Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management

Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder in which retrograde flow of gastric content into the oesophagus causes uncomfortable symptoms and/or complications. It has a multifactorial and partially understood pathophysiology. GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or extra-oesophageal symptoms. Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. The intensity of the symptoms is affected by peripheral and central neural and psychological mechanisms. In this Review, we describe an updated understanding of the complex and multifactorial pathophysiology of GERD. It is now recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. These variations are probably due to the occurrence of a predominant pathophysiological mechanism in each patient. We also describe the main pathophysiological mechanisms of GERD and their implications for personalized diagnosis and management. In this Review, Arguero and Sifrim describe the core pathophysiological mechanisms involved in gastro-oesophageal reflux disease (GERD). They also discuss the implications for clinical management of GERD. Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder and has a multifactorial pathophysiology; there are two phenotypes of GERD, erosive and non-erosive reflux disease, and their distinct pathophysiology is not completely known.The oesophagogastric junction works as a functional antireflux barrier; transient lower oesophageal sphincter relaxations are the most frequent mechanism for reflux in healthy individuals and in patients with GERD. Hiatal hernia is an important mechanism of GERD.Motility impairment of both the oesophagus and the proximal stomach is involved in GERD pathophysiology.The refluxate is a mix of gastric and biliopancreatic secretions. Acid reflux is associated with heartburn and mucosal damage. Bile reflux provokes more severe oesophagitis or Barrett oesophagus. Non-acid reflux is mainly associated with symptoms but no mucosal damage.Impairment of oesophageal mucosal integrity, innervation and microinflammation has a crucial role in symptom perception.Severity of GERD symptoms is influenced by psychoneuroimmune modulation; psychosocial comorbidities and hypervigilance determine the severity of GERD symptoms as well as response to treatment.