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  • Review Article
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Gastroesophageal reflux disease—from reflux episodes to mucosal inflammation

Nature Reviews Gastroenterology & Hepatology volume 9, pages 15–22 (2012)Cite this article

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Abstract

Gastroesophageal reflux disease (GERD) affects 20–30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.

Key Points

  • GERD-associated mucosal inflammation is characterized by epithelial release of IL-8 and other proinflammatory markers

  • PAR2 expression is upregulated in patients with GERD and induced by acid conditions in cell-culture models; PAR2 activation leads to epithelial IL-8 release and contributes to the pathogenesis of GERD

  • Structural abnormalities and microscopic changes in GERD are characterized by papillary elongation, basal cell hyperplasia, dilated intercellular spaces and an infiltrate of immune cells, and can even be identified using light microscopy

  • Beyond PPI therapy, new pharmacological targets include mechanisms related to transient lower esophageal sphincter relaxation and mechanisms involved in symptom perception (TRPV1, cannabionoid receptors)

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Figure 1: The inflammatory changes that occur in GERD pathogenesis.

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  1. Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Straβe 44, Magdeburg, 39120, Germany

    Arne Kandulski & Peter Malfertheiner

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  1. Arne Kandulski
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A. Kandulski researched data for the article. Both authors contributed equally to discussions of content, writing, reviewing and editing the manuscript.

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Correspondence to Peter Malfertheiner.

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P. Malfertheiner declares that he has received grant or research support from Movetis and Novartis. A. Kandulski declares no competing interests.

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Kandulski, A., Malfertheiner, P. Gastroesophageal reflux disease—from reflux episodes to mucosal inflammation. Nat Rev Gastroenterol Hepatol 9, 15–22 (2012). https://doi.org/10.1038/nrgastro.2011.210

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