Is the etiology of eosinophilic esophagitis in adults a response to allergy or reflux injury? Study of cellular proliferation markers

Abstract

Recent research suggests that allergy may be the key factor in the etiology of eosinophilic esophagitis (EE); however, historically, the condition was hypothesized as related to reflux injury to the esophageal mucosa. We studied this hypothesis by comparing markers of inflammation and cellular proliferation in EE and reflux esophagitis. Lower esophageal biopsies of adult patients with EE (n = 10), reflux esophagitis (n = 8), and normal controls (n = 13) were assessed quantitatively for the expression of the cyclooxygenase-2 (COX-2) enzyme, cellular proliferation, and oncogenic resistance to apoptosis using monoclonal antibodies for COX-2, Ki-67, and Bcl-2, respectively. Normal esophageal epithelium demonstrated weak diffuse uptake of COX-2 stain in the basal layer. No COX-2 expression was demonstrated in the EE group, significantly less than the control and reflux groups (P < 0.01 and P < 0.001, respectively). Cellular proliferation measured by Ki-67 expression was higher in EE and reflux compared with control (P < 0.001 and P < 0.01). Ki-67 expression, and thus degree of hyperplasia, appeared greater in EE than reflux, but was not statistically significant (P = 0.228). The degree of apoptosis was similar in all study groups. EE and reflux esophagitis are proliferative conditions expressing Ki-67 in higher concentrations than control. Mucosal proliferation in reflux esophagitis is COX-2 dependent. This novel research in EE has demonstrated downregulation of COX-2 expression compared with reflux esophagitis and control. We hypothesize that the allergy-related cytokine IL-13 known to inhibit COX-2 expression and found in high concentrations in EE as responsible for this. The pathogenesis of EE is likely dependent on allergy rather than reflux injury to the esophagus.

Enhanced activation of eosinophils in peripheral blood and implications for eosinophilic esophagitis diagnosis

“…showed that inhibiting 5‐LOX pathway with montelukast, a selective leukotriene D4 receptor antagonist, was ineffective to maintain steroid‐induced remission in adult EoE. Nonetheless, differing from our observations, Lewis et al . showed downregulation of COX‐2 expression in the esophageal biopsies of patients with EoE when compared with patients with gastroesophageal reflux disease and control subjects.…”

Biology and Treatment of Eosinophilic Esophagitis

“…61 Consistent with increased proliferation of the basal cells in response to allergen provocation rather than acid exposure, the biopsies from EE patients have down regulation of cyclooxygenase 2 (COX2). 62 Furthermore, esophageal biopsies from EE patients may have eosinophil surface layering and eosinophilic microabscesses, processes rarely associated with GERD. 63 In addition to eosinophils, esophageal biopsies from EE patients have increased levels of dendritic cells and mast cells, at levels generally higher than in GERD.…”

Clinical lesson: eosinophilic oesophagitis, a new diagnosis to swallow

“…Although EoE may coexist with GORD, the conditions appear to be distinct, and although the exact relationship between the conditions remains controversial, there is currently little evidence to suggest an aetiological link 18. As demonstrated in all three of the presented patients, asthma and allergies are common (seen in 50%) 10.…”