Gastroesophageal Reflux Disease: Pathophysiology and New Treatment Trends

Abstract

Gastroesophageal reflux disease (GERD) is caused by the reflux of gastric contents into the esophagus due to a decline in esophageal clearance and anti-reflux barrier mechanisms. Mucosal injury is caused by a combination of gastric juice directly damaging the esophageal mucosa and the immune and inflammatory mechanism in which inflammatory cytokines released from the esophageal mucosal epithelium cause neutrophil migration, triggering inflammation. Gastric secretion inhibitors are the first-line treatment for GERD, but they can be combined with prokinetic agents and Chinese herbal remedies. However, pharmacotherapy cannot improve anatomical problems or prevent physical causes of GERD, such as reflux of non-acidic contents. Therefore, surgery can be warranted, depending on the pathology. Intraluminal endoscopic therapy, which is both less invasive and more effective than surgery, was recently developed and applied in Europe and the United States. In Japan, intraluminal endoscopic therapies, such as anti-reflux mucosectomy, anti-reflux mucosal ablation, and endoscopic submucosal dissection, for GERD have been independently developed.

Keywords: anti-reflux mucosal ablation (ARMA); endoscopic submucosal dissection for GERD (EGD-G); gastroesophageal reflux disease (GERD); intraluminal endoscopic therapy; potassium-competitive acid blocker (P-CAB); proton pump inhibitor (PPI).

Figure 1.

Characterization of acidity in the distal esophagus and proximal stomach under fasting conditions and in response to a large meal using high-resolution pH-metry in healthy subjects (8). The left panel shows the position of the 12-electrode catheter relative to that of the squamocolumnar junction (SCJ). The catheter was clipped to the SCJ with an endoclip using a loop tied between electrodes 4 and 5, 10.5 cm proximal to electrode 12, at the tip of the catheter. The right panel illustrates the pH contour plots (120 s duration each) of the high-resolution 12-electrode pH-meter (a) in the fasting state, showing marked intragastric acidity; (b) 3 min after the meal, showing intragastric buffering by food; (c) 17 min after the meal, showing emergence of the acid pocket at the esophagogastric junction; (d) 43.5 min after the meal, showing acid pocket enlargement; (e) 47.5 min after the meal, showing an acid reflux episode from the acid pocket (circled) despite simultaneous distal intragastric buffering; and (f) 73.5 min after the meal, simultaneously recording the proximal acid pocket and distal gastric acidity. This figure is from reference 8, and its use has been permitted by the publisher.

Figure 2.

Pathophysiological classification of PPI-refractory NERD. Based on the results obtained from intra-esophageal manometry and 24-h-long intra-esophageal pH/impedance monitoring, the subjects were classified into three groups according to the Rome III criteria: acid reflux-related mechanism, non-acid reflux-related mechanism, and functional heartburn. This figure is original from the present authors.

Figure 3.

Actual ELGP for patients with PPI-refractory NERD. A: Preoperative image (GERD with mild esophageal hiatal hernia). B: Immediately after ELGP (plication performed in three locations). C: Three months after ELGP (plication remains in two locations). This figure is original from the present authors. ELGP: endoluminal gastroplication, GERD: gastroesophageal reflux disease, NERD: non-erosive reflux disease, PPI: proton pump inhibitor

Figure 4.

Medigus Ultrasonic Surgical Endostapler (MUSE^®) (44). A: Endoscopic tool. B: Tip part (15.5-mm diameter). C: The cartridge was positioned 3 cm proximal to the esophagogastric junction, and plication was performed. This figure is from reference 44, and its use was permitted by the publisher.

Figure 5.

Anti-reflux mucosectomy (ARMS) (46). A: Before ARMS. B: Immediately after ARMS, the lesser curvature remained, and an ulcer accounting for two-thirds of the circumference was found. C, D: Two months after ARMS, the cardia lip was reshaped. This figure is from reference 46, and its use was permitted by the publisher.