Can gastroesophageal reflux disease without concomitant eosinophilic esophagitis cause high-level esophageal eosinophilia?

The presence of ≥15 eosinophils per high-power field (HPF) in esophageal biopsies is a histological hallmark for diagnosing eosinophilic esophagitis (EoE). However, since eosinophilia may also be observed in gastroesophageal reflux disease (GERD), there is ongoing debate about whether GERD without EoE can induce high-level esophageal eosinophilia. This review examines the evidence and mechanisms behind GERD-associated eosinophilia and evaluates whether GERD alone can meet EoE-level eosinophilic thresholds.

 

Introduction

GERD is a multifactorial disorder affecting up to 20% of the Western population and characterized by heartburn, regurgitation, and reflux-induced complications. EoE is a distinct Th2-driven allergic inflammatory condition associated with dysphagia and food impaction, marked histologically by eosinophilic infiltration. The overlap in clinical and histological features between GERD and EoE has historically made differential diagnosis challenging. Although GERD is known to cause low-grade eosinophilia, whether it can cause high-level eosinophilia (≥15 eosinophils/HPF) akin to EoE remains unclear.

 

Mechanisms of Reflux-Induced Esophageal Eosinophilia

Acid exposure in GERD can induce expression of vascular cell adhesion molecule 1 (VCAM-1) and release platelet-activating factor (PAF) by esophageal cells—both promoting eosinophil recruitment and activation. In contrast, EoE is mediated through IL-4 and IL-13 cytokines stimulating eotaxin-3 production by esophageal epithelial cells. Since GERD-related acidity can suppress eotaxin-3, the mechanisms underlying GERD and EoE eosinophilia appear distinct.

 

Evidence from Pediatric Studies

Early studies in children often lacked modern diagnostic criteria for GERD and failed to rule out EoE. In one study from 1982, eosinophils were found in 18 of 46 children with abnormal acid clearance, though counts were typically low (<15/HPF). Another study in infants reported high eosinophil counts (≥25/HPF) in some cases attributed to GERD—but predating the identification of EoE, it’s possible these were misdiagnosed EoE cases. More recent pediatric studies continue to show elevated eosinophil levels in GER-like presentations, but without formal GERD testing, EoE cannot be excluded.

 

Evidence from Adult Studies

A frequently cited adult study from 2008 identified 40 of 3,648 patients (1.1%) with >20 eosinophils/HPF. Most of these patients were diagnosed clinically with GERD, but EoE could not be definitively excluded. Similarly, a study in patients with Barrett’s esophagus—considered definitive evidence of GERD—found 7% had ≥15 eosinophils/HPF, but without ruling out coexisting EoE.

 

Distinguishing GERD from EoE in Clinical Practice

While both disorders can coexist, the current diagnostic algorithm for EoE begins with excluding GERD. Yet, in rare cases of confirmed GERD with high eosinophilia and no EoE-specific features (e.g., rings, strictures), the cause of eosinophilia remains uncertain.

1. Response to PPIs: Not definitive, as PPIs have both acid-suppressive and anti-inflammatory effects.
2. Response to Fundoplication: Limited data suggest surgical reflux correction may reduce eosinophilia in some cases, but may also resolve GERD-driven EoE.
3. Transcriptomics: Tools like the EoE Diagnostic Panel (EDP) show promise in distinguishing EoE from GERD but cannot yet rule out GERD with coexisting EoE in eosinophilic presentations.

 

Conclusion

The authors conclude that GERD alone very rarely (likely <1% of GERD cases) causes high-level esophageal eosinophilia. In most cases, either undiagnosed EoE or a GERD-triggered EoE process is a more likely explanation. Given current limitations in diagnostics, such cases remain a clinical challenge. The best approach involves thorough mapping biopsies, cessation of PPIs prior to endoscopy, and documentation of objective GERD evidence. Until more definitive tests are developed, distinguishing GERD-alone eosinophilia from true EoE will remain an unresolved issue in gastroenterology.

 

Full text

https://www.xiahepublishing.com/2994-8754/JTG-2024-00033

 

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

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