Prevalence of dry eye disease in autoimmune thyroid disease and the association of dry eye with clinical signs of thyroid associated ophthalmopathy: observational, noncomparative, cross-sectional study

This observational, noncomparative, cross-sectional study was approved by the Institutional Review Board, Research Affairs, King Chulalongkorn Memorial Hospital and Faculty of Medicine, Chulalongkorn University (approval No. 187/55). The protocol was registered at www.clinicaltrials.in.th No. TCTR20130713001. The study adhered to the informed consent regulations (both written informed consent and documented verbal consent in cases of illiteracy) and the principles of the most recent revisions of the Declaration of Helsinki. We recruited patients older than 20 years of age who were diagnosed with AITD, and were treated, and followed in the Endocrinology Unit, Department of Medicine between May 1 and August 31, 2013. All medical records and the patients’ medical history were reviewed. Well-known risk factors for dry eye disease, such as pregnancy, postmenopausal hormone therapy, postradiation of the head or neck region, hematopoietic stem cell transplantation, vitamin A deficiency, androgen deficiency, hepatitis C infection, postexcimer laser surgery, connective tissue diseases, and antihistamine intake within two weeks, were excluded from the study. None of the patients had used any eye drops within 48 h before the ocular examinations. We enrolled 92 patients. Ocular examination was performed to verify dry eye by using the Ocular Surface Disease Index (OSDI) Thai version-questionnaire, Schirmer test, tear break-up time (TBUT), fluorescein staining of the ocular surface, and meibomian glands were inspected by a corneal specialist (RU), and fluorescein staining of the ocular surface. Meibomian glands were inspected by a corneal specialist (RU), then followed by an oculoplastic specialist (TS) to establish thyroid eye signs. Demographic data were gathered, and ocular disease or systemic disease history was elicited. The onset, duration, diagnosis and treatment of autoimmune thyroid disease were also recorded.

Dry eye in the study was defined as an OSDI score of >20%, TBUT <10 s, ocular surface staining (Oxford schema; panels B–E), and Schirmer test of <5 mm. The appearance of meibomian glands was examined and the quality of meibum. Meibomian gland dysfunction (MGD) was graded as none, mild, moderate, or severe. Thyroid eye examination was performed and classified into activity score and severity adhered to the consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy [8]. Statistical analysis used the SPSS for Windows (version 17.0, SPSS, Chicago, IL, USA). Prevalence of dry eye disease in AITD was reported as percentage, and 95% confidence interval. The association between variables was determined using a Chi-square test, and multiple logistic regression was used to determine risk factors for dry eye and AITD. P < 0.05 was considered to be significant.

There were 92 patients (184 eyes), 76 women and 16 men with a ratio of 4.75 to 1. The age range was 20-70 years with the mean age of 43.6 years old (SD 11.3). We diagnosed 88 patients (96%) with Graves’ disease, 4 patients (4%) with Hashimoto’s thyroiditis. Euthyroid status was found in 38 patients (41%), 21 were hyperthyroid (23%), and 33 were hypothyroid (36%). A disease duration of 1-5 y was found in 39 patients (42%). About one-third (62 out of 184 eyes, 34%) had no thyroid eye sign. Of the remaining (122 eyes, 66%), 50% had one thyroid eye sign, the other half had multiple eye signs. Most cases (136 out of 184 eyes, 74%) were inactive, in which clinical activity score was 0/7, the remaining 48 eyes (26%) had activity score ≤2. A mild degree severity was found in 115 eyes (63%), only 29 eyes (16%) had a moderate-to-severe form. The ocular manifestations were ptosis (MRD1 <4) in 59 eyes (32%), eyelid swelling in 42 eyes (23%), proptosis and eyelid retraction were equally found in 35 eyes (19%), lagophthalmos in 19 eyes (10%), strabismus in 14 eyes (8%), and conjunctival injection in 12 eyes (7%). The prevalence of dry eye in all 92 AITD patients is shown in Table 1.

By univariate analysis, thyroid eye signs were found to be associated with dry eye in Table 2.

When calculated by multiple logistic regression only proptosis was shown to be a risk factor in developing superior staining, which represents dry eye (Table 3).

There was an association of dry eye with moderate-to-severe form TAO by TBUT (Table 4).

By multivariate analysis, the association of dry eye with AITD is shown in Table 5.

Only three features in patients with AITD: lagophthalmos, proptosis, and MGD were demonstrated to be risk factors for dry eye. The prevalence of MGD in patients with AITD was 68% (125/184 eyes) (95% CI, 61-75), but there was no significant difference in MGD between AITD patients with and without TAO (P = 0.53), and also within the subgroup analysis of the severity (P = 0.65) (data not shown).

In the present study, women with AITD were more numerous than men with the disease. The sex ratio was similar to previous studies, which were approximately 5-10:1 and the age range in AITD is typically between 20 and 50 years [9, 10]. Patients may present without or with ocular symptoms or signs. The present study found that the prevalence of dry eye in AITD was 96% by TBUT, but only 27% by OSDI criteria. We showed higher prevalence of dry eye revealed by TBUT when compared to previous studies showing the prevalence in normal populations with different criteria [11, 12]. However, even excluding patients with risk factors highly suggestive of dry eye in the present study, we still needed an age and sex matched design to avoid confounding factors when comparing dry eye in patients with AITD and normal populations. The criteria for clinical symptoms of dry eye by OSDI are less than for TBUT and ocular surface staining criteria, which might reflect subclinical dry eye in patients with AITD. Gupta et al. [13] reported occult thyroid eye disease in patients presenting with dry eye symptoms. Interestingly, ptosis was found in 32%, which was not consistent with the characteristics of TAO and was unanticipated. However, this could be a racial characteristic associated with small orbits, or involutional ptosis because of age ≥30 years old with normal levator function and minimal amount of ptosis (1–2 mm). Similarly, Naseem et al. [14] reported an AITD patient presenting with ptosis, but as a sign of severe Graves’ orbitopathy. Most patients (74%) were inactive (including all strabismic patients who were in the burn-out stage), only 26% were active with activity score of only 2 or less, and 63% had a mild degree of severity. Nowak et al. [15] found that 85% of ocular discomfort in active thyroid orbitopathy came from dry eye proven by TBUT, Schirmer test, and ocular surface staining. Dryness can be caused by evaporation or a reduction in tear secretion. A mechanism that would explain an attenuation of tear secretion is lacrimal gland impairment because of the attack of autoantibodies to the thyroid-stimulating hormone receptor found in lacrimal glands [16, 17]. The prevalence of dry eye shown by a Schirmer test in the present study was only 18%. We need to consider that, according to the International Dry Eye Workshop definition, dry eye is a multifactorial disease and the Schirmer test alone is not adequate to evaluate dry eye disease. Many patients might present with tearing secondary to a continuous reflex corneal irritation because of increased palpebral height. Therefore, Schirmer measurements are not especially reduced in these patients. Considering this, there is evidence that patients without excessive exophthalmos might suffer from diminished corneal sensitivity because of the ocular surface inflammation, which could satisfactorily explain the occult character of the dry eye disease in Graves’ ophthalmopathy [18, 19]. Dry eye in AITD was also found to be associated with lagophthalmos by ocular surface staining with an OR of 5.8, and TAO with proptosis had OR of 9.3. Lagophthalmos, which usually accompanies proptosis caused more exposure of the eyeball, results in dryness. Iskeleli et al. [20] also found that dry eye in thyroid ophthalmopathy was related to increased palpebral fissure width and proptosis, resulting in increment of tear film osmolarity and decrement of TBUT. Although strabismus was significant in univariate analysis by OSDI, we could not elucidate how the patients were getting dryness; they might be getting discomfort from the strabismus and misreported this as having dry eye. The present study showed the association of dry eye in AITD with lagophthalmos, proptosis, and MGD. These three features appear to be risk factors for dry eye in patients with AITD and TAO. However, dry eye seems to be present even in mild active disease and occult disease, which is difficult to diagnose. It might be beneficial to schedule a routine eye examination both for thyroid severity and activity, and for the ocular surface dryness test to prevent severe ocular inflammation and ocular surface damage. The prevalence of MGD, which was found as a risk factor in AITD, was 68%. MGD might be a coincidence, or it could be sequelae of inflammation in AITD. We found greater association of dry eye in the moderate-to-severe group than in the group with a mild degree of AITD with TAO, which represented more exposure from proptosis as shown by superior staining, but not with eyelid retraction. However, according to the primary objective in reporting the prevalence of dry eye in AITD, the sample size and study design might not be appropriate in verifying the association of dry eye disease and the thyroid eye signs because of the wider range of the confidence interval. Another limitation was a nonhomogenous population of AITD patients with different stages and activity of the disease. More subjects should be included and a subgroup analysis should be performed to clarify these points.

The prevalence of dry eye varied by the criteria setting. There was no significant difference in dry eye between AITD with and without TAO. Proptosis and lagophthalmos were more strongly associated with dry eye disease in AITD with TAO.