1.Vakil N, van Zanten SV, Kahrilas K, et al.2006. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am. J. Gastroenterol 101: 1900–1920.[DOI] [PubMed] [Google Scholar]2.Ang D, How CH & Ang TL 2016. Persistent gastrooesophagealreflux symptoms despite proton pump inhibitor therapy. Singapore Med. J 57: 546–551.[DOI] [PMC free article] [PubMed] [Google Scholar]3.Castell DO, Murray JA, Tutuian OR, et al. 2004. Review article: the pathophysiology of gastro-oesophageal reflux disease–oesophageal manifestations. Aliment. Pharmacol. Ther 20(Suppl. 9): 14–15.[DOI] [PubMed] [Google Scholar]4.Tack J & Pandolfino JE 2018. Pathophysiology of gastroesophageal reflux disease. Gastroenterology 54: 277–288.[DOI] [PubMed] [Google Scholar]5.Orlando RC, Powell DW & Carney CN 1981. Pathophysiology of acute acid injury in rabbit esophageal epithelium. J. Clin. Invest 68: 286–293.[DOI] [PMC free article] [PubMed] [Google Scholar]6.Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliot M, et al. 2002. Diversity in oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut 50: 451–459.[DOI] [PMC free article] [PubMed] [Google Scholar]7.Ma J, Altomare A, de la Monte S, et al. 2010. HCl-induced inflammatory mediators in esophageal mucosa increase migration and production of H2O2 by peripheral blood leukocytes. Am. J. Physiol. Gastrointest. Liver Physiol 299: G791–G798.[DOI] [PMC free article] [PubMed] [Google Scholar]8.Isomoto H, Wang A, Mizuta Y, et al. 2003. Elevated levels of chemokines in esophageal mucosa of patients with reflux esophagitis. Am. J. Gastroenterol 98: 551–556.[DOI] [PubMed] [Google Scholar]9.Kahrilas PJ, McColl K, Fox M, et al. 2013. The acid pocket: a target for treatment in reflux disease? Am. J. Gastroenterol 108: 1058–1064.[DOI] [PubMed] [Google Scholar]10.Mitchell DR,Derakhshan MH, Robertson EV, et al. 2016. The role of the acid pocket in gastroesophageal reflux disease. J. Clin. Gastroenterol 50: 111–119.[DOI] [PubMed] [Google Scholar]11.Emerenziani S, Ribolsi M, Guarino MPL, et al. 2014. Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non-erosive reflux disease patients. Neurogastroent. Motil 26: 108–114.[DOI] [PubMed] [Google Scholar]12.Zerbib F, Duriez A, Roman S, et al. 2008. Determinants of gastro-esophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 57: 156–160.[DOI] [PubMed] [Google Scholar]13.Lin KM, Ueda RK, Hinder RA, et al. 1991. Etiology and importance of alkaline esophageal reflux. Am. J. Surg 162: 553–557.[DOI] [PubMed] [Google Scholar]14.Stein HJ, Feussner H, Kauer W, et al. 1994. Alkaline gastroesophageal reflux: assessment by ambulatory esophageal aspiration and pH monitoring. Am. J.Surg 167: 163–168.[DOI] [PubMed] [Google Scholar]15.Kauer WK, Peters JH, DeMeester TR, et al. 1997. Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease. Surgery 122: 874–881.[DOI] [PubMed] [Google Scholar]16.Siddiqui A, Rodriguez-Stanley R, Zubaidi S, et al. 2005. Esophageal visceral sensitivity to bile salts in patients with functional heartburn andin health control subjects. Dig. Dis. Sci 50: 81–85.[DOI] [PubMed] [Google Scholar]17.Nehra D, Howell P, Williams CP, et al. 1999. Toxic bile acids in gastroesophageal refluxdisease: influence of gastric acidity. Gut 44: 598–602.[DOI] [PMC free article] [PubMed] [Google Scholar]18.Pace F, SangalettiO, Pallotta S, et al. 2007. Biliary reflux and non-acid reflux are two distinct phenomena: a comparison between 24-hour multichannel intraesophageal impedance and bilirubin monitoring. Scand. J. Gastroenterol 42: 1031–1039.[DOI] [PubMed] [Google Scholar]19.Gasiorowska A, Navarro-Rodriguez T, Wendel C, et al. 2009. Comparison of the degree of duodenogastroesophageal reflux and acid reflux between patients who failed to respond and those who were successfully treated with a proton pump inhitibor once daily. Am. J. Gastroenterol 104: 2005–2013.[DOI] [PubMed] [Google Scholar]20.de Bortoli N, Gyawali CP, Frazzoni M, et al. 2020. Bile reflux in patients with nerd is associated with more severe heartburn and lower values of mean nocturnal base-line impedance and chemical clearance. Neurogastroenterol. Motil e13919. 10.1111/nmo.13919[DOI] [PubMed]21.Vaezi MF & Richter JE 1996. Role of acid and duo-denogastroesophagealreflux in gastroesophageal reflux disease. Gastroenterology 111: 1192–1199.[DOI] [PubMed] [Google Scholar]22.Sun D, Wang X, Gai Z, et al. 2015. Bile acids but not acidic acids induce Barrett’s esophageal. Int. J. Clin. Exp. Pathol 8: 1384–1392.[PMC free article] [PubMed] [Google Scholar]23.McQuaid KR, Laine L, Fennerty MB, et al. 2011. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment. Pharmacol. Ther 34: 146–165.[DOI] [PubMed] [Google Scholar]24.Dvorak K, Payne CM, Chavarria M, et al. 2007. 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.[DOI] [PMC free article] [PubMed] [Google Scholar]25.Vaezi MF, Fass R, Vakil N, et al. 2020. IW-3718 reduces heartburn severity in patients with refractory gastroesophageal reflux disease in a randomized trial. Gastroenterology 158: 2093–2103.[DOI] [PubMed] [Google Scholar]