Pathophysiology of Gastroesophageal Reflux Disease

  • Samuel NurkoEmail author


The pathophysiology of gastroesophageal reflux disease (GERD) is multifactorial. It usually involves the function of the lower esophageal sphincter and esophageal peristalsis, as well as mucosal changes that result from the presence of the refluxate and their consequences on pain perception. Transient lower esophageal sphincter relaxation is the most common event associated with reflux, and esophageal peristalsis is necessary to clear the esophagus from the refluxate. Abnormal permeability of the esophageal mucosa can result from reflux, and this may result in increased mucosal permeability that may lead to esophageal damage and pain sensitization. There are specific pathologic conditions that affect the mechanisms responsible for the prevention of GERD, so it is more common in certain populations.


Gastroesophageal reflux disease Transient lower esophageal sphincter relaxations (TLSERs) Mucosal integrity Intracellular spaces Pain sensitization 


  1. 1.
    Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49(4):498–547.CrossRefPubMedGoogle Scholar
  2. 2.
    Singendonk MM, Rommel N, Omari TI, Benninga MA, van Wijk MP. Upper gastrointestinal motility: prenatal development and problems in infancy. Nat Rev Gastroenterol Hepatol. 2014;11(9):545–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Pena EM, Parks VN, Peng J, Fernandez SA, Di Lorenzo C, Shaker R, et al. Lower esophageal sphincter relaxation reflex kinetics: effects of peristaltic reflexes and maturation in human premature neonates. Am J Physiol Gastrointest Liver Physiol. 2010;299(6):G1386–95.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology. 1997;113(2):399–408.CrossRefPubMedGoogle Scholar
  5. 5.
    Hoffman I, De Greef T, Haesendonck N, Tack J. Esophageal motility in children with suspected gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2010;50(6):601–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Omari TI, Benninga MA, Barnett CP, Haslam RR, Davidson GP, Dent J. Characterization of esophageal body and lower esophageal sphincter motor function in the very premature neonate. J Pediatr. 1999;135(4):517–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Roman S, Holloway R, Keller J, Herbella F, Zerbib F, Xiao Y, et al. Validation of criteria for the definition of transient lower esophageal sphincter relaxations using high-resolution manometry. Neurogastroenterol Motil. 2016;29:e12920.CrossRefGoogle Scholar
  8. 8.
    Roman S, Zerbib F, Bruley des Varannes S, Mion F. Esophageal high resolution manometry: a new gold standard for the detection of transient lower esophageal sphincter relaxations? Neurogastroenterol Motil. 2012;24(5):498–9. Author reply 500.CrossRefPubMedGoogle Scholar
  9. 9.
    van Wijk MP, Benninga MA, Davidson GP, Haslam R, Omari TI. Small volumes of feed can trigger transient lower esophageal sphincter relaxation and gastroesophageal reflux in the right lateral position in infants. J Pediatr. 2010;156(5):744–8. 8 e1.CrossRefPubMedGoogle Scholar
  10. 10.
    Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol. 2001;96(9):2569–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Salvia G, De Vizia B, Manguso F, Iula VD, Terrin G, Spadaro R, et al. Effect of intragastric volume and osmolality on mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease. Am J Gastroenterol. 2001;96(6):1725–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Sifrim D, Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful? Am J Gastroenterol. 2001;96(9):2529–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Sifrim D, Holloway R, Silny J, Tack J, Lerut A, Janssens J. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2001;96(3):647–55.CrossRefPubMedGoogle Scholar
  14. 14.
    Mitchell DR, Derakhshan MH, Robertson EV, McColl KE. The role of the acid pocket in gastroesophageal reflux disease. J Clin Gastroenterol. 2016;50(2):111–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Penagini R, Bravi I. The role of delayed gastric emptying and impaired oesophageal body motility. Best Pract Res Clin Gastroenterol. 2010;24(6):831–45.CrossRefPubMedGoogle Scholar
  16. 16.
    Knatten CK, Avitsland TL, Medhus AW, Fjeld JG, Pripp AH, Emblem R, et al. Gastric emptying in children with gastroesophageal reflux and in healthy children. J Pediatr Surg. 2013;48(9):1856–61.CrossRefPubMedGoogle Scholar
  17. 17.
    Herregods TV, van Hoeij FB, Oors JM, Bredenoord AJ, Smout AJ. Effect of running on gastroesophageal reflux and reflux mechanisms. Am J Gastroenterol. 2016;111(7):940–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Guan J, Mao C, Feng X, Zhang H, Xu F, Geng C, et al. Fetal development of regulatory mechanisms for body fluid homeostasis. Braz J Med Biol Res. 2008;41(6):446–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2002;35(2):119–36.CrossRefPubMedGoogle Scholar
  20. 20.
    Murray JA, Camilleri M. The fall and rise of the hiatal hernia. Gastroenterology. 2000;119(6):1779–81.CrossRefPubMedGoogle Scholar
  21. 21.
    Chitkara DK, Fortunato C, Nurko S. Esophageal motor activity in children with gastro-esophageal reflux disease and esophagitis. J Pediatr Gastroenterol Nutr. 2005;40(1):70–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Iwanczak BM, Kosmowska-Miskow A, Kofla-Dlubacz A, Palczewski M, Grabinski M, Pawlowska K, et al. Assessment of clinical symptoms and multichannel intraluminal impedance and pH monitoring in children after thoracoscopic repair of esophageal atresia and distal tracheoesophageal fistula. Adv Clin Exp Med. 2016;25(5):917–22.CrossRefPubMedGoogle Scholar
  23. 23.
    Crowell MD, Umar SB, Griffing WL, DiBaise JK, Lacy BE, Vela MF. Esophageal motor abnormalities in patients with scleroderma: heterogeneity, risk factors, and effects on quality of life. Clin Gastroenterol Hepatol. 2017;15(2):207–213.e1.CrossRefPubMedGoogle Scholar
  24. 24.
    Frazzoni M, de Bortoli N, Frazzoni L, Furnari M, Martinucci I, Tolone S, et al. Impairment of chemical clearance and mucosal integrity distinguishes hypersensitive esophagus from functional heartburn. J Gastroenterol. 2017;52(4):444–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology. 1991;101(5):1149–58.CrossRefPubMedGoogle Scholar
  26. 26.
    Farre R, van Malenstein H, De Vos R, Geboes K, Depoortere I, Vanden Berghe P, 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. 2008;57(10):1366–74.CrossRefPubMedGoogle Scholar
  27. 27.
    Pardon NA, Vicario M, Vanheel H, Vanuytsel T, Ceulemans LJ, Vieth M, et al. A weakly acidic solution containing deoxycholic acid induces esophageal epithelial apoptosis and impairs integrity in an in vivo perfusion rabbit model. Am J Physiol Gastrointest Liver Physiol. 2016;310(7):G487–96.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ghatak S, Reveiller M, Toia L, Ivanov AI, Zhou Z, Redmond EM, et al. Bile salts at low pH cause dilation of intercellular spaces in in vitro stratified primary esophageal cells, possibly by modulating Wnt signaling. J Gastrointest Surg. 2016;20(3):500–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Quitadamo P, Di Nardo G, Miele E, Campione S, Mancusi V, Oliva S, et al. Gastroesophageal reflux in young children and adolescents: is there a relation between symptom severity and esophageal histological grade? J Pediatr Gastroenterol Nutr. 2015;60(3):318–21.CrossRefPubMedGoogle Scholar
  30. 30.
    van Hoeij FB, Weijenborg PW, van den Bergh Weerman MA, van den Wijngaard RM, Verheij J, Smout AJ, et al. Mucosal integrity and sensitivity to acid in the proximal esophagus in patients with gastroesophageal reflux disease. Am J Physiol Gastrointest Liver Physiol. 2016;311(1):G117–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Borrelli O, Mancini V, Thapar N, Ribolsi M, Emerenziani S, de'Angelis G, et al. Dilated intercellular space diameter as marker of reflux-related mucosal injury in children with chronic cough and gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2014;39(7):733–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Borrelli O, Salvatore S, Mancini V, Ribolsi M, Gentile M, Bizzarri B, et al. Relationship between baseline impedance levels and esophageal mucosal integrity in children with erosive and non-erosive reflux disease. Neurogastroenterol Motil. 2012;24(9):828–e394.CrossRefPubMedGoogle Scholar
  33. 33.
    Mauritz FA, Rinsma NF, van Heurn EL, Sloots CE, Siersema PD, Houwen RH, et al. Esophageal mucosal integrity improves after laparoscopic antireflux surgery in children with gastroesophageal reflux disease. Surg Endosc. 2016; doi: 10.1007/s00464-016-5304-0.
  34. 34.
    Kandulski A, Weigt J, Caro C, Jechorek D, Wex T, Malfertheiner P. Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. Clin Gastroenterol Hepatol. 2015;13(6):1075–81.CrossRefPubMedGoogle Scholar
  35. 35.
    Herregods TV, Bredenoord AJ, Smout AJ. Pathophysiology of gastroesophageal reflux disease: new understanding in a new era. Neurogastroenterol Motil. 2015;27(9):1202–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Coss-Adame E, Rao SSA. Review of esophageal chest pain. Gastroenterol Hepatol. 2015;11(11):759–66.Google Scholar
  37. 37.
    Shieh KR, Yang SC, Tseng HL, Yi CH, Liu TT, Chen CL. Evidence for up-regulation of purinergic receptor genes associating with TRPV1 receptors and neurotrophic factors in the inflamed human esophagus. Curr Mol Med. 2014;14(9):1205–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Lawal A, Kern M, Sanjeevi A, Antonik S, Mepani R, Rittmann T, et al. Neurocognitive processing of esophageal central sensitization in the insula and cingulate gyrus. Am J Physiol Gastrointest Liver Physiol. 2008;294(3):G787–94.CrossRefPubMedGoogle Scholar
  39. 39.
    Phillips ML, Gregory LJ, Cullen S, Coen S, Ng V, Andrew C, et al. The effect of negative emotional context on neural and behavioural responses to oesophageal stimulation. Brain. 2003;126(Pt 3):669–84.CrossRefPubMedGoogle Scholar
  40. 40.
    Campanozzi A, Staiano A. Impact of malnutrition on gastrointestinal disorders and gross motor abilities in children with cerebral palsy. Brain Dev. 2010;32(2):168.CrossRefPubMedGoogle Scholar
  41. 41.
    Del Giudice E, Staiano A, Capano G, Romano A, Florimonte L, Miele E, et al. Gastrointestinal manifestations in children with cerebral palsy. Brain Dev. 1999;21(5):307–11.CrossRefPubMedGoogle Scholar
  42. 42.
    Vincent MV, Duncan ND. Gastroesophageal reflux and reflux oesophageal strictures in children with Cornelia de Lange syndrome. West Indian Med J. 2013;62(2):161–4.PubMedGoogle Scholar
  43. 43.
    Sistonen SJ, Koivusalo A, Nieminen U, Lindahl H, Lohi J, Kero M, et al. Esophageal morbidity and function in adults with repaired esophageal atresia with tracheoesophageal fistula: a population-based long-term follow-up. Ann Surg. 2010;251(6):1167–73.CrossRefPubMedGoogle Scholar
  44. 44.
    Alexander CL, Urbanski SJ, Hilsden R, Rabin H, MacNaughton WK, Beck PL. The risk of gastrointestinal malignancies in cystic fibrosis: case report of a patient with a near obstructing villous adenoma found on colon cancer screening and Barrett’s esophagus. J Cyst Fibros. 2008;7(1):1–6.CrossRefPubMedGoogle Scholar
  45. 45.
    El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol. 2005;100(6):1243–50.CrossRefPubMedGoogle Scholar
  46. 46.
    Nam SY. Obesity-related digestive diseases and their pathophysiology. Gut Liver. 2017;11(3):323–34.CrossRefPubMedGoogle Scholar
  47. 47.
    Lee YY, McColl KE. Pathophysiology of gastroesophageal reflux disease. Best Pract Res Clin Gastroenterol. 2013;27(3):339–51.CrossRefPubMedGoogle Scholar
  48. 48.
    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(11):1662–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Center for Motility and Functional Gastrointestinal DisordersBoston Children’s HospitalBostonUSA

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