MGD Is Not an Inflammatory Disease

Tear dysfunction is one of the most common problems encountered by ophthalmologists, with prevalence ranging from 2% to 14.2%.^1,2 The condition has been found to increase with age from the 4th to 8th decades of life and is more prevalent in women than men throughout this period.^3,4 Patients with tear dysfunction typically report irritation symptoms, including foreign-body sensation, burning and dryness, as well as vision-related symptoms, such as photophobia and fluctuating vision.

Tear dysfunction results from disease of one or more components of the lacrimal functional unit that consists of the tear-producing glands and their neural connections. Many patients over the age of 40 with tear dysfunction have evidence of meibomian gland disease (MGD) as an underlying cause, particularly in patients who have an unstable tear film but normal tear production and tear volume. Our research has found that the majority of these patients have delayed tear clearance and altered tear composition.^5-7 Furthermore, many have age-related pathologic changes of the conjunctiva, eyelids or tear-drainage system that contribute to the delayed tear clearance.

Our research and the intriguing “solute gradient hypothesis,” recently proposed by Bron and colleagues, suggest that altered tear dynamics and the accompanying tear compositional changes promote pathologic hyperkeratinization of the terminal meibomian gland (MG) ductal epithelium, which obstructs secretion of MG lipids onto the ocular surface.^8,9 Hyperkeratinization of the meibomian gland orifices is a common feature of MGD.

Marx’s Line

In the young healthy eyelid, the MG orifices are located anterior to the mucocutaneous junction that can be identified as Marx’s line, a physiologic line of staining with diagnostic dyes, such as fluorescein, lissamine green and rose bengal. Yamaguchi and colleagues evaluated the location of Marx’s line in 251 subjects without a history of ocular surface disease and found anterior migration of the Marx’s line (mucocutaneous junction) with aging.¹⁰ We often observe Marx’s line extending anteriorly on the lower lid margin up to or beyond the MG ductal orifices in elderly patients with tear instability.

This phenomenon is often accompanied by temporal and/or nasal conjunctivochalasis that prevents spread of the tear meniscus along the entire lower lid and results in an increased volume of the central inferior tear meniscus (Figure).¹¹ Anterior migration of this swollen tear meniscus exposes the MG orifices to factors in the tears that may stimulate proliferation and increased production of cornified envelope precursors that are usually found in the skin epidermis.

Figure

Table 1. Dry Eye Syndrome Diagnosis and Treatment

A. Meibomian gland disease in a patient with chalasis of the temporal bulbar conjunctiva that obstructed flow of the inferior tear meniscus over the lateral aspect of the lower lid (black arrow) and increased the central tear meniscus (white arrow). B. Anterior segment optical coherence tomography of the central inferior lid (L) and cornea (C) showed increased height and width of the tear meniscus and thickening of the posterior lid margin (white arrow) in the area of tear contact. C. Anterior displacement of scalloped Marx’s line stained by lissamine green (black arrow) beyond the meibomian gland (MG) orifices. Hyperkeratinization of the MG ductal orifi ces with decreased expressibility of meibum and a rapid tear break-up time was noted in this eye.
Source: Stephen C. Pflugfelder, MD

Click here for a larger view of this image.

Solute Gradient Hypothesis

Bron has proposed the solute gradient hypothesis, which predicts a rise in solute concentration at the peripheral apex of the tear meniscus on the lid margin.⁸ This increased concentration would result in increased osmolarity in that area, as well as stagnation of larger molecules such as mucins, growth factors and cytokines near the apex of the meniscus because of limited capacity to diffuse. The changes in tear composition on the lower lid would be compounded by underlying tear dysfunction and delayed tear clearance.

Our group has reported that high osmolarity is a potent proinflammatory stressor on the ocular surface epithelia, as has been found for epithelia in other organ systems, such as the lung and kidney.¹² In this scenario, osmostress would be capable of stimulating production of inflammatory mediators, proteases and proapoptotic factors by the conjunctival, epidermal and MG duct epithelia in the area of tear meniscus stagnation. We recently identified a subset of patients with tear dysfunction who had delayed tear clearance with normal Schirmer’s test scores and tear epidermal growth factor concentrations up to twice the normal levels.¹³ This subset of patients was found to have significantly greater MG orifice metaplasia (hyperkeratinization). These findings are consistent with and strongly support the solute gradient hypothesis.

A Noninflammatory Condition

Taken together, this evidence indicates that alterations of the ocular surface tissues with aging may create an environment around the MG orifices that promotes pathologic hyperkeratinization of the MG ducts, leading to obstruction of glandular secretion. While lid margin inflammation associated with rosacea can also cause MGD, the solute gradient hypothesis offers another, noninflammatory etiology for development of MGD. This mechanism proposes that development of MGD is a secondary, rather than primary phenomenon in many aging patients. This concept also suggests that early intervention aimed at normalizing the tear meniscus dimensions and volume, such as removal of conjunctivochalasis or punctal enlargement, may have beneficial effects on the meibomian glands over time.

References

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Gumus K, Crockett CH, Pflugfelder SC. Anterior segment optical coherence tomography: a diagnostic instrument for conjunctivochalasis. Am J Ophthalmol. 2010;150:798-806.
Li D-Q, Luo L, Chen Z, Kim H-S, Song XJ, and Pflugfelder SC. JNK and ERK MAP kinases mediate induction of IL-1β, TNF-α and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res. 2006;82:588–596.
Rao K, Farley WJ, Pflugfelder SC. Association between high tear epidermal growth factor levels and corneal subepithelial fibrosis in dry eye conditions. Invest Ophthalmol Vis Sci. 2010;51(2): 844–849.