Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathophysiology of reflux esophagitis

Peter J Kahrilas, MD
Section Editor
Nicholas J Talley, MD, PhD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


Some degree of reflux is physiologic [1]. Physiologic reflux episodes typically occur postprandially, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux often occurs nocturnally and is associated with symptoms or mucosal injury. In general, the term gastroesophageal reflux disease (GERD) is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with, esophageal inflammation. Reflux esophagitis describes a subset of patients with GERD who have endoscopic evidence of esophageal inflammation.

The pathophysiology of GERD will be reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)


The development of gastroesophageal reflux disease (GERD) reflects an imbalance between injurious or symptom-eliciting factors (reflux events, acidity of refluxate, esophageal hypersensitivity) and defensive factors (esophageal acid clearance, mucosal integrity) [2]. The extent of symptoms and of mucosal injury is proportional to the frequency of reflux events, the duration of mucosal acidification, and the caustic potency of refluxed fluid.

Esophagitis results from cytokine-triggered inflammation rather than a direct chemical effect of prolonged exposure to acid, pepsin, and bile on the esophageal epithelium [3-5]. This is substantiated by the observation that histopathological events in the development of esophagitis (lymphocytic inflammation, dilated intercellular spaces) occur deep in the epithelium, not at the luminal surface, and that regenerative changes (basal cell hyperplasia, papillary elongation) are initiated prior to the development of surface necrosis that was formerly hypothesized as the stimulus for those changes. Cytokine-triggered inflammation may also cause alterations in esophageal sensitivity in the absence of esophagitis.

Gastroesophageal junction incompetence — The antireflux barrier at the gastroesophageal junction is anatomically and physiologically complex and vulnerable to several potential mechanisms of reflux. The three dominant pathophysiologic mechanisms causing esophagogastric junction (EGJ) incompetence are:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Nov 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Richter JE. Typical and atypical presentations of gastroesophageal reflux disease. The role of esophageal testing in diagnosis and management. Gastroenterol Clin North Am 1996; 25:75.
  2. Boeckxstaens G, El-Serag HB, Smout AJ, Kahrilas PJ. Symptomatic reflux disease: the present, the past and the future. Gut 2014; 63:1185.
  3. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 2009; 137:1776.
  4. Dunbar KB, Agoston AT, Odze RD, et al. Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes. JAMA 2016; 315:2104.
  5. Kahrilas PJ. Turning the Pathogenesis of Acute Peptic Esophagitis Inside Out. JAMA 2016; 315:2077.
  6. Barham CP, Gotley DC, Mills A, Alderson D. Precipitating causes of acid reflux episodes in ambulant patients with gastro-oesophageal reflux disease. Gut 1995; 36:505.
  7. Massey BT, Simuncak C, LeCapitaine-Dana NJ, Pudur S. Transient lower esophageal sphincter relaxations do not result from passive opening of the cardia by gastric distention. Gastroenterology 2006; 130:89.
  8. Pandolfino JE, Zhang QG, Ghosh SK, et al. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry. Gastroenterology 2006; 131:1725.
  9. Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980; 65:256.
  10. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982; 307:1547.
  11. Mittal RK, Holloway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology 1995; 109:601.
  12. Martin CJ, Dodds WJ, Liem HH, et al. Diaphragmatic contribution to gastroesophageal competence and reflux in dogs. Am J Physiol 1992; 263:G551.
  13. Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995; 268:G128.
  14. Martin CJ, Patrikios J, Dent J. Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockade in the dog. Gastroenterology 1986; 91:890.
  15. Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking. Gut 1990; 31:4.
  16. Pandolfino JE, Shi G, Trueworthy B, Kahrilas PJ. Esophagogastric junction opening during relaxation distinguishes nonhernia reflux patients, hernia patients, and normal subjects. Gastroenterology 2003; 125:1018.
  17. Kahrilas PJ, Dodds WJ, Hogan WJ, et al. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986; 91:897.
  18. Dent J, Dodds WJ, Hogan WJ, Toouli J. Factors that influence induction of gastroesophageal reflux in normal human subjects. Dig Dis Sci 1988; 33:270.
  19. Mittal RK, Rochester DF, McCallum RW. Sphincteric action of the diaphragm during a relaxed lower esophageal sphincter in humans. Am J Physiol 1989; 256:G139.
  20. Sloan S, Rademaker AW, Kahrilas PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med 1992; 117:977.
  21. Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 1991; 101:1149.
  22. Powell DW. Barrier function of epithelia. Am J Physiol 1981; 241:G275.
  23. Goldberg HI, Dodds WJ, Montgomery C, et al. Controlled production of acute esophagitis. Experimental animal model. Invest Radiol 1970; 5:254.
  24. Vaezi MF, Singh S, Richter JE. Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies. Gastroenterology 1995; 108:1897.
  25. Helm JF, Dodds WJ, Pelc LR, et al. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984; 310:284.
  26. Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988; 94:73.
  27. Mittal RK, Lange RC, McCallum RW. Identification and mechanism of delayed esophageal acid clearance in subjects with hiatus hernia. Gastroenterology 1987; 92:130.
  28. Sloan S, Kahrilas PJ. Impairment of esophageal emptying with hiatal hernia. Gastroenterology 1991; 100:596.
  29. Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 2001; 121:775.
  30. Kahrilas PJ, McColl K, Fox M, et al. The acid pocket: a target for treatment in reflux disease? Am J Gastroenterol 2013; 108:1058.
  31. Pandolfino JE, Zhang Q, Ghosh SK, et al. Acidity surrounding the squamocolumnar junction in GERD patients: "acid pocket" versus "acid film". Am J Gastroenterol 2007; 102:2633.
  32. Clarke AT, Wirz AA, Manning JJ, et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. Gut 2008; 57:292.
  33. Kahrilas PJ, Gupta RR. The effect of cigarette smoking on salivation and esophageal acid clearance. J Lab Clin Med 1989; 114:431.
  34. Korsten MA, Rosman AS, Fishbein S, et al. Chronic xerostomia increases esophageal acid exposure and is associated with esophageal injury. Am J Med 1991; 90:701.
  35. Sonnenberg A, Steinkamp U, Weise A, et al. Salivary secretion in reflux esophagitis. Gastroenterology 1982; 83:889.
  36. Quigley EM, Turnberg LA. pH of the microclimate lining human gastric and duodenal mucosa in vivo. Studies in control subjects and in duodenal ulcer patients. Gastroenterology 1987; 92:1876.
  37. Orlando RC, Lacy ER, Tobey NA, Cowart K. Barriers to paracellular permeability in rabbit esophageal epithelium. Gastroenterology 1992; 102:910.
  38. Orlando RC, Bryson JC, Powell DW. Mechanisms of H+ injury in rabbit esophageal epithelium. Am J Physiol 1984; 246:G718.
  39. Orlando RC. Esophageal epithelial defenses against acid injury. Am J Gastroenterol 1994; 89:S48.
  40. Trimble KC, Douglas S, Pryde A, Heading RC. Clinical characteristics and natural history of symptomatic but not excess gastroesophageal reflux. Dig Dis Sci 1995; 40:1098.
  41. Jones MP, Sloan SS, Rabine JC, et al. Hiatal hernia size is the dominant determinant of esophagitis presence and severity in gastroesophageal reflux disease. Am J Gastroenterol 2001; 96:1711.
  42. Pandolfino JE, Kim H, Ghosh SK, et al. High-resolution manometry of the EGJ: an analysis of crural diaphragm function in GERD. Am J Gastroenterol 2007; 102:1056.
  43. Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 2000; 118:688.
  44. van Herwaarden MA, Samsom M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000; 119:1439.
  45. Beaumont H, Bennink RJ, de Jong J, Boeckxstaens GE. The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD. Gut 2010; 59:441.
  46. Johnson LF. 24-hour pH monitoring in the study of gastroesophageal reflux. J Clin Gastroenterol 1980; 2:387.
  47. Corley DA, Kubo A, Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms. Gut 2007; 56:756.
  48. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006; 354:2340.
  49. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006; 130:639.
  50. El-Serag HB, Ergun GA, Pandolfino J, et al. Obesity increases oesophageal acid exposure. Gut 2007; 56:749.
  51. de Vries DR, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure. Am J Gastroenterol 2008; 103:1349.
  52. Wu JC, Mui LM, Cheung CM, et al. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007; 132:883.
  53. Zheng Z, Margolis KL, Liu S, et al. Effects of estrogen with and without progestin and obesity on symptomatic gastroesophageal reflux. Gastroenterology 2008; 135:72.