Pathophysiology of Gastroesophageal Reflux Disease

| May 1, 2023

by Katherine Kendrick, MD, and Shanu N. Kothari, MD, FACS, FASMBS

Dr. Kendrick is with the Department of Gastroenterology and Hepatology, Prisma Health Upstate-Greenville Memorial Hospital in Greenville, South Carolina. Dr. Kothari is with University of South Carolina School of Medicine Greenville and Prisma Health Upstate in Greenville, South Carolina.

Funding: This supplement was sponsored by Medtronic.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Bariatric Times. 2023;20(5–6 Suppl 1):S8–S9.

Key Points

  • Gastroesophageal reflux disease (GERD) symptoms occur due to reflux of gastric contents into the esophagus.
  • The pathophysiology of GERD is multifactorial.
  • The antireflux barrier remains a critical component of GERD pathophysiology.

Gastroesophageal reflux disease (GERD) has been described since the second century.1 In the early 19th century, Charles Billard, Heinrich Quincke, and Carl Rokintansky became the early pioneers of GERD. Billard is credited with documenting the first case of pediatric esophagitis in 1828, and Rokintansky documented gastroesophageal reflux as a cause of esophagitis in 1855.2,3 In 1879, Quincke reported regurgitation of gastric juices as a cause of esophageal ulceration.3 It wasn’t until 1906 that the symptoms of esophagitis were described, and later, in 1934, the term peptic esophagitis was born. Subsequently in the 20th century, Philip Allison and Norman Barrett played important roles in investigating key elements of the pathophysiology of GERD. Allison emphasized the necessity of a competent gastroesophageal junction, with a focus on the crural fibers.3 Barrett’s focus was the cardioesophageal angle, and he theorized the importance of a flap valve.3 The fusion of these two theories and the astute observations of Rudolph Nissen led to what we now know as the Nissen fundoplication. Many more scientists and physicians have contributed to our current understanding of the pathophysiology of GERD, which we will briefly review here. 

Pathophysiology of GERD 

To explain the pathophysiology of GERD, we must first define it. A unifying definition has been difficult, but the American College of Gastroenterology recently defined GERD as “the condition in which the reflux of gastric contents into the esophagus result in symptoms and/or complications.”4 Heartburn and regurgitation are considered the typical symptoms of GERD. A plethora of atypical symptoms can occur and include chest pain, cough, dysphagia, globus, water brash, nausea, vomiting, pulmonary fibrosis, and worsening asthma, among others.4,5 Symptoms of GERD are due to mucosal injury from the caustic gastric fluid. The acidic fluid was thought to directly kill the esophageal epithelial cells, but newer data suggest that the gastric fluid causes the injured cells to attract inflammatory cells and eventually damage the mucosa. This is termed the “cytokine sizzle.”6 

Whether or not injury in the esophagus is from chemical injury or the cytokine sizzle, the lower esophageal sphincter (LES) is a critical component of GERD physiology. The LES is a functional unit with intrinsic and extrinsic components.7 Intrinsically, the LES is comprised of tonically contracted circular muscle and gastric sling fibers. The extrinsic component is comprised of the crural diaphragm.8 The LES, crural diaphragm, angle of His, and the phrenoesophageal ligament form the antireflux barrier. 

The components of the antireflux barrier work in synchrony to create pressure at the esophagogastric junction.9 This pressure works in harmony with the migrating motor complex of the stomach, providing a physiologic mechanism for preventing gastroesophageal reflux during pressure changes in the esophagus and stomach.10 It is important to note that pressure changes occur from both intrathoracic and intra-abdominal sources. Pressure changes can occur from variations in respiratory muscle or abdominal muscle contractions. Because of the variation in pressure, it is not surprising that a small amount of physiologic gastroesophageal reflux occurs daily. Pathologic GERD occurs when there is a failure of the normal physiologic mechanisms. 

Transient LES relaxations (TLESR) are reflux events independent of a swallow.9 TLESR are increased with gastric distension; thus, they often occur postprandially. An additional phenomenon, which also occurs postprandially, is the formation of an “acid pocket.” The acid pocket is an area abutting the gastroesophageal junction that contains a lower pH than the intragastric pH, the latter of which is buffered by a meal.11,12 In patients with a hiatal hernia, the acid pocket is typically extended the entire length of the gastric mucosa in the hernia, which likely worsens GERD and its symptoms.12

Hiatal hernias disrupt the anatomical antireflux barrier. The disruption of the antireflux barrier occurs because of crural diaphragm separation and weakening of the LES, which allows the reflux of gastric contents into the esophagus. The presence of a hiatal hernia also leads to decreased esophageal clearance and causes gastric acid trapping in the hernia sac.8,13 

Decreased esophageal clearance can occur separate from a hiatal hernia and lead to a continuous cycle of inflammation. The inflammation causes failed and hypotensive peristalsis, thereby further impairing esophageal clearance.14 Impaired clearance is also present in patients with esophageal dysmotility. It is estimated that about 50 percent of patients with GERD have abnormal peristalsis.15

Additional factors that contribute to the pathophysiology of GERD include delayed gastric emptying and obesity. It is theorized that in gastroparesis, delayed emptying increases TLESR due to increased intragastric pressure and prolonged gastric distension.16,17  

Conclusion

The pathophysiology of GERD remains a dynamic area of research. The antireflux barrier is currently a key component of GERD. As research continues to improve our understanding of the pathophysiology of GERD, we will likely see the development of more targeted treatments for GERD.   

References

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  2. Yahya AI, ed. Gastroesophageal Reflux Disease: Theory and Research. IntechOpen; 2019.
  3. Stylopoulos N, Rattner DW. The history of hiatal hernia surgery: from Bowditch to laparoscopy. Ann Surg. 2005;241(1):185–193. 
  4. Katz PO, Dunbar KB, Schnoll-Sussman FH, et al. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2022;117(1):27–56.
  5. Chhabra P, Ingole N. Gastroesophageal reflux disease (GERD): highlighting diagnosis, treatment, and lifestyle changes. Cureus. 2022;14(8):e28563.
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  7. Urma D, Kuo B. Esophagus – anatomy and development. GI Motility online. 2006. https://www.nature.com/gimo/contents/pt1/full/gimo6.html. Accessed 24 Apr 2023. 
  8. Mittal RK, Balaban DH. The esophagogastric junction. New Engl J Med. 1997;336(13):924–932. 
  9. Mikami DJ, Murayama KM. Physiology and pathogenesis of gastroesophageal reflux disease. Surgical Clin North Am. 2015;95(3):515–525. 
  10. Dent J, Dodds WJ, Sekiguchi T, et al. Interdigestive phasic contractions of the human lower esophageal sphincter. Gastroenterology. 1983;84(3):453–460. 
  11. Kahrilas PJ, McColl K, Fox M, et al. The acid pocket: a target for treatment in reflux disease? Am J Gastroenterol. 2013;108(7):1058–1064. 
  12. Clarke AT, Wirz AA, Manning JJ, et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. Gut. 2008;57(3):292–297. 
  13. Sloan S, Radmaker AW, Kahrilas PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med. 1992;117(12):977–982. 
  14. Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology. 1988;94(1):73–80. 
  15. Patti MG, Perretta S. Gastro-oesophageal reflux disease: a decade of changes. Asian J Surg. 2003;26(1):4–6. 
  16. Pauwels A, Altan E, Tack J. The gastric accommodation response to meal intake determines the occurrence of transient lower esophageal sphincter relaxations and reflux events in patients with gastro‐esophageal reflux disease. Neurogastroenterol Motil. 2014;26(4):581–588.
  17. Mariani G, Boni G, Barreca M, et al. Radionuclide gastroesophageal motor studies. J Nucl Med. 2004;45(6):1004–1028.

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