ABSTRACT Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder in which retrograde flow of gastric content into the oesophagus causes uncomfortable symptoms and/or

complications. It has a multifactorial and partially understood pathophysiology. GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the

failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or

extra-oesophageal symptoms. Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage.

recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. These variations are probably due to the

occurrence of a predominant pathophysiological mechanism in each patient. We also describe the main pathophysiological mechanisms of GERD and their implications for personalized diagnosis

and management. KEY POINTS * Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder and has a multifactorial pathophysiology; there are two phenotypes of GERD,

erosive and non-erosive reflux disease, and their distinct pathophysiology is not completely known. * The oesophagogastric junction works as a functional antireflux barrier; transient lower

oesophageal sphincter relaxations are the most frequent mechanism for reflux in healthy individuals and in patients with GERD. Hiatal hernia is an important mechanism of GERD. * Motility

impairment of both the oesophagus and the proximal stomach is involved in GERD pathophysiology. * The refluxate is a mix of gastric and biliopancreatic secretions. Acid reflux is associated

with heartburn and mucosal damage. Bile reflux provokes more severe oesophagitis or Barrett oesophagus. Non-acid reflux is mainly associated with symptoms but no mucosal damage. * Impairment

of oesophageal mucosal integrity, innervation and microinflammation has a crucial role in symptom perception. * Severity of GERD symptoms is influenced by psychoneuroimmune modulation;

psychosocial comorbidities and hypervigilance determine the severity of GERD symptoms as well as response to treatment. Access through your institution Buy or subscribe This is a preview of

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* Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GASTRO-OESOPHAGEAL REFLUX DISEASE Article 29 July 2021

CLINICAL SIGNIFICANCE OF GASTROESOPHAGEAL REFLUX DISEASE WITH MINIMAL CHANGE: A MULTICENTER PROSPECTIVE OBSERVATIONAL STUDY Article Open access 03 September 2022 QUALITY OF LIFE AND SEVERITY

OF SYMPTOMS AMONG PATIENTS WITH VARIOUS DEGREES OF REFLUX ESOPHAGITIS: A PROSPECTIVE STUDY Article Open access 26 August 2023 REFERENCES * Delaney, B. C. Review article: prevalence and

epidemiology of gastro-oesophageal reflux disease. _Aliment. Pharmacol. Ther._ 20, 2–4 (2004). Article  PubMed  Google Scholar  * Richter, J. E. & Rubenstein, J. H. Presentation and

epidemiology of gastroesophageal reflux disease. _Gastroenterology_ 154, 267–276 (2018). Article  PubMed  Google Scholar  * Vakil, N. et al. The Montreal definition and classification of

gastroesophageal reflux disease: a global evidence-based consensus. _Am. J. Gastroenterol._ 101, 1900–1920 (2006). Article  PubMed  Google Scholar  * Locke, G. R., Talley, N. J., Fett, S.

L., Zinsmeister, A. R. & Melton, L. J. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. _Gastroenterology_ 112,

1448–1456 (1997). Article  PubMed  Google Scholar  * McColl, K. E. L., Clarke, A. & Seenan, J. Acid pocket, hiatus hernia and acid reflux. _Gut_ 59, 430–431 (2010). Article  PubMed 

Google Scholar  * Fletcher, J., Wirz, A., Young, J., Vallance, R. & McColl, K. E. L. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal.

_Gastroenterology_ 121, 775–783 (2001). Article  CAS  PubMed  Google Scholar  * Boecxstaens, V. et al. Modulation of the postprandial acid and bile pockets at the gastro-oesophageal junction

by drugs that affect gastric motility. _Aliment. Pharmacol. Ther._ 33, 1370–1377 (2011). Article  CAS  PubMed  Google Scholar  * Vaezi, M. F. & Richter, J. E. Role of acid and

duodenogastroesophageal reflux in gastroesophageal reflux disease. _Gastroenterology_ 111, 1192–1199 (1996). Article  CAS  PubMed  Google Scholar  * Pandolfino, J. E. et al. Acidity

surrounding the squamocolumnar junction in GERD patients: ‘acid pocket’ versus ‘acid film’. _Am. J. Gastroenterol._ 102, 2633–2641 (2007). Article  PubMed  Google Scholar  * Clarke, A. T. et

al. Paradox of gastric cardia: it becomes more acidic following meals while the rest of stomach becomes less acidic. _Gut_ 58, 904–909 (2009). Article  CAS  PubMed  Google Scholar  *

Clarke, A. T. et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. _Gut_ 57, 292–297 (2008). Article  CAS  PubMed  Google Scholar  *

Derakhshan, M. H. et al. Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with _Helicobacter pylori_. _J. Clin. Pathol._ 59,

1293–1299 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Abe, Y. et al. The prevalence of _Helicobacter pylori_ infection and the status of gastric acid secretion in

patients with Barrett’s esophagus in Japan. _Am. J. Gastroenterol._ 99, 1213–1221 (2004). Article  PubMed  Google Scholar  * El-Serag, H. B. et al. Corpus gastritis is protective against

reflux oesophagitis. _Gut_ 45, 181–185 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vaezi, M. F. et al. CagA-positive strains of _Helicobacter pylori_ may protect against

Barrett’s esophagus. _Am. J. Gastroenterol._ 95, 2206–2211 (2000). Article  CAS  PubMed  Google Scholar  * Azpiroz, F. Control of gastric emptying by gastric tone. _Dig. Dis. Sci._ 39,

18S–19S (1994). Article  CAS  PubMed  Google Scholar  * Zerbib, F. et al. Proximal gastric tone in gastro-oesophageal reflux disease. _Eur. J. Gastroenterol. Hepatol._ 11, 511–515 (1999).

Article  CAS  PubMed  Google Scholar  * Penagini, R. et al. Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. _Gut_ 42, 251–257 (1998).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Cunningham, K. M. et al. Relations among autonomic nerve dysfunction, oesophageal motility, and gastric emptying in gastro-oesophageal

reflux disease. _Gut_ 32, 1436–1440 (1991). Article  CAS  PubMed  PubMed Central  Google Scholar  * Stacher, G. Gastric emptying: a contributory factor in gastro-oesophageal reflux

activity. _Gut_ 47, 661–666 (2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Emerenziani, S. et al. Gastric fullness, physical activity, and proximal extent of

gastroesophageal reflux. _Am. J. Gastroenterol._ 100, 1251–1256 (2005). Article  PubMed  Google Scholar  * Gonlachanvit, S., Maurer, A. H., Fisher, R. S. & Parkman, H. P. Regional

gastric emptying abnormalities in functional dyspepsia and gastro-oesophageal reflux disease. _Neurogastroenterol. Motil._ 18, 894–904 (2006). Article  CAS  PubMed  Google Scholar  * Ayazi,

S. et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of

patients with reflux symptoms. _J. Gastrointest. Surg._ 13, 1440–1447 (2009). Article  PubMed  PubMed Central  Google Scholar  * Tutuian, R. Obesity and GERD: pathophysiology and effect of

bariatric surgery. _Curr. Gastroenterol. Rep._ 13, 205–212 (2011). Article  PubMed  Google Scholar  * Pandolfino, J. E., Howden, C. W. & Kahrilas, P. J. H. Pylori and GERD: is less more?

_Am. J. Gastroenterol._ 99, 1222–1225 (2004). Article  PubMed  Google Scholar  * Nocon, M., Labenz, J. & Willich, S. N. Lifestyle factors and symptoms of gastro-oesophageal reflux — a

population-based study. _Aliment. Pharmacol. Ther._ 23, 169–174 (2006). Article  CAS  PubMed  Google Scholar  * Murray, L. et al. Relationship between body mass and gastro-oesophageal reflux

symptoms: the Bristol _Helicobacter_ Project. _Int. J. Epidemiol._ 32, 645–650 (2003). Article  PubMed  Google Scholar  * El-Serag, H. B., Graham, D. Y., Satia, J. A. & Rabeneck, L.

Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. _Am. J. Gastroenterol._ 100, 1243–1250 (2005). Article  PubMed  Google Scholar  * O’Brien, P. E. et al.

Long-term outcomes after bariatric surgery: a systematic review and meta-analysis of weight loss at 10 or more years for all bariatric procedures and a single-centre review of 20-year

outcomes after adjustable gastric banding. _Obes. Surg._ 29, 3–14 (2019). Article  PubMed  Google Scholar  * Patti, M. G., Di Corpo, M. & Schlottmann, F. (eds) _Foregut Surgery:

Achalasia, Gastroesophageal Reflux Disease and Obesity_ (Springer Nature, 2019). * Langer, F. B. et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. _Obes.

Surg._ 15, 1024–1029 (2005). Article  CAS  PubMed  Google Scholar  * Foster, A., Laws, H. L., Gonzalez, Q. H. & Clements, R. H. Gastrointestinal symptomatic outcome after laparoscopic

Roux-en-Y gastric bypass. _J. Gastrointest. Surg._ 7, 750–753 (2003). Article  PubMed  Google Scholar  * Vaezi, M. F. & Richter, J. E. Contribution of acid and duodenogastrooesophageal

reflux to oesophageal mucosal injury and symptoms in partial gastrectomy patients. _Gut_ 41, 297–302 (1997). Article  CAS  PubMed  PubMed Central  Google Scholar  * Guo, Z., Wu, H., Jiang,

J. & Zhang, C. Pepsin in saliva as a diagnostic marker for gastroesophageal reflux disease: a meta-analysis. _Med. Sci. Monit._ 24, 9509–9516 (2018). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Tobey, N. A. et al. The role of pepsin in acid injury to esophageal epithelium. _Am. J. Gastroenterol._ 96, 3062–3070 (2001). Article  CAS  PubMed  Google Scholar  *

Wang, J., Zhao, Y., Ren, J. & Xu, Y. Pepsin in saliva as a diagnostic biomarker in laryngopharyngeal reflux: a meta-analysis. _Eur. Arch. Otorhinolaryngol._ 275, 671–678 (2018). Article

  PubMed  Google Scholar  * Kahrilas, P. J. et al. The acid pocket: a target for treatment in reflux disease? _Am. J. Gastroenterol._ 108, 1058–1064 (2013). Article  CAS  PubMed  Google

Scholar  * Mittal, R. & Vaezi, M. F. Esophageal motility disorders and gastroesophageal reflux disease. _N. Engl. J. Med._ 383, 1961–1972 (2020). Article  CAS  PubMed  Google Scholar  *

Dodds, W. J. et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. _N. Engl. J. Med._ 307, 1547–1552 (1982). Article  CAS  PubMed  Google Scholar  * Sears, V. W.

Jr, Castell, J. A. & Castell, D. O. Comparison of effects of upright versus supine body position and liquid versus solid bolus on esophageal pressures in normal humans. _Dig. Dis. Sci._

35, 857–864 (1990). Article  PubMed  Google Scholar  * Schoeman, M. N., Tippett, M. D., Akkermans, L. M., Dent, J. & Holloway, R. H. Mechanisms of gastroesophageal reflux in ambulant

healthy human subjects. _Gastroenterology_ 108, 83–91 (1995). Article  CAS  PubMed  Google Scholar  * Jiang, Y., Bhargava, V. & Mittal, R. K. Mechanism of stretch-activated excitatory

and inhibitory responses in the lower esophageal sphincter. _Am. J. Physiol. Gastrointest. Liver Physiol._ 297, G397–G405 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Babaei, A., Bhargava, V., Korsapati, H., Zheng, W. H. & Mittal, R. K. A unique longitudinal muscle contraction pattern associated with transient lower esophageal sphincter relaxation.

_Gastroenterology_ 134, 1322–1331 (2008). Article  PubMed  Google Scholar  * Sifrim, D. & Holloway, R. Transient lower esophageal sphincter relaxations: how many or how harmful. _Am. J.

Gastroenterol._ 96, 2529–2532 (2001). Article  CAS  PubMed  Google Scholar  * van Herwaarden, M. A., Samsom, M. & Smout, A. J. Excess gastroesophageal reflux in patients with hiatus

hernia is caused by mechanisms other than transient LES relaxations. _Gastroenterology_ 119, 1439–1446 (2000). Article  PubMed  Google Scholar  * Kahrilas, P. J., Kim, H. C. &

Pandolfino, J. E. Approaches to the diagnosis and grading of hiatal hernia. _Best Pract. Res. Clin. Gastroenterol._ 22, 601–616 (2008). Article  PubMed  PubMed Central  Google Scholar  *

Mittal, R. K. Current concepts of the antireflux barrier. _Gastroenterol. Clin. North Am._ 19, 501–516 (1990). Article  CAS  PubMed  Google Scholar  * Kahrilas, P. J., Lin, S., Chen, J.

& Manka, M. The effect of hiatus hernia on gastro-oesophageal junction pressure. _Gut_ 44, 476–482 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Mittal, R. K. &

Balaban, D. H. The esophagogastric junction. _N. Engl. J. Med._ 336, 924–932 (1997). Article  CAS  PubMed  Google Scholar  * Andrici, J., Tio, M., Cox, M. R. & Eslick, G. D. Hiatal

hernia and the risk of Barrett’s esophagus. _J. Gastroenterol. Hepatol._ 28, 415–431 (2013). Article  PubMed  Google Scholar  * Gordon, C., Kang, J. Y., Neild, P. J. & Maxwell, J. D. The

role of the hiatus hernia in gastro-oesophageal reflux disease. _Aliment. Pharmacol. Ther._ 20, 719–732 (2004). Article  CAS  PubMed  Google Scholar  * Pandolfino, J. E. et al. Obesity: a

challenge to esophagogastric junction integrity. _Gastroenterology_ 130, 639–649 (2006). Article  PubMed  Google Scholar  * Sloan, S. & Kahrilas, P. J. Impairment of esophageal emptying

with hiatal hernia. _Gastroenterology_ 100, 596–605 (1991). Article  CAS  PubMed  Google Scholar  * Sawada, A. et al. Effect of hiatus hernia on reflux patterns and mucosal integrity in

patients with non-erosive reflux disease. _Neurogastroenterol. Motil._ 34, e14412 (2022). Article  PubMed  Google Scholar  * Pauwels, A. et al. How to select patients for antireflux surgery?

The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery). _Gut_ 68,

1928–1941 (2019). Article  CAS  PubMed  Google Scholar  * Blondeau, K. et al. Baclofen improves symptoms and reduces postprandial flow events in patients with rumination and supragastric

belching. _Clin. Gastroenterol. Hepatol._ 10, 379–384 (2012). Article  CAS  PubMed  Google Scholar  * Tack, J. Review article: the role of bile and pepsin in the pathophysiology and

treatment of gastro-oesophageal reflux disease. _Aliment. Pharmacol. Ther._ 24, 10–16 (2006). Article  CAS  PubMed  Google Scholar  * Emerenziani, S. et al. Presence of gas in the refluxate

enhances reflux perception in non-erosive patients with physiological acid exposure of the oesophagus. _Gut_ 57, 443–447 (2008). Article  CAS  PubMed  Google Scholar  * Sifrim, D. et al.

Acid, nonacid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH-impedance recordings. _Gastroenterology_ 120, 1588–1598 (2001). Article  CAS 

PubMed  Google Scholar  * Bredenoord, A. J., Hemmink, G. J. M. & Smout, A. J. P. Relationship between gastro-oesophageal reflux pattern and severity of mucosal damage.

_Neurogastroenterol. Motil._ 21, 807–812 (2009). Article  CAS  PubMed  Google Scholar  * Bredenoord, A. J. Determinants of perception of heartburn and regurgitation. _Gut_ 55, 313–318

(2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Boeckxstaens, G. E. & Smout, A. Systematic review: role of acid, weakly acidic and weakly alkaline reflux in

gastro-oesophageal reflux disease. _Aliment. Pharmacol. Ther._ 32, 334–343 (2010). Article  CAS  PubMed  Google Scholar  * López-Alonso, M. et al. Twenty-four-hour esophageal impedance-pH

monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. _Pediatrics_ 118, e299–e308 (2006). Article  PubMed 

Google Scholar  * Koek, G. H., Sifrim, D., Lerut, T., Janssens, J. & Tack, J. Multivariate analysis of the association of acid and duodeno-gastro-oesophageal reflux exposure with the

presence of oesophagitis, the severity of oesophagitis and Barrett’s oesophagus. _Gut_ 57, 1056–1064 (2008). Article  CAS  PubMed  Google Scholar  * McQuaid, K. R., Laine, L., Fennerty, M.

B., Souza, R. & Spechler, S. J. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. _Aliment. Pharmacol. Ther._ 34,

146–165 (2011). Article  CAS  PubMed  Google Scholar  * Farre, R. et al. Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal

integrity and provoke dilated intercellular spaces. _Gut_ 57, 1366–1374 (2008). Article  CAS  PubMed  Google Scholar  * Siddiqui, A., Rodriguez-Stanley, S., Zubaidi, S. & Miner, P. B.

Jr. Esophageal visceral sensitivity to bile salts in patients with functional heartburn and in healthy control subjects. _Dig. Dis. Sci._ 50, 81–85 (2005). Article  PubMed  Google Scholar  *

Sun, D. et al. Bile acids but not acidic acids induce Barrett’s esophagus. _Int. J. Clin. Exp. Pathol._ 8, 1384–1392 (2015). PubMed  PubMed Central  Google Scholar  * Dvorak, K. et al. Bile

acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett’s oesophagus. _Gut_ 56, 763–771 (2007). Article  CAS  PubMed 

Google Scholar  * Kessing, B. F., Bredenoord, A. J., Velosa, M. & Smout, A. J. P. Supragastric belches are the main determinants of troublesome belching symptoms in patients with

gastro-oesophageal reflux disease. _Aliment. Pharmacol. Ther._ 35, 1073–1079 (2012). Article  CAS  PubMed  Google Scholar  * Koukias, N., Woodland, P., Yazaki, E. & Sifrim, D.

Supragastric belching: prevalence and association with gastroesophageal reflux disease and esophageal hypomotility. _J. Neurogastroenterol. Motil._ 21, 398–403 (2015). Article  PubMed 

PubMed Central  Google Scholar  * Sifrim, D., Silny, J., Holloway, R. H. & Janssens, J. J. Patterns of gas and liquid reflux during transient lower oesophageal sphincter relaxation: a

study using intraluminal electrical impedance. _Gut_ 44, 47–54 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sifrim, D. et al. Normal values and regional differences in

oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. _Gut_ https://doi.org/10.1136/gutjnl-2020-322627 (2020). Article  PubMed  Google Scholar

  * Gyawali, C. P. et al. Modern diagnosis of GERD: the Lyon Consensus. _Gut_ 67, 1351–1362 (2018). Article  PubMed  Google Scholar  * Gyawali, C. P. et al. Value of pH impedance monitoring

while on twice-daily proton pump inhibitor therapy to identify need for escalation of reflux management. _Gastroenterology_ 161, 1412–1422 (2021). Article  CAS  PubMed  Google Scholar  *

Pandolfino, J. E., Schreiner, M. A., Lee, T. J., Zhang, Q. & Kahrilas, P. J. Bravo capsule placement in the gastric cardia: a novel method for analysis of proximal stomach acid

environment. _Am. J. Gastroenterol._ 100, 1721–1727 (2005). Article  PubMed  Google Scholar  * Woodland, P. et al. Distinct afferent innervation patterns within the human proximal and distal

esophageal mucosa. _Am. J. Physiol. Gastrointest. Liver Physiol._ 308, G525–G531 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ahlawat, S. K. et al. Day-to-day variability

in acid reflux patterns using the BRAVO pH monitoring system. _J. Clin. Gastroenterol._ 40, 20–24 (2006). Article  PubMed  Google Scholar  * Penagini, R. et al. Inconsistency in the

diagnosis of functional heartburn: usefulness of prolonged wireless pH monitoring in patients with proton pump inhibitor refractory gastroesophageal reflux disease. _J. Neurogastroenterol.

Motil._ 21, 265–272 (2015). Article  PubMed  PubMed Central  Google Scholar  * Tutuian, R. & Castell, D. O. Nocturnal acid breakthrough — approach to management. _MedGenMed_ 6, 11

(2004). PubMed  PubMed Central  Google Scholar  * Domingues, G. et al. Potassium-competitive acid blockers, a new therapeutic class, and their role in acid-related diseases: a narrative

review. _Prz. Gastroenterol._ 18, 47–55 (2023). CAS  PubMed  Google Scholar  * Savarino, V. et al. Pharmacological management of gastro-esophageal reflux disease: an update of the

state-of-the-art. _Drug Des. Devel. Ther._ 15, 1609–1621 (2021). Article  PubMed  PubMed Central  Google Scholar  * Sawada, A. et al. Management of supragastric belching with cognitive

behavioural therapy: factors determining success and follow-up outcomes at 6–12 months post-therapy. _Aliment. Pharmacol. Ther._ 50, 530–537 (2019). Article  PubMed  Google Scholar  *

Argüero, J. & Sifrim, D. Actualización en la fisiopatología de la enfermedad por reflujo gastroesofágico. _Acta Gastroenterol. Latinoam._ 52, 135–152 (2022). Article  Google Scholar  *

Gyawali, C. P. et al. Classification of esophageal motor findings in gastro-esophageal reflux disease: conclusions from an international consensus group. _Neurogastroenterol. Motil._ 29,

e13104 (2017). Article  Google Scholar  * Lei, W.-Y. et al. Impact of ineffective esophageal motility on secondary peristalsis: studies with high-resolution manometry. _Neurogastroenterol.

Motil._ 33, e14024 (2021). Article  CAS  PubMed  Google Scholar  * Singh, P., Adamopoulos, A., Taylor, R. H. & Colin-Jones, D. G. Oesophageal motor function before and after healing of

oesophagitis. _Gut_ 33, 1590–1596 (1992). Article  CAS  PubMed  PubMed Central  Google Scholar  * Helm, J. F. et al. Effect of esophageal emptying and saliva on clearance of acid from the

esophagus. _N. Engl. J. Med._ 310, 284–288 (1984). Article  CAS  PubMed  Google Scholar  * Korsten, M. A. et al. Chronic xerostomia increases esophageal acid exposure and is associated with

esophageal injury. _Am. J. Med._ 90, 701–706 (1991). Article  CAS  PubMed  Google Scholar  * Frazzoni, M. et al. Analyses of the post-reflux swallow-induced peristaltic wave index and

nocturnal baseline impedance parameters increase the diagnostic yield of impedance-pH monitoring of patients with reflux disease. _Clin. Gastroenterol. Hepatol._ 14, 40–46 (2016). Article 

PubMed  Google Scholar  * Alcalá-González, L. G., Jiménez-Masip, A., Relea Pérez, L., Barber-Caselles, C. & Barba-Orozco, E. Opioid-induced esophageal dysfunction — prevalence and

manometric findings. _Rev. Esp. Enferm. Dig._ 114, 16–21 (2022). PubMed  Google Scholar  * Bakhos, C. T., Petrov, R. V., Parkman, H. P., Malik, Z. & Abbas, A. E. Role and safety of

fundoplication in esophageal disease and dysmotility syndromes. _J. Thorac. Dis._ 11, S1610–S1617 (2019). Article  PubMed  PubMed Central  Google Scholar  * Shaker, A. et al. Multiple rapid

swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve. _Am. J. Gastroenterol._ 108, 1706–1712 (2013). Article  PubMed  PubMed Central 

Google Scholar  * Ribolsi, M., Savarino, E., Frazzoni, M. & Cicala, M. Prospective validation of reflux monitoring by impedance-pH in predicting PPI response in typical GERD. _Dig. Liver

Dis._ 55, 721–726 (2023). Article  CAS  PubMed  Google Scholar  * Ustaoglu, A. et al. Mucosal pathogenesis in gastro-esophageal reflux disease. _Neurogastroenterol. Motil._ 32, e14022

(2020). Article  PubMed  Google Scholar  * Ustaoglu, A. & Woodland, P. Sensory phenotype of the oesophageal mucosa in gastro-oesophageal reflux disease. _Int. J. Mol. Sci._ 24, 2502

(2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * El-Serag, H. B. Epidemiology of non-erosive reflux disease. _Digestion_ 78, 6–10 (2008). Article  PubMed  Google Scholar  *

Calabrese, C. et al. Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. _Am. J. Gastroenterol._ 100, 537–542 (2005). Article  CAS  PubMed 

Google Scholar  * Woodland, P., Al-Zinaty, M., Yazaki, E. & Sifrim, D. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux

disease. _Gut_ 62, 1256–1261 (2013). Article  PubMed  Google Scholar  * Calabrese, C. et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in

gastro-oesophageal reflux disease with or without bile reflux. _Aliment. Pharmacol. Ther._ 18, 525–532 (2003). Article  CAS  PubMed  Google Scholar  * Tadiparthi, R. A. et al. Dilated

intercellular spaces and lymphocytes on biopsy relate to symptoms in erosive GERD but not NERD. _Aliment. Pharmacol. Ther._ 33, 1202–1208 (2011). Article  CAS  PubMed  Google Scholar  *

Azumi, T. et al. Esophageal epithelial surface in patients with gastroesophageal reflux disease: an electron microscopic study. _World J. Gastroenterol._ 14, 5712–5716 (2008). Article 

PubMed  PubMed Central  Google Scholar  * Jovov, B. et al. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. _Am. J. Gastroenterol._ 106, 1039–1047 (2011). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Ustaoglu, A. et al. Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial

cells expressing ASIC3 receptors. _Am. J. Physiol. Gastrointest. Liver Physiol._ 320, G804–G815 (2021). Article  CAS  PubMed  Google Scholar  * Dunbar, K. B. et al. Association of acute

gastroesophageal reflux disease with esophageal histologic changes. _JAMA_ 315, 2104–2112 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Souza, R. F. et al. Gastroesophageal

reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. _Gastroenterology_ 137, 1776–1784 (2009). Article  CAS  PubMed  Google Scholar  *

McDonald, S. A. C., Lavery, D., Wright, N. A. & Jansen, M. Barrett oesophagus: lessons on its origins from the lesion itself. _Nat. Rev. Gastroenterol. Hepatol._ 12, 50–60 (2015).

Article  PubMed  Google Scholar  * Souza, R. F. & Spechler, S. J. Mechanisms and pathophysiology of Barrett oesophagus. _Nat. Rev. Gastroenterol. Hepatol._ 19, 605–620 (2022). Article 

PubMed  Google Scholar  * Hahn, H. P. et al. Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus. _Am. J. Surg. Pathol._ 33, 1006–1015 (2009). Article 

PubMed  PubMed Central  Google Scholar  * Jiang, M. et al. Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus. _Nature_ 550, 529–533 (2017). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Milano, F. et al. Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells.

_Gastroenterology_ 132, 2412–2421 (2007). Article  CAS  PubMed  Google Scholar  * Quante, M. et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of

Barrett-like metaplasia. _Cancer Cell_ 21, 36–51 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lata, T., Trautman, J., Townend, P. & Wilson, R. B. Current management of

gastro-oesophageal reflux disease-treatment costs, safety profile, and effectiveness: a narrative review. _Gastroenterol. Rep._ 11, goad008 (2023). Article  Google Scholar  * Vaezi, M. F.

_Diagnosis and Treatment of Gastroesophageal Reflux Disease_ (Springer, 2015). * Martinucci, I. et al. Barrett’s esophagus in 2016: from pathophysiology to treatment. _World J. Gastrointest.

Pharmacol. Ther._ 7, 190–206 (2016). Article  PubMed  PubMed Central  Google Scholar  * Sharma, P. Barrett esophagus: a review. _JAMA_ 328, 663–671 (2022). Article  CAS  PubMed  Google

Scholar  * Weijenborg, P. W., Smout, A. J. P. M. & Bredenoord, A. J. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn. _Neurogastroenterol. Motil._

28, 1649–1654 (2016). Article  CAS  PubMed  Google Scholar  * Shi, G., des Varannes, S. B., Scarpignato, C., Le Rhun, M. & Galmiche, J. P. Reflux related symptoms in patients with

normal oesophageal exposure to acid. _Gut_ 37, 457–464 (1995). Article  CAS  PubMed  PubMed Central  Google Scholar  * Byrne, P. J., Mulligan, E. D., O’Riordan, J., Keeling, P. W. N. &

Reynolds, J. V. Impaired visceral sensitivity to acid reflux in patients with Barrett’s esophagus. The role of esophageal motility. _Dis. Esophagus_ 16, 199–203 (2003). Article  CAS  PubMed

  Google Scholar  * Farré, R. et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. _Gut_ 56, 1191–1197 (2007). Article  PubMed 

PubMed Central  Google Scholar  * Schey, R. et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. _Gastroenterology_ 133, 1787–1795 (2007). Article 

PubMed  Google Scholar  * Kahrilas, P. J., Keefer, L. & Pandolfino, J. E. Patients with refractory reflux symptoms: what do they have and how should they be managed? _Neurogastroenterol.

Motil._ 27, 1195–1201 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Riehl, M. E. & Keefer, L. Hypnotherapy for esophageal disorders. _Am. J. Clin. Hypn._ 58, 22–33

(2015). Article  PubMed  PubMed Central  Google Scholar  * Guadagnoli, L. et al. Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations.

_Neurogastroenterol. Motil._ 33, e14081 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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._ 32, 720–737 (2010). Article  CAS  PubMed  Google Scholar  * Fass, R. & Tougas, G.

Functional heartburn: the stimulus, the pain, and the brain. _Gut_ 51, 885–892 (2002). Article  CAS  PubMed  PubMed Central  Google Scholar  * Frazzoni, L. et al. Critical appraisal of Rome

IV criteria: hypersensitive esophagus does belong to gastroesophageal reflux disease spectrum. _Ann. Gastroenterol. Hepatol._ 31, 1–7 (2018). Google Scholar  * Sawada, A. et al.

Identification of different phenotypes of esophageal reflux hypersensitivity and implications for treatment. _Clin. Gastroenterol. Hepatol._ 19, 690–698.e2 (2021). Article  CAS  PubMed 

Google Scholar  * Farmer, A. D., Ruffle, J. K. & Aziz, Q. The role of esophageal hypersensitivity in functional esophageal disorders. _J. Clin. Gastroenterol._ 51, 91–99 (2017). Article

  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank A. Ustaoglu, M. Peiris and P. Woodland from the Wingate Institute of Neurogastroenterology, Queen Mary

University of London, UK, for sharing their research data (now published) on the role of the oesophageal mucosa in the pathophysiology of GERD. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Neurogastroenterology section of Gastroenterology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina Julieta Argüero * Wingate Institute of Neurogastroenterology, Queen

Mary University of London, London, UK Daniel Sifrim Authors * Julieta Argüero View author publications You can also search for this author inPubMed Google Scholar * Daniel Sifrim View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Both authors contributed equally to all aspects of the manuscript. CORRESPONDING AUTHOR Correspondence

to Daniel Sifrim. ETHICS DECLARATIONS COMPETING INTERESTS D.S. has served as a consultant for Reckitt Benckiser (UK), Jinshan Technology (China) and AlfaSigma (Italy). J.A. declares no

competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Reviews Gastroenterology & Hepatology_ thanks Ravinder Mittal and the other, anonymous, reviewer(s) for their

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Argüero, J., Sifrim, D. Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management. _Nat Rev

Gastroenterol Hepatol_ 21, 282–293 (2024). https://doi.org/10.1038/s41575-023-00883-z Download citation * Accepted: 28 November 2023 * Published: 04 January 2024 * Issue Date: April 2024 *

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