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Review
. 2025 Jun 25:1-17.
doi: 10.1159/000547023. Online ahead of print.

Pathophysiology of Gastroesophageal Reflux Disease

Luisa Bertin  1   2 , Vincenzo Savarino  3   4 , Elisa Marabotto  3   4 , Matteo Ghisa  1   2 , Nicola de Bortoli  5 , Edoardo Vincenzo Savarino  1   2
Affiliations
Review

Pathophysiology of Gastroesophageal Reflux Disease

Luisa Bertin et al. Digestion. .

Abstract

Background: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder caused by the retrograde flow of gastric contents into the esophagus, leading to bothersome symptoms and complications. Its pathophysiology is complex and multifactorial, and recent research has aimed to explain the heterogeneity of GERD phenotypes, each influenced by different underlying mechanisms that contribute to symptom presentation and disease progression.

Summary: GERD arises from an imbalance between defensive mechanisms and disruptive factors. Key pathophysiological contributors include esophageal gastric junction dysfunction, transient lower esophageal sphincter relaxations, esophageal motility abnormalities, delayed gastric emptying, and thoracoabdominal pressure gradients. Mucosal damage is exacerbated by prolonged exposure to acid and bile, pepsin activity, and impaired esophageal volume and chemical clearance. Additionally, central and peripheral neural modulation influences symptom perception, with heightened visceral sensitivity and esophageal hypervigilance playing significant roles in symptom severity and treatment response. Emerging diagnostic techniques such as high-resolution manometry, impedance-pH monitoring, and EndoFLIP® are improving our ability to identify specific pathophysiological abnormalities, leading to more personalized approaches to GERD management.

Key messages: (i) GERD results from a multifactorial interplay between anatomical, functional, and neurophysiological mechanisms. (ii) Esophageal clearance, EGJ structure and function, acid exposure, mucosal resistance, and neural modulation are crucial determinants of symptom severity and disease progression. (iii) The presence of different phenotypes of the reflux disease (e.g., GERD, functional heartburn, and reflux hypersensitivity) underscores the need for individualized diagnostic and therapeutic strategies. (iv) Advances in diagnostic technologies enhance our understanding of GERD pathophysiology, facilitating tailored management approaches beyond acid suppression therapies. Future research should focus on refining GERD phenotyping and integrating mechanistic insights into personalized treatment paradigms.

Keywords: Esophageal motility; Gastroesophageal reflux disease; Hypersensitivity; Lower esophageal sphincter; Mucosal resistance; Pathophysiology.

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Conflict of interest statement

Edoardo Vincenzo Savarino has served as speaker for AbbVie, Agave, AGPharma, Alfasigma, Aurora Pharma, Cadigroup, Celltrion, Dr. Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; he has also served as a consultant for AbbVie, Agave, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, SYNformulas GmbH, Takeda, and Unifarco, and he has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. Vincenzo Savarino, Elisa Marabotto, Matteo Ghisa, and Luisa Bertin have no conflict to declare. Nicola de Bortoli has served as an advisory board member for Alfasigma, Sanofi Genzyme, and Dr. Falk and received lecture grants from Reckitt Benckiser, Malesci, Dr. Flak, Sofar, Alfasigma, and Pharma Line.

Figures

Fig. 1.
Fig. 1.
Main mechanisms driving GERD and its symptoms. Created with Biorender.com (last accessed February 15, 2025).
See this image and copyright information in PMC

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