Eosinophilic Esophagitis and Gastroesophageal Reflux Disease

There and Back Again

Ikuo Hirano, Md

Disclosures

Clin Gastroenterol Hepatol. 2011;9(2):99-101. 

Abstract and Introduction

Introduction

Studies from the 1980s identified esophageal eosinophilia in both children and adults as a diagnostic, histologic criterion for gastroesophageal reflux disease (GERD).[1,2] The presence of esophageal eosinophilia correlated with abnormal esophageal acid exposure. Moreover, proximal esophageal eosinophilia was associated with even greater degrees of acid exposure. In most cases, the eosinophils numbered less than 10 per microscopic high-power field (hpf) and were concentrated in the distal esophagus.[3] At the time, eosinophilic esophagitis (EoE) was viewed as an esoteric diagnosis, confined to a few case reports of adults with concomitant eosinophilic gastroenteritis.

In the early 1990s, 2 adult case series first described EoE as an entity distinct from GERD.[4,5] The presentation of dysphagia and food impaction in atopic individuals with endoscopic findings of esophageal rings and longitudinal furrows was distinct from the heartburn, regurgitation, and erosive esophagitis that typified GERD. The degree of esophageal eosinophilic infiltration of the squamous epithelium in EoE exceeded that typically seen in GERD. Furthermore, these first EoE series included patients with normal pH testing or failed response to proton pump inhibitor (PPI) therapy. The distinction between EoE and GERD was supported in a retrospective pediatric study that found an inverse correlation between the degree of esophageal eosinophilia and reflux severity determined by pH testing.[6] Abnormal reflux testing was more likely in children with ≤5 eosinophils/hpf and uncommon in those with >20 eosinophils/hpf. Another pediatric study characterized esophageal eosinophilia as a predictor of poor symptom response to reflux therapy.[7] The notion that EoE and GERD were separate entities was furthered by investigations of allergic cell mediators and biomarkers. Histologic detection of mast cells and tissue expression of eotaxin-3 and eosinophil peroxidase were significantly greater in EoE compared with GERD.[3,8–10] Genome-wide microarray analysis detected an mRNA transcript signature involving 1% of the human genome in EoE that was distinct from chronic esophagitis (presumably related to GERD).[9] These observations led to the concept that detection of elevated esophageal eosinophilia was indicative of an "allergic," non-GERD esophagitis effectively treated with steroids or elimination diet, and not acid suppression. A recent study identified independent predictors of EoE compared with GERD included younger age, symptoms of dysphagia, food allergy, presence of esophageal rings/furrows/plaques, absence of hiatal hernia, higher eosinophil counts, and eosinophil degranulation.11 The authors proposed that these clinical features might distinguish patients with EoE from those with GERD to facilitate initiation of appropriate therapy.

During the past decade, it has become evident that esophageal eosinophilia does not exclude the presence of GERD. Twenty-five percent to 50% of pediatric and adult EoE patients have evidence of increased distal esophageal acid exposure on pH monitoring.[12–14] Additional studies have demonstrated the presence of distal esophageal erosions in patients with symptoms and histologic evidence of EoE. The presence of objective GERD diagnostic parameters did not implicate GERD as the cause of the esophageal eosinophilia because these series identified patients who had failed therapeutic trials of PPI. Instead, the data supported the coexistence of EoE and GERD. The intersection between the entities is not only reasonable but expected, given the high prevalence of GERD in the general population. To deal with this overlap, consensus recommendations put forth by the American Gastroenterological Association Institute and North American Society of Pediatric Gastroenterology, Hepatology and Nutrition suggested that the diagnosis of EoE be considered in patients with clinical symptoms of esophageal dysfunction with ≥15 eosinophils/hpf with either lack of response to high dose PPI or normal pH monitoring.[15]

The notion that EoE could be caused by GERD originated in a case series of 3 patients with symptoms, endoscopic features, and histopathology consistent with EoE who responded to PPI.[16] Two recent, retrospective pediatric studies involving 79 children with EoE reported a 39% response to PPI therapy, with response defined by <5 eosinophils/hpf.[17,18] Furthermore, a randomized controlled trial comparing esomeprazole with fluticasone in adults with dysphagia and esophageal eosinophilia found no difference in the symptom or histologic response.[19] In this issue of Clinical Gastroenterology and Hepatology, Molina-Infante et al[20] report important data from a prospective study examining the response to PPI therapy among adults with esophageal eosinophilia. Esophageal biopsies were obtained from 712 patients undergoing esophagogastroduodenoscopy (EGD) for foregut symptoms, identifying 35 (4.9%) with ≥15 eosinophils/hpf. A surprising 75% of the patients with esophageal eosinophilia responded to an 8-week course of rabeprazole 20 mg twice a day, with response defined by achieving <5 eosinophils/hpf. Furthermore, a subgroup of esophageal eosinophilia patients with a symptom profile (dysphagia or food impaction) and endoscopic findings (rings, furrows) characteristic for EoE had a 50% response to the PPI trial. Although pH monitoring was more likely to be abnormal in those responding to PPI, one-third of those with a normal pH test responded. Likewise, a higher degree of esophageal eosinophilia at the time of index EGD reduced but did not exclude response to PPI. The authors propose that EoE might be overdiagnosed without a therapeutic trial of PPI.

At first glance, it would appear that our understanding of EoE has taken a step back to the 1980s. The high response rate of esophageal eosinophilia to PPI implies that the majority of reported EoE is a manifestation of GERD. Following the consensus statement diagnostic criteria for EoE, calling for the exclusion of GERD by a pH study or PPI trial would reclassify most suspected EoE patients as GERD. On closer inspection, however, the delineation between GERD and EoE is not that straightforward.[21] An important limitation to the generalizability of the results by Molina-Infante et al[20] is the study design. Patients were included on the basis of the finding of esophageal eosinophilia, regardless of the indication for EGD. Moreover, a symptom or histologic response to PPI should not necessarily define GERD in the context of patients with suspected EoE. It is plausible, although unproven, that acid reflux in and of itself might cause or exacerbate an allergic inflammatory response. Proposed mechanisms whereby GERD can cause or exacerbate EoE include the following observations: (1) Acid increases eosinophil viability,[22] (2) esophageal acid exposure induces the release of mast cell mediators,[23] and (3) GERD is associated with dilated intercellular spaces in the squamous epithelium that might allow penetration of allergens. To further confuse matters, preliminary data suggest that PPI therapy might have anti-inflammatory effects beyond acid suppression.[24]

During the past 30 years, esophageal eosinophilia has gone from a GERD diagnostic criterion to a fundamental histologic marker of EoE and now back to a seemingly complex interplay between the 2 entities. What can we conclude at this time? The study by Molina-Infante et al,[20] combined with prior studies, indicates that a significant proportion of patients with suspected EoE respond to PPI therapy. Clinical and endoscopic features are highly predictive of the presence of esophageal eosinophilia, but not predictive of a PPI response. It remains to be determined whether more sophisticated biomarkers can more accurately distinguish GERD and EoE, as it pertains to PPI response. Intriguing but preliminary studies indicate that a PPI response in EoE might not be specific for acid reflux and can occur with an allergic pattern of esophageal inflammation.

What is the clinical significance of differentiating GERD from EoE? One of the earliest studies on EoE reported a cohort of children with esophageal eosinophilia who were diagnosed with GERD deemed refractory to medical therapy, the majority of whom underwent fundoplication without improvement.[25] The children were subsequently shown to respond symptomatically and histologically to an elemental diet. EoE should be considered in patients with "refractory reflux" before consideration of antireflux surgery. Although this scenario is more commonly encountered in pediatrics, prospective adult studies have detected EoE in 1%–4% of patients with reflux symptoms failing PPI therapy.[26,27] On the other hand, committing patients with suspected EoE to long-term steroid or elimination diet therapy who might otherwise respond to PPI is also important. The safety profile of PPI is established, whereas the long-term physical and psychosocial implications of topical steroids and dietary intervention are unknown. As the controversy over distinguishing GERD from a PPI responsive form of EoE continues, an empiric therapeutic trial of PPI therapy in suspected EoE patients seems the most practical strategy[28] (Figure 1).

Figure 1.

Suggested diagnostic approach to adult patient with EoE. EoE is suspected on the basis of a clinical profile of symptoms dominated by dysphagia and food impaction in a younger, typically male patient with history of atopy. Considerations in the decision to perform an EGD or to proceed with an empiric PPI trial at this juncture include symptom severity and preference to minimize testing. In cases where an EGD is available (*), features supportive of diagnosis of EoE include esophageal rings, longitudinal furrows, and exudates with histologic evidence of esophageal eosinophilia. Following a therapeutic trial of PPI therapy, an EGD differentiates PPI-responsive esophageal eosinophilia from the 2007 AGA Institute/NASPGHAN consensus recommendation for the diagnosis of primary EoE.15 It remains controversial whether the PPI-responsive form of esophageal eosinophilia represents GERD or a PPI-responsive subtype of EoE.

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