**4.1 Etiology and pathophysiology of GERD**

Various critical factors and mechanisms are contributing to GERD: LES incompetence, hiatal hernia, and hiatal anatomic changes, protrusion or herniation of the upper part of the stomach into the thorax, an altered frequency of transient LES relaxations, esophageal acid exposure, insufficient esophageal motility, and delayed gastric emptying [7]. Diet and conditions, which increase intra-abdominal pressure such as pregnancy, obesity, and straining play a role, as well as presence of Helicobacter pylori [8]. In addition, alcohol, nicotine, caffeine, and certain medications, such as calcium channel blockers or anticholinergic agents, have been shown to cause LES incompetence, which is the main cause of GERD [9].

Many GERD patients exhibit esophageal dysmotility and prolonged clearance rates [10]. GERD and psychosocial disorders often occur together and can affect each other [11]. Obstructive sleep apnea (OSA), obstructive sleep apnea syndrome (OSAS), and GERD have a strong relationship and share several common risk factors: approximately 40–60% of patients with OSA also suffer from GERD [12].

The pathological effect of refluxed gastric contents is complex and caused by acids, pepsin, bile acids, and trypsin. The overall mechanism of cell damage is penetration of the epithelium by acids at low pH and proteolysis of collagen, which disrupts the basement membrane of the squamous epithelial cells. Acid and bile reflux play a critical role—hydrochloric acid is a major cause of esophageal irritation and reflux symptoms causing injury to mucosal epithelial cells and inflammation. The abnormal secretion and activation of pepsin can also cause proteolysis and cell damage [13]. Pathohistological changes in the esophageal mucosa can be divided into three categories: nonerosive reflux disease, reflux oesophagitis, and Barett's esophagus [14].
