Background
Thyroid eye disease (TED), also known as Graves’ ophthalmopathy and thyroid-associated orbitopathy, is an ocular manifestation of a systemic autoimmune disorder. The orbit presents the same antigens as the thyroid gland, such as the thyroid-stimulating hormone receptor, thyrotropin receptor, and insulin-like receptor [
1]. Consequently, for patients with immune-related thyroid dysfunction, the circulating autoantibodies may also attack the orbit by triggering a cytokine cascade and causing orbital fibroblast proliferation, adipose tissue expansion, and glycosaminoglycan secretion [
2]. Finally, patients may develop lid edema, chemosis, lid retraction, exophthalmos, lagophthalmos, restrictive myopathy, and compressive optic neuropathy, and may complain of diplopia and decreased vision [
3].
Dry eye disease (DED) is very common in patients with TED: the prevalence rate of DED in TED is up to 65.2% [
4,
5]. Coulter et al. reported that 97% of patients with TED in a cohort study had dry eye symptoms [
6]. Some underlying mechanisms have been proposed. First, lid retraction, exophthalmos, and lagophthalmos may cause ocular surface changes and blinking abnormalities [
2,
7,
8], which increase the evaporation of tears and lead to DED in patients with TED [
2,
9]. Second, lacrimal acinar cells physiologically express thyroid-stimulating hormone receptors [
10]; thus, the antigen−antibody reaction of TED may impair the lacrimal gland and subsequently result in a decreased volume of reflex tearing [
10,
11]. Third, TED may disturb the secretion of aqueous tears and make the tear film unstable, leading to shorter tear film breakup time and increased tear film osmolality [
7,
10‐
12].
However, increasing evidence indicates that meibomian gland (MG) dysfunction is a major risk factor of DED [
13,
14]. The International Dry Eye Work Shop have classified DED into aqueous tear deficiency (ATD) and evaporative dry eye (EDE) [
15,
16], and recognized MG dysfunction as the primary cause of EDE [
17]. Similar to patients with MG dysfunction, patients with TED usually also have dry eye symptoms. However, previous studies only focused on the ATD in patients with TED but neglected the MG dysfunction in these patients. MGs, which are special sebaceous glands in the eyelids, secrete lipids to stabilize the tear film, decrease the surface tension, and prevent the evaporation of aqueous tears [
18]. MGs are arranged in parallel palisades throughout the tarsus plates of the eyelids, and the blinking motion serves as a pumping force that releases the meibomian lipids, which are formed by meibocytes within the acini, onto the lid margin [
19,
20]. TED may cause eyelid inflammation, disturb the blinking motion, and gradually change the ocular surface environment as it progresses. Therefore, we hypothesized that TED may influence the performance of MGs, similar to many systemic inflammatory diseases, such as Sjögren syndrome, psoriasis, and rosacea [
21‐
24], causing MG dysfunction. The aim of the present preliminarily study was to investigate the performance of MGs in patients with TED.
Discussion
The impact of MG dysfunction, the leading cause of DED, on patients with TED, has remained unclear. Interestingly, 27 eyes (87.1%) had signs of MG dysfunction, but the mean age of these TED patients was only 44.7 years (Table
1). We also found that active TED eyes (CAS 2−3) had a higher MGd, but thicker LLT, than inactive TED eyes (CAS 0−1) (Table
2 and Fig.
2). Although active TED eyes had more severe exophthalmos and lagophthalmos, only lagophthalmos was associated with a thicker LLT (Fig.
3). The finding of a thicker LLT, but higher MGd, in active TED suggests not only compensatory activity from the residual MGs, but also that lagophthalmos-mediated forceful blinking is involved. This could be a potential mechanism for decreasing ocular surface injury from the more severe lagophthalmos in active TED.
Active ocular inflammation may cause typical ocular surface changes in TED in patients with thyroid disease [
2]. We hypothesized that active TED would further impede the performance of the MGs in these patients. Although the CAS score proposed by Mourits to reflect the inflammation status of TED ranged from 0 to 7 [
25], only patients with a CAS of less than 4 were included in this study. All patients with CAS exceeding 3 received pulse-corticosteroid treatment, and they were excluded from this study to prevent a possible bias due to this treatment. A flair-up of TED may result in greater extraocular muscle enlargement, and this may be reflected in the greater exophthalmos and lagophthalmos of the active TED eyes in this study (Table
2).
In this study, the mean MGd of TED patients was 2.1 (Table
1), representing about 25−50% loss of MGs. Active TED eyes had significantly greater loss of MGs than inactive TED eyes (Table
2). However, loss of MGs was not associated with the target indices of TED complications (Figs.
3a, b, and c). Several studies have shown a strong association between MGd and inflammatory ocular surface diseases. Mathers et al. reported that patients with chronic blepharitis and giant papillary conjunctivitis demonstrated a greater loss of MGs [
40,
41]. Shimazaki et al. reported that Sjögren syndrome was associated with MG dysfunction [
22]. Knop et al. pointed out that inflammatory mediators could spread and lead to glandular dropout and potentially to acinar atrophy by way of the conjunctiva, through the tarsus and toward the MGs [
42]. Thus, TED-associated ocular surface inflammation might cause periglandular inflammation, and subsequent loss of MGs.
A recent study proposed that a thinner LLT may predict a higher risk of MG dysfunction [
43]. Eom et al. also found that greater loss of MGs is correlated with a thinner LLT [
44]. It is reasonable that a stasis of lipid inside the MGs may increase pressure in the MGs, causing the ducts to dilate, and finally resulting in acinar atrophy [
19]. However, in our study, the active TED eyes showed a greater loss of MGs, but thicker LLT, than the inactive TED eyes (Table
2 and Fig.
2). Additionally, we found a positive correlation between lagophthalmos and LLT (Fig.
3), and active TED eyes had greater lagophthalmos than inactive TED eyes (Table
2). Kim et al. reported that some MGs may be obstructive and atrophic, while other MGs may secrete lipids at normal or enhanced levels to compensate for MG dysfunction, whereby normal LLT is maintained [
45]. Korb et al. found that forceful blinking could increase the LLT [
46]. It is possible that active TED patients had more severe MGd, but thicker LLT, not only as a compensatory effect, but also as a stimulatory effect. The compensatory effect may be induced by MGd, based to some degree on a physiological response from residual MGs, but not on the over-production of lipids. However, patients with more severe lagophthalmos may show more severe punctate erosion on the ocular surface. Additionally, MG disease may increase corneal sensitivity [
47]. Therefore, active TED patients with more severe lagophthalmos may have pathological lipid hypersecretion due to forceful blinks. Patients with TED might blink more forcefully, unconsciously, due to greater lagophthalmos. Although the active TED eyes demonstrated more severe MGd, the mixed compensatory and stimulatory effect may cause temporarily thicker LLT than that seen in inactive TED eyes.
In addition, the function of MGs may be maintained at a certain level, because the loss of MGs is partial (on average 25−50%) even in active TED eyes. Active TED eyes had greater exophthalmos than inactive TED eyes (Table
2 and Fig.
2). Exophthalmos could stretch the eyelid, inducing even higher lid tension and making it easier for the lipids in the MGs to be squeezed out. However, there was no significant correlation between exophthalmos and LLT (Fig.
3).
All but 1 of the patients with TED suffered from dry eye symptoms, as identified on the SPEED questionnaire. Despite the lack of statistically significant difference, lower aqueous tear secretion (ST-1) was found in patients with active TED (9.2 ± 5.6) than in patients with inactive TED and in the normal control group (14.5 ± 10.0 and 13.0 ± 10.2, respectively). These findings were compatible with those of Eckstein et al. [
10], who concluded that ATD may be caused by diminished lacrimal gland function in active TED. The expression of inactive TED may be the same as proposed by Arita et al. [
48], who pointed out that increased tear fluid is produced as a temporary compensatory response to loss of MGs.
There were some limitations in this preliminary study. The non-TED control group may be suitable for comparison with the TED group in our clinical practice, but this control group cannot truly represent a normal population. Some participants in the control group also had dry eye symptoms and inadequate MG performance. Both eyes of bilateral TED patients were pooled with the 3 eyes of the 3 unilateral TED patients. We had found similar results in the analyses of right eyes or left eyes. Although a trend for thicker LLT in active TED was noted, the wide range of standard deviation resulted in a non-significant difference. Thus, we classified both eyes of the same patient into the same CAS group, which might have caused a bias. However, all patients with active TED (CAS 2−3) in our study had ocular signs of similar severity, only 2 patients with inactive TED (CAS 0−1) had single eye involvement. One eye in the active TED group was excluded due to previous eyelid surgery. Furthermore, most patients routinely used eye ointment for lubrication at night. The usage of topical ointment should be more strictly limited to avoid its influence on LLT. The ingredients of an eye ointment might affect the tear film composition, yet all patients had ceased ointment application at least 12 h before examination. Moreover, we set LLT as 100 nm for the 5 eyes with LLT > 100 nm, which may have caused underestimation of the average value of LLT. Because the LipiView® II Ocular Surface Interferometer did not have a sensor to identify the blinking force, we cannot clearly prove the association between LLT and forceful blinks. A further study adopting simultaneous electromyography of the eyelid should be considered to verify this causality. Finally, the small sample size implies that our results should be interpreted with some caution. Subgroup analysis revealed that inactive TED eyes were not significantly different from non-TED eyes in terms of MG performance and LLT, but a trend for greater MGd and thicker LLT was observed between active TED eyes and non-TED eyes. Thus, a small proportion of active TED patients in our subjects might be the reason for the lack of statistically significant differences in many parameters between the TED group and the non-TED group. The performance of MGs in TED patients should be verified in a future study with a larger sample.