Scholar 

  41. Fass R, Sontag SJ, Traxler B, Sostek M. Treatment of patients with persistent heartburn symptoms: a double-blind, randomized trial. Clin Gastroenterol Hepatol. 2006;4:50–6. https://doi.org/10.1016/S1542-3565(05)00860-8.

    Article  CAS  PubMed  Google Scholar 

  42. Nabi Z, Reddy DN. Endoscopic management of gastroesophageal reflux disease: revisited. Clin Endosc. 2016;49:408–16. https://doi.org/10.5946/ce.2016.133.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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 : 52–0. Doi: https://doi.org/10.1007/s11894-018-0659-0.

  44. Yamasaki T, O'Neil J, Fass R. Update on functional heartburn. Gastroenterol Hepatol. 2017;13:725–34.

    Google Scholar 

  45. Watson RG, Tham TC, Johnston BT, McDougall NI. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux--the “sensitive oesophagus”. Gut. 1997;40:587–90. https://doi.org/10.1136/gut.40.5.587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rodriguez-Stanley S, Ciociola AA, Zubaidi S, Proskin HM, Miner PB. A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn. Aliment Pharmacol Ther. 2004;20:975–82. https://doi.org/10.1111/j.1365-2036.2004.02217.x.

    Article  CAS  PubMed  Google Scholar 

  47. Marrero JM, de Caestecker JS, Maxwell JD. Effect of famotidine on oesophageal sensitivity in gastro-oesophageal reflux disease. Gut. 1994;35:447–50. https://doi.org/10.1136/gut.35.4.447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308–28; quiz 329. https://doi.org/10.1038/ajg.2012.444.

    Article  PubMed  Google Scholar 

  49. Park SW, Lee H, Lee HJ, Park JC, Shin SK, Lee SK, et al. Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol. 2013;19:4958–65. https://doi.org/10.3748/wjg.v19.i30.4958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee H, Kim JH, Min B, Lee JH, Son HJ, Kim JJ, et al. Efficacy of venlafaxine for symptomatic relief in young adult patients with functional chest pain: a randomized, double-blind, placebo-controlled, crossover trial. Am J Gastroenterol. 2010;105:1504–12. https://doi.org/10.1038/ajg.2010.82.

    Article  CAS  PubMed  Google Scholar 

  51. 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;107:1662–7. https://doi.org/10.1038/ajg.2011.179.

    Article  CAS  PubMed  Google Scholar 

  52. Weijenborg PW, de Schepper HS, Smout AJ, Bredenoord AJ. Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2015;13:251–259.e1. https://doi.org/10.1016/j.cgh.2014.06.025.

    Article  CAS  PubMed  Google Scholar 

  53. Amitriptyline hydrochloride [package insert]. princeton, NJ: Sandoz pharmaceuticals; 2014.

  54. Zoloft (sertraline) [package insert]. new york, NY: Pfizer; 2016.

  55. Effexor (venlafaxine hydrochloride) [package insert]. Philadelphia, PA: Wyeth pharmaceuticals; 2008.

  56. Silva RO, Bingana RD, Sales TM, Moreira RLR, Costa DVS, Sales KMO, et al. Role of TRPV1 receptor in inflammation and impairment of esophageal mucosal integrity in a murine model of nonerosive reflux disease. Neurogastroenterol Motil. 2018;30:30. https://doi.org/10.1111/nmo.13340.

    Article  CAS  Google Scholar 

  57. Krarup AL, Ny L, Åstrand M, Bajor A, Hvid-Jensen F, Hansen MB, et al. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment Pharmacol Ther. 2011;33:1113–22. https://doi.org/10.1111/j.1365-2036.2011.04629.x.

    Article  CAS  PubMed  Google Scholar 

  58. Krarup AL, Ny L, Gunnarsson J, Hvid-Jensen F, Zetterstrand S, Simrén M, et al. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand J Gastroenterol. 2013;48:274–84. https://doi.org/10.3109/00365521.2012.758769.

    Article  CAS  PubMed  Google Scholar 

  59. Spechler SJ, Hunter JG, Jones KM, Lee R, Smith BR, Mashimo H, et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med. 2019;381:1513–23. https://doi.org/10.1056/NEJMoa1811424.

    Article  PubMed  Google Scholar 

  60. Riehl ME, Keefer L. Hypnotherapy for esophageal disorders. Am J Clin Hypn. 2015;58:22–33. https://doi.org/10.1080/00029157.2015.1025355.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. University of Texas Health Science Center San Antonio, San Antonio, TX, USA

    Pankaj Aggarwal

  2. Division of Gastroenterology, Stanford University, 420 Broadway Street, Pavilion D, Redwood City, CA, 94063, USA

    Afrin N. Kamal

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Aggarwal, P., Kamal, A.N. Reflux Hypersensitivity: How to Approach Diagnosis and Management. Curr Gastroenterol Rep 22, 42 (2020). https://doi.org/10.1007/s11894-020-00779-x

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