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. Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. The intensity of the symptoms is affected by peripheral and central neural and psychological mechanisms. In this Review, we describe an updated understanding of the complex and multifactorial pathophysiology of GERD. It is now 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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Delaney, B. C. Review article: prevalence and epidemiology of gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 20, 2–4 (2004).
Richter, J. E. & Rubenstein, J. H. Presentation and epidemiology of gastroesophageal reflux disease. Gastroenterology 154, 267–276 (2018).
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).
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).
McColl, K. E. L., Clarke, A. & Seenan, J. Acid pocket, hiatus hernia and acid reflux. Gut 59, 430–431 (2010).
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).
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).
Vaezi, M. F. & Richter, J. E. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 111, 1192–1199 (1996).
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).
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).
Clarke, A. T. et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. Gut 57, 292–297 (2008).
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).
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).
El-Serag, H. B. et al. Corpus gastritis is protective against reflux oesophagitis. Gut 45, 181–185 (1999).
Vaezi, M. F. et al. CagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am. J. Gastroenterol. 95, 2206–2211 (2000).
Azpiroz, F. Control of gastric emptying by gastric tone. Dig. Dis. Sci. 39, 18S–19S (1994).
Zerbib, F. et al. Proximal gastric tone in gastro-oesophageal reflux disease. Eur. J. Gastroenterol. Hepatol. 11, 511–515 (1999).
Penagini, R. et al. Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. Gut 42, 251–257 (1998).
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).
Stacher, G. Gastric emptying: a contributory factor in gastro-oesophageal reflux activity. Gut 47, 661–666 (2000).
Emerenziani, S. et al. Gastric fullness, physical activity, and proximal extent of gastroesophageal reflux. Am. J. Gastroenterol. 100, 1251–1256 (2005).
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).
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).
Tutuian, R. Obesity and GERD: pathophysiology and effect of bariatric surgery. Curr. Gastroenterol. Rep. 13, 205–212 (2011).
Pandolfino, J. E., Howden, C. W. & Kahrilas, P. J. H. Pylori and GERD: is less more? Am. J. Gastroenterol. 99, 1222–1225 (2004).
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).
Murray, L. et al. Relationship between body mass and gastro-oesophageal reflux symptoms: the Bristol Helicobacter Project. Int. J. Epidemiol. 32, 645–650 (2003).
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).
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).
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).
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).
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).
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).
Tobey, N. A. et al. The role of pepsin in acid injury to esophageal epithelium. Am. J. Gastroenterol. 96, 3062–3070 (2001).
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).
Kahrilas, P. J. et al. The acid pocket: a target for treatment in reflux disease? Am. J. Gastroenterol. 108, 1058–1064 (2013).
Mittal, R. & Vaezi, M. F. Esophageal motility disorders and gastroesophageal reflux disease. N. Engl. J. Med. 383, 1961–1972 (2020).
Dodds, W. J. et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N. Engl. J. Med. 307, 1547–1552 (1982).
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).
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).
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).
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).
Sifrim, D. & Holloway, R. Transient lower esophageal sphincter relaxations: how many or how harmful. Am. J. Gastroenterol. 96, 2529–2532 (2001).
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).
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).
Mittal, R. K. Current concepts of the antireflux barrier. Gastroenterol. Clin. North Am. 19, 501–516 (1990).
Kahrilas, P. J., Lin, S., Chen, J. & Manka, M. The effect of hiatus hernia on gastro-oesophageal junction pressure. Gut 44, 476–482 (1999).
Mittal, R. K. & Balaban, D. H. The esophagogastric junction. N. Engl. J. Med. 336, 924–932 (1997).
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).
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).
Pandolfino, J. E. et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 130, 639–649 (2006).
Sloan, S. & Kahrilas, P. J. Impairment of esophageal emptying with hiatal hernia. Gastroenterology 100, 596–605 (1991).
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).
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).
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).
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).
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).
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).
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).
Bredenoord, A. J. Determinants of perception of heartburn and regurgitation. Gut 55, 313–318 (2006).
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).
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).
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).
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).
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).
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).
Sun, D. et al. Bile acids but not acidic acids induce Barrett’s esophagus. Int. J. Clin. Exp. Pathol. 8, 1384–1392 (2015).
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).
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).
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).
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).
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).
Gyawali, C. P. et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 67, 1351–1362 (2018).
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).
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).
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).
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).
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).
Tutuian, R. & Castell, D. O. Nocturnal acid breakthrough — approach to management. MedGenMed 6, 11 (2004).
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).
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).
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).
Argüero, J. & Sifrim, D. Actualización en la fisiopatología de la enfermedad por reflujo gastroesofágico. Acta Gastroenterol. Latinoam. 52, 135–152 (2022).
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).
Lei, W.-Y. et al. Impact of ineffective esophageal motility on secondary peristalsis: studies with high-resolution manometry. Neurogastroenterol. Motil. 33, e14024 (2021).
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).
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).
Korsten, M. A. et al. Chronic xerostomia increases esophageal acid exposure and is associated with esophageal injury. Am. J. Med. 90, 701–706 (1991).
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).
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).
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).
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).
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).
Ustaoglu, A. et al. Mucosal pathogenesis in gastro-esophageal reflux disease. Neurogastroenterol. Motil. 32, e14022 (2020).
Ustaoglu, A. & Woodland, P. Sensory phenotype of the oesophageal mucosa in gastro-oesophageal reflux disease. Int. J. Mol. Sci. 24, 2502 (2023).
El-Serag, H. B. Epidemiology of non-erosive reflux disease. Digestion 78, 6–10 (2008).
Calabrese, C. et al. Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. Am. J. Gastroenterol. 100, 537–542 (2005).
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).
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).
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).
Azumi, T. et al. Esophageal epithelial surface in patients with gastroesophageal reflux disease: an electron microscopic study. World J. Gastroenterol. 14, 5712–5716 (2008).
Jovov, B. et al. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am. J. Gastroenterol. 106, 1039–1047 (2011).
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).
Dunbar, K. B. et al. Association of acute gastroesophageal reflux disease with esophageal histologic changes. JAMA 315, 2104–2112 (2016).
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).
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).
Souza, R. F. & Spechler, S. J. Mechanisms and pathophysiology of Barrett oesophagus. Nat. Rev. Gastroenterol. Hepatol. 19, 605–620 (2022).
Hahn, H. P. et al. Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus. Am. J. Surg. Pathol. 33, 1006–1015 (2009).
Jiang, M. et al. Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus. Nature 550, 529–533 (2017).
Milano, F. et al. Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells. Gastroenterology 132, 2412–2421 (2007).
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).
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).
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).
Sharma, P. Barrett esophagus: a review. JAMA 328, 663–671 (2022).
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).
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).
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).
Farré, R. et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 56, 1191–1197 (2007).
Schey, R. et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 133, 1787–1795 (2007).
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).
Riehl, M. E. & Keefer, L. Hypnotherapy for esophageal disorders. Am. J. Clin. Hypn. 58, 22–33 (2015).
Guadagnoli, L. et al. Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations. Neurogastroenterol. Motil. 33, e14081 (2021).
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).
Fass, R. & Tougas, G. Functional heartburn: the stimulus, the pain, and the brain. Gut 51, 885–892 (2002).
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).
Sawada, A. et al. Identification of different phenotypes of esophageal reflux hypersensitivity and implications for treatment. Clin. Gastroenterol. Hepatol. 19, 690–698.e2 (2021).
Farmer, A. D., Ruffle, J. K. & Aziz, Q. The role of esophageal hypersensitivity in functional esophageal disorders. J. Clin. Gastroenterol. 51, 91–99 (2017).
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
Contributions
Both authors contributed equally to all aspects of the manuscript.
Corresponding author
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 contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-023-00883-z