“…Repeated exposure to regurgitated acidic gastric juice is well known to defeat the first line of squamous epithelial defense mechanisms [65] and, in the long run, lead to metaplasia. However, acid is not the full story as many patients with GERD who have controlled gastric and esophageal pH with proton pump regulators still progress to Barrett's and EADC [8,28]. The presence of pepsin, bile, and trypsin in refluxed gastric juice are proposed an additional, or alternative, disruptive factors for the development of IM in the esophagus [41,42,61,67], and more recent tests of this hypothesis have been carried out in patients [56] and in vitro [61].…”