22 The more likely explanation is that these individuals had abnormal levels of reflux, but that this defect caused such low levels of reflux-induced symptoms that their reflux disease never came to medical attention. The fact that reflux disease is asymptomatic in a significant Roscovitine minority, whether BE is present or not, is now well established. It is relatively unusual for the observed extent of the metaplastic segment to increase over years, or for BE to appear de novo during clinical observation of reflux disease,2–4 even if this is not treated adequately. This suggests that, in most

cases, columnar metaplasia develops abruptly. Since only a minority (around 10–15%) of patients with reflux esophagitis has BE,2–4 there must be additional factors that play important roles in determining the apparently sudden development of BE. One plausible trigger factor is major acute esophageal mucosal injury, superimposed on continuing reflux-induced esophageal mucosal damage. This “double trouble” might prevent normal esophageal mucosal healing with squamous mucosa. Though this is an uninvestigated hypothesis, it has strong indirect support from

both observations of esophageal mucosal healing after endoscopic mucosal ablation or resection of areas of esophageal metaplasia and animal models; much data from these scenarios show consistently that the presence or absence of damaging reflux determines whether esophageal mucosa 上海皓元医药股份有限公司 that is severely and acutely injured heals with squamous or metaplastic columnar epithelium.2–4 Several categories of transient, but sometimes very severe esophageal mucosal damage EPZ6438 could cause “double trouble”, including, for example, acute infective esophagitis, “pill-induced” esophagitis

and the severe stasis “drunkard’s esophagitis”. These are speculative causes, but development of esophageal columnar metaplasia has been documented in a patient after severe mucositis caused by cancer chemotherapeutic agents23 and in another with caustic esophageal mucosal injury.24 Unfortunately, neither of these patients was adequately investigated for reflux disease.23,24 Interestingly, in the case of lye-induced injury, BE was confined to the mid-esophagus, presumably the area of most severe acute mucosal lye-induced damage.24 In a long-term follow-up study of achalasia patients treated by a relatively aggressive open esophageal/gastric myotomy, coupled with a Dor patch antireflux procedure, BE was found to develop in 12/67 (18%) of patients.25 This could represent “double trouble” of a different type—chronic esophageal stasis with a superimposed therapy-induced defect of gastroesophageal competence, since all but one of the BE patients had abnormal esophageal acid exposure. Several systemic factors have been identified which may predispose to columnar metaplastic healing of the previously squamous esophageal mucosa.