Clinical relevance of lipids in the tear film
Lipids play a critical role in the health of the eyelids and the tear film. Abnormalities of these lipids are common in the general population and provoke frequent disease manifested by clinical conditions of eyelid inflammation and tear film instability. Such conditions, although not life-threatening, cause considerable irritation to patients and interference with their quality of life. The most common clinical problems are meibomian gland disease (MGD) and dry-eye disease, but focal lesions of hordeola and chalazia are also often a nuisance.
Normal anatomy and production
Lipids are normally produced by the meibomian glands of the eyelid and the main and accessory lacrimal glands, as well as epithelial cells of the ocular surface. The lipids are distributed in five pools including within the eyelid, the eyelid margin, the surface of the tear film, within the aqueous layer of the tear film, and on the ocular surface.
Most of the lipid is thought to be produced by the meibomian glands of the eyelid, although contributions are also made by the main lacrimal gland, the glands of Wolfring, and the glands of Krause. The meibomian glands are modified sebaceous glands, that is, tubuloacinar, holocrine glands whose acini discharge their entire contents in the process of secretion. They are distributed vertically in the substance of the tarsal plate of the eyelid with their openings on the eyelid margin just posterior to the eyelash follicles. There are about 30–40 glands in the upper eyelid and 20–30 glands in the lower eyelid. Their secretion is conditioned by hormonal influences particularly of androgens with neural control by parasympathetic, sympathetic, and peptidergic innervations.
It is estimated that there are over 30 000 molecular species of lipids in human meibum, which complicates their quantification. The accuracy and precision of measurements of the lipid composition of meibum are also complicated by the large variation in composition from person to person, and the paucity of sample. Because of these complications, it is not surprising that the value reported for the predominant class of meibum lipid, esters, composes between 20 and 80% of the meibum. There is also loose agreement on the composition of other meibum lipids; for instance, alkanes compose 0–36% of the meibum ( Box 17.1 ). In an older study using column chromatography, phospholipids constituted as much as 16% of meibomian gland secretions ; however, more sensitive mass spectroscopic techniques indicate that phospholipids are not present. Of the total lipid hydrocarbon chains 58% are saturated. Most of the saturated hydrocarbon chains are in the form of sterol esters, which are 85% saturated. The wax esters and triglycerides are the least saturated, at 22% and 38%, respectively.
Conflicting information
>30 000 molecular species present
Esters: 20–80%
Sterol esters 85% saturated
Wax esters 22% saturated
Triglycerides 38% unsaturated
Alkanes: 0–36%
Phospholipids: 0%
Chromatographic and spectroscopic data indicate major compositional differences between the lipids in tears and meibum. This is consistent with the compositional differences reported in the only comprehensive study of tear fluid lipids.
Meibum normally has a melting point between 19 and 39°C. At ambient lid temperature, the lipid is about 37% ordered, in between a solid (gel phase) and liquid (liquid crystalline phase; Box 17.2 ). As the temperature increased from 25 to 45°C, lipid delivery to the margins was observed to increase. Under similar conditions, other studies show a concomitant decrease in the refractive index, hydrocarbon disorder, and meibum lipid hydrocarbon motion. This raises the possibility that hydrocarbon chain order and motion could contribute to the delivery of meibum lipid from the meibomian glands to the lid margins.
Melting point: 19–39°C
At ambient lid temperature: 37% ordered lipid
(in between gel phase and liquid crystalline phase)
As temperature increases:
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Delivery to eyelid margin increases
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Refractive index decreases
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Lipid becomes more disordered
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Lipid motion increases
The function of the meibomian gland secretion is most importantly to retard evaporation of the tear film by distribution across the surface of the tear film. The secretions also function to provide a smooth optical surface for the cornea at the air–lipid interface, enhance stability of the tear film, enhance spreadability of the tear film, prevent contamination of the tear film by sebum of the cutaneous sebaceous glands, and to help seal the eyelid margin during eyelid closure ( Table 17.1 ). Although the initial concept of the tear film as that of a three-layer structure of surface lipid layer, bulk aqueous layer, and ocular surface-wetting mucin layer has been replaced by the characterization of the tear film as a lipid-coated hydrated mucin gel with multiple interacting components of electrolyte, protein, and lipid entities, the lipid component is still responsible for stability of the tear film and protection of the ocular surface.
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Changes occurring with age
The tear film is incredibly stable in infancy yet with advancing years such tear stability decreases. This progressive instability is associated with changes in the conformation of the lipids of the tear film and meibomian gland secretion. With increasing age, the ordering of the lipid changes from that of a more ordered conformation to that of a less ordered conformation as determined by Fourier transform infrared spectroscopy (FTIR) ( Figures 17.1 and 17.2 ). If the lipid disorder is maintained by the lipid on the tear film surface, lipid–lipid interactions would be weaker with increasing age ( Box 17.3 ). Hence, the rate of evaporation would be expected to be greater since water escaping through the lipid layer would have to pass through lipid less tightly packed. Furthermore, if lipid–lipid interactions are weaker, one might expect that this could contribute to faster tear breakup times observed with age.
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More ordered conformation (trans) changes to less ordered conformation (gauche) (as measured by Fourier transform infrared (FTIR) spectroscopy ( Figures 17.1 and 17.2 )
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Decrease in ordering of lipid correlates with decreased tear film stability
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Decrease in ordering of lipid correlates with increased tear evaporation
Lipid–protein interactions
Lipocalin, present in tears, is capable of sequestering cholesterol, fatty acids, glycolipids, and glycerophospholipids. Lipid binding promotes protein conformational changes. It has been proposed that lipocalin scavenges lipid from the corneal surface and may enhance the transport and equilibration of lipid in the lipid surface layer. An in vitro fluorescent probe study shows components in tears bind to the surface of tear film lipids. If similar interactions occur in vivo at the tear film lipid–aqueous interface, they would reduce the rate of evaporation. Mucins, lysozyme, lipocalin and other proteins present in tears could potentially bind to tear film surface lipids.
Changes occurring with disease
The most characteristic clinical change associated with lipid abnormalities of the eyelid and tear is tear film instability. Tear film instability is a hallmark feature of dry-eye disease as well as MGD. Tear breakup time of less than 2–3 seconds often accompanies dry eye and MGD compared to normal tear breakup times of greater than 10–20 seconds. This functional disturbance seen in dry-eye disease can be due either to inadequate volume of secreted aqueous tear that is below that necessary to sustain the normal evaporative rate (aqueous-deficient dry eye), or to overly rapid evaporation of the tear film (evaporative dry eye). In the case of MGD, the functional disturbance of tear film instability is most likely due to increased evaporation of the tear film.
In 18 of 20 patients with meibomian dysfunction, an infrared study showed lipid order (stiffness) increased ( Figure 17.2 ). As discussed in the previous paragraph regarding lipid melting, stiffer meibum lipid could impede the flow of meibum, resulting in less lipid on the lid margin, creating a higher rate of tear evaporation ( Box 17.4 ).
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Clinically, the most prominent change of the tear film is decreased stability
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This decreased stability is associated with increased evaporation of tears
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In 18 of 20 patients with meibomian dysfunction, infrared study showed lipid order (stiffness) increased in meibomian gland secretion ( Figure 17.2 )
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In patients with meibomitis, breakdown of the more complex lipid structures (triglycerides) into diglycerides and increased free fatty acids proves irritative to the tissues and ocular surface
Specific abnormal polar lipids have been reported in meibum of patients with dry eye associated with meibomianitis by chromatography techniques, but the precise meaning of such findings is unclear, since subsequent mass spectroscopy studies have shown very little polar lipid in meibomian secretion.
Clinical manifestation of disease: dry-eye disease and meibomian gland disease
The most common clinical manifestations of abnormality of the lipids in the eyelid and tear film are evaporative dry-eye disease and MGD. Dry eye is etiopathologically categorized into aqueous production-deficient or evaporative dry eye. The evaporative aspect of dry eye occurs in many dry-eye sufferers and the most common cause of evaporative dry eye is meibomian gland dysfunction. Dry-eye disease has been documented by numerous epidemiological studies to affect 7–30% of the older (>55 years) population depending upon geographic location. It is more frequent in women, particularly those who are postmenopause.
Several clinical studies have identified MGD as a frequent problem in the general population, with prevalence at 39% of patients ( Box 17.5 ). MGD occurs most frequently in older men but also affects postmenopausal women. MGD is often a major reason for discontinuing contact lens wear.
Congenital absence
Dystichiasis
Obstructive
Simple
Epithelial hypertrophic plugging
Inspissated meibomian secretion
Cicatricial
Postinflammatory
Medication-induced (13- cis retinoic acid; chlorobiphenyls)
Hypersecretory
Meibomian seborrhea
Rosacea
The clinical characteristics of meibomian gland disease
MGD includes a broad spectrum of etiopathogenic events that are discussed in depth elsewhere. Nonetheless a brief synopsis identifies the most common pathogenic events as obstructive, hypersecretory, infectious, inflammatory, or obliterative ( Table 17.2 ). Obstructive disease can occur due to hypertrophy of the epithelium lining the orifice of the meibomian gland or due to inspissation of the secretion produced ( Figure 17.3 ). Clinical evaluation of the abnormal secretions is usefully described as clear, turbid, turbid with clumps, or solid (paste-like). Associated inflammatory changes include telangiectasis of the eyelid margin or more severe changes of notching, dimpling, or scarring of the eyelid margin if the disease has been chronic ( Figure 17.4 ). Since the meibomian eyelid secretions are a rich cholesterol-containing culture medium for bacteria, stasis of the secretions can be accompanied by bacterial superinfection, most commonly by Staphylococcus species. Such focal infections can produce hordeola (styes) of the eyelid with associated swelling, erythema, and pain ( Figure 17.5 ). A more chronic inflammation due to the stasis of the lipid secretion in the meibomian glands is a lipogranulomatous reaction (chalazion) that is probably due to breakdown of the complex lipids into more inflammation-provoking small digylcerides and free fatty acids ( Figure 17.6 ).
