Gastroesophageal reflux disease (GERD) results from failure of the anti-reflux barrier, allowing gastric acid, pepsin, and bile to contact esophageal squamous epithelium. The lower esophageal sphincter (LES) is the primary anti-reflux mechanism: a 3-4 cm zone of tonic smooth muscle contraction at the gastroesophageal junction (GEJ), augmented by the crural diaphragm. Transient LES relaxations (TLESRs) are the predominant mechanism of reflux - mediated by vagal afferents triggered by gastric distension, which activate brainstem swallowing centers causing inappropriate LES relaxation via nitrergic (NO) and VIP inhibitory neurons. Hiatal hernia disrupts the GEJ anatomy, separating the LES from diaphragmatic crura, creating an acid pocket above the diaphragm that facilitates reflux. Gastric acid (pH 1.5-3.5) damages esophageal epithelium by activating pepsin (which digests mucosal proteins) and directly injuring cell membranes. Chronic acid exposure causes basal cell hyperplasia, papillary elongation, and neutrophilic/eosinophilic infiltration (reflux esophagitis). Metaplasia from squamous to intestinal columnar epithelium (Barrett esophagus) represents an adaptive response to chronic acid injury but carries 0.5% annual risk of progression to esophageal adenocarcinoma. Proton pump inhibitors (PPIs) irreversibly inhibit the H+/K+-ATPase proton pump on the...