Abstract
The cause of reflux esophagitis (RE) is excessive esophageal acid exposure. Acid reflux and acid clearance after acid reflux are important factors related to excessive esophageal acid exposure. The main mechanism responsible for acid reflux is transient lower esophageal sphincter relaxation (TLESR), which is LES relaxation not associated with swallowing, and acid reflux caused by low LES pressure is rare. The frequency of TLESR in the postprandial period does not significantly differ between healthy subjects and gastroesophageal reflux disease (GERD) patients; however, the proportion of acid reflux episodes during TLESR is significantly higher in GERD patients. The layer of acid that appears above the dietary layer immediately below the esophagogastric junction (acid pocket) is attracting increasing attention as a cause of the difference in the proportion of acid reflux episodes during TLESR. The proportion of acid reflux episodes during TLESR is significantly higher when the acid pocket is present in the hernia sac than when it is located below the diaphragm. The acid pocket also shows upward migration and reaches the esophageal side of the esophagogastric junction, and the acid pocket itself has been suggested to cause mucosal damage in the lower esophagus. The amplitude and success rate of primary peristalsis decreases with increases in the severity of RE, leading to excessive esophageal acid exposure. Furthermore, the success rate of secondary peristalsis is lower in GERD patients than in healthy subjects.
Similar content being viewed by others
References
Iwakiri K, Kinoshita Y, Habu Y, et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015. J Gastroenterol. 2016;51:751–67.
Mizuno H, Matsuhashi N, Sakaguchi M, et al. Recent effectiveness of proton pump inhibitors for severe reflux esophagitis: the first multicenter prospective study in Japan. J Clin Biochem Nutr. 2015;57:233–8.
Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–80.
Iwakiri K, Sakamoto C. Pathophysiology of gastroesophageal reflux disease: mitility factor. Jpn J Gastroenterol. 2003;100:1084–94 (in Japanese).
Iwakiri K. The role of excessive esophageal acid exposure in patients with gastroesophageal reflux disease. Clin J Gastroenterol. 2009;2:371–9.
Holloway RH. The anti-reflux barrier and mechanisms of gastro-oesophageal reflux. Baillieres Best Pract Res Clin Gastroenterol. 2000;14:681–99.
Mittal RK, Holloway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology. 1995;109:601–10.
Schoeman MN, Tippett MD, Akkermans LM, et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology. 1995;108:83–91.
Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med. 1982;307:1547–52.
Dent J, Holloway RH, Toouli J, et al. Mechanisms of lower esophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux. Gut. 1988;29:1020–8.
Mittal RK, McCallum RW. Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis. Gastroenterology. 1988;95:593–9.
Dodds WJ, Kahrilas PJ, Dent J, et al. Analysis of spontaneous gastroesophageal reflux and esophageal acid clearance in patients with reflux esophagitis. J Gastrointest Motil. 1990;2:79–89.
Sifrim D, Holloway R, Silny J, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2001;96:647–55.
Sano H, Iwakiri K, Kawami N, et al. Mechanisms of acid reflux and how refluxed Acid extends proximally in patients with non-erosive reflux disease. Digestion. 2014;90:108–15.
Mittal RK, Fisher MJ. Electrical and mechanical inhibition of the crural diaphragm during transient relaxation of the lower esophageal sphincter. Gastroenterology. 1990;99:1265–8.
Hayashi Y, Iwakiri K, Kotoyori M, et al. Mechanisms of acid gastroesophageal reflux in the Japanese population. Dig Dis Sci. 2008;53:1–6.
Iwakiri K, Hayashi Y, Kotoyori M, et al. Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism of gastroesophageal reflux but are not the cause of reflux disease. Dig Dis Sci. 2005;50:1072–7.
Lidums I, Lehmann A, Checklin H, et al. Control of transient lower esophageal sphincter relaxations and reflux by the GABAB agonist baclofen in normal human subjects. Gastroenterology. 2000;118:7–13.
Zhang Q, Lehmann A, Rigda R, et al. Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-oesophageal reflux disease. Gut. 2002;50:19–24.
Holloway RH, Hongo M, Berger K, et al. Gastric distention: a mechanism for postprandial reflux. Gastroenterology. 1985;89:779–84.
Wyman JB, Dent J, Heddle R, et al. Control of belching by the lower oesophageal sphincter. Gut. 1990;31:639–46.
Holloway R, Kocyan FP, Dent J, et al. Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux. Dig Dis Sci. 1991;36:1034–9.
Penagini R, Bartesaghi B, Conte D, et al. Rate of transient lower oesophageal sphincter relaxations of healthy humans after eating a mixed nutrient meal: time course and comparison with fasting. Eur J Gastroenterol Hepatol. 1992;4:35–8.
Wu JC, Mui LM, Cheung CM, et al. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology. 2007;132:83–9.
Franzi SJ, Martin CJ, Cox MR, et al. Response of canine lower esophageal sphincter to gastric distension. Am J Physiol. 1990;159:G380–5.
Iwakiri K, Kobayashi M, Kotoyori M, et al. Relationship between postprandial esophageal acid exposure and meal volume and fat content. Dig Dis Sci. 1996;41:926–30.
Becker DJ, Sinclair J, Castell DO, et al. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol. 1989;84:782–6.
Holloway RH, Lyrenas E, Ireland A, et al. Effect of intraduodenal fat on lower oesophageal sphincter function and gastro-oesophageal reflux. Gut. 1998;42:449–53.
Penagini R, Mangano M, Bianchi PA. Effect of increasing The fat content but not The energy load of a meal on gastro-oesophageal reflux and lower oesophageal sphincter motor function. Gut. 1998;42:330–3.
Freidin N, Mittal RK, McCallum RW, et al. Does body posture affect the incidence and mechanism of gastro-oesophageal reflux? Gut. 1991;32:133–6.
Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic subjects. J Clin Invest. 1980;65:256–67.
Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut. 1991;32:1275–9.
Cox MR, Martin CJ, Dent J, et al. Effect of general anaesthesia on transient lower oesophageal sphincter relaxations in the dog. Aust NZ J Surg. 1988;58:825–30.
Martin CJ, Patrikios J, Dent J. Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockade in the dog. Gastroenterology. 1986;91:890–6.
Staunton E, Smid SD, Dent J, et al. Triggering of transient LES relaxations in ferrets: role of sympathetic pathways and effects of baclofen. Am J Physiol. 2000;279:G157–62.
Neuhuber WL. Sensory vagal innervation of the rat esophagus and cardia: a light and electron microscopic anterograde tracing study. J Auton Nerv Syst. 1987;20:243–55.
Altschuler SM, Bao XM, Bieger D, et al. Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J Comp Neurol. 1989;283:248–68.
Kalia M, Sullivan JM. Brainstem projections of sensory and motor components of the vagus nerve in the rat. J Comp Neurol. 1982;211:248–65.
Barber WD, Burks TF. Brain stem response to phasic gastric distension. Am J Physiol. 1983;245:G242–8.
Hornby P. How are transient LES relaxations triggered? In: Guili R, Galmiche J-P, Jamieson GG, Scarpignato C, editors. The esophagogastric junction. Paris: John Libbey, Eurotext; 1988. p. 62–72.
Rinaman L, Card JP, Schwaber JS, et al. Ultrastructural demonstration of a gastric monosynaptic vagal circuit in the nucleus of the solitary tract in rat. J Neuosci. 1989;9:1985–96.
Hopkins DA. Ultrastructure and synaptology of the nucleus ambiguus in the rat: the compact formation. J Comp Neurol. 1995;360:705–25.
Sang Q, Goyal RK. Lower esophageal sphincter relaxation and activation of medullary neurons by subdiaphragmatic vagal stimulation in the mouse. Gastroenterology. 2000;119:1600–9.
Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med. 1997;27(336):924–32.
Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic subjects. J Clin Invest. 1980;65:256–67.
Iwakiri K, Kawami N, Sano H, et al. Mechanisms of excessive esophageal acid exposure in patients with reflux esophagitis. Dig Dis Sci. 2009;54:1686–92.
Helm JF, Dodds WJ, Riedel DR, et al. Determinants of esophageal acid clearance in normal subjects. Gastroenterology. 1983;85:607–12.
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;31:284–8.
Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Arndorfer RC, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology. 1986;91:897–904.
Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology. 1988;94:73–80.
Iwakiri K, Sugiura T, Hayashi Y, et al. Esophageal motility in Japanese patients with Barrett’s esophagus. J Gastroenterol. 2003;38:1036–41.
Sugiura T, Iwakiri K, Kotoyori M, et al. Relationship between severity of reflux esophagitis according to the Los Angeles classification and esophageal motility. J Gastroenterol. 2001;36:226–30.
Bredenoord AJ, Fox M, Kahrilas PJ, et al. International High Resolution Manometry Working Group. Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil. 2012;24(Suppl 1):57–65.
Iwakiri K, Hayashi Y, Kotoyori M, et al. Defective triggering of secondary peristalsis in patients with non-erosive reflux disease. J Gastroenterol Hepatol. 2007;22:2208–11.
Holloway RH, Penagini R, Schoeman MN, Dent J. Effects of cisapride on secondary peristalsis in patients with gastroesophageal reflux disease. Am J Gastroenterol. 1999;94:799–803.
Kahrilas PJ, Shi G, Manka M, et al. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distension in reflux patients with hiatal hernia. Gastroenterology. 2000;118:688–95.
van Herwaarden MA, Samson M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology. 2000;119:1439–46.
Kahrilas PJ, McColl K, Fox M, et al. The acid pocket: a target for treatment in reflux disease? Am J Gastroenterol. 2013;108:1058–64.
Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology. 2001;121:775–83.
Clarke AT, Wirz AA, Manning JJ, et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. Gut. 2008;57:292–7.
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;102:2633–41.
Beaumont H, Bennink RJ, de Jong J, et al. The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD. Gut. 2010;59:441–51.
Bredenoord AJ, Weusten BL, Timmer R, et al. Intermittent spatial separation of diaphragm and lower esophageal sphincter favors acidic and weakly acidic reflux. Gastroenterology. 2006;130:334–40.
Lee YY, Whiting JG, Robertson EV, et al. Kinetics of transient hiatus hernia during transient lower esophageal sphincter relaxations and swallows in healthy subjects. Neurogastroenterol Motil. 2012;24:e539–990.
Sloan S, Kahrilas PJ. Impairment of esophageal emptying with hiatal hernia. Gastroenterology. 1991;100:596–605.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical Statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients included in the cited studies.
Conflict of interest
The authors report no conflicts of interest.
Rights and permissions
About this article
Cite this article
Iwakiri, K., Hoshino, S. & Kawami, N. Mechanisms underlying excessive esophageal acid exposure in patients with gastroesophageal reflux disease. Esophagus 14, 221–228 (2017). https://doi.org/10.1007/s10388-017-0575-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10388-017-0575-7