Association between High Tear Epidermal Growth Factor Levels and Corneal Subepithelial Fibrosis in Dry Eye Conditions

Dry eye syndrome is one of the most common ocular diseases, affecting 14% to 33% of the population worldwide and accounting for a high percentage of patient visits to eye care practitioners.1–3 Evidence suggests that alterations in tear composition are responsible in part for the irritation symptoms and ocular surface disease that develops in DE.4,5 Indeed, a study report showed an association between increased concentrations of inflammatory cytokines in tears and the severity of irritation symptoms and ocular surface disease in DE, regardless of the etiology.6 Epidermal growth factor (EGF), secreted by the lacrimal gland, is one of the most abundant growth factors in human tears. EGF receptors are expressed by the corneal epithelium, keratocytes, and endothelium.7 EGF is a pleiotropic cytokine that can stimulate proliferation, migration, and adhesion of corneal epithelial cells during wound healing.8,9 In conjunction with TGF-β, it stimulates myofibroblastic differentiation and production of extracellular matrix by corneal keratocytes.10 In a survey of tear proteins in patients with DE conditions, the highest concentration of EGF was noted to be in the subset of patients with meibomian gland disease (MGD).6 We have reported that the presence of MG orifice metaplasia is associated with decreased tear clearance.11 Corneal complications, such as epithelial basement membrane disease, Salzmann's nodules, and subepithelial fibrosis are commonly observed in patients with MGD.12 These fibrotic changes are frequently located in the peripheral cornea that is in contact with the upper and lower tear menisci. Based on these findings, we hypothesized that the presence of corneal subepithelial fibrosis and metaplasia of the MG orifice epithelium, two common findings in patients with chronic DE and MG disease, is associated with increased tear EGF concentration. The purpose of this study was to measure tear EGF concentrations in an asymptomatic control group and in with DE. Furthermore, the correlations between tear EGF concentrations, tear production and clearance, and severity of clinical parameters of DE, including corneal subepithelial fibrosis and MG orifice metaplasia, were determined.