Abstract
Purpose:
Dry eye is a prevalent disorder of tear film resulting from either decreased tear production or increased tear evaporation. It is becoming a serious issue due to its disturbing symptoms, which become progressively troublesome affecting the work efficiency of patients and increasing financial burden due to lifelong dependency on eye drops. If not detected early, it can lead to sight-threatening complications. This study aims to explore serum vitamin D3 deficiency as a causative factor of dry eye.
Methods:
The study was conducted in the outpatient department of a tertiary care hospital in India, for a period of two years from September 2018 to September 2020. About 40 patients who had dry eye and 20 controls were enrolled in this study. They were given an Ocular Surface Disease Index (OSDI) questionnaire, examined for signs of dry eye on slit lamp with Schirmer’s test and tear film break-up time. All 60 participants were subjected to serum vitamin D3 level laboratory test and its deficiency prevalence was correlated with dry eye and its severity.
Results:
Serum vitamin D3 deficiency was found to be more prevalent in patients with dry eye. There was no gender predilection or change in prevalence with increasing age. Vitamin D3 level was negatively correlated with OSDI and positively with Schirmer’s test 1 and 2 and tear film break-up time (TBUT) scores.
Conclusion:
The prevalence of vitamin D3 deficiency was not consistently found to be associated with the increasing severity of dry eye.
Keywords: Dry eye, OSDI, vitamin D3
Dry eye disease is one of the most common reasons for patients to visit an eye care professional. We are today better equipped to treat dry eye, with the ever-increasing number of patients presenting, continuously changing lifestyles and the development of newer diagnostic instruments. A better understanding of the key presenting symptoms, external and systemic factors contributing to dry eye, and the ideal battery of tests, helps in the early diagnosis of this chronic condition with more efficient and effective treatment with long-term patient satisfaction.
The term used commonly to denote dry eye in clinical practice is “keratoconjunctivitis sicca.” Also known as dry eye syndrome (DES), dry eye disease, chronic dry eye disease, or keratitis sicca, it refers to disorders of the tear film caused by reduced tear production, poor tear quality, or excessive tear evaporation.[1-3] These disorders are associated with such symptoms of ocular discomfort as irritation, foreign body sensation, or redness, and may cause disease of the ocular surface.[4]
It can be caused by deficiency of any one or more of the tear film components or can be a component of systemic diseases, including Sjögren’s syndrome, lupus, and Stevens-Johnson syndrome. Additionally, factors such as contact lens wear and adverse environmental exposures such as arid environments, windy conditions, or visual tasking can exacerbate the symptoms of dry eye. It is estimated that nearly 75% of people over 65 will experience DES.[5] Blepharitis, meibomian gland dysfunction, eyelid deformity, and conjunctivochalasis are known risk factors for DES. Systemic diseases associated with DES include diabetes mellitus, rheumatoid arthritis, depression, anxiety, thyroid disease, allergic diseases, irritable bowel syndrome, chronic pain syndrome, and hyperlipidemia.[6]
Recently, vitamin D deficiency has been suggested to be a contributory factor in DES. An association between DES and serum 25-hydroxyvitamin D (25(OH) D) concentration has been suggested.[7] It has been reported that vitamin D plays an immunomodulatory role in innate and adaptive immunity. Vitamin D and the vitamin D receptor (VDR) regulate several genes involved in inflammation, immunity, cellular proliferation, differentiation, and apoptosis.[8] It has also been found that fat-soluble vitamins such as vitamin D, may have a role in the pathogenic immunoregulatory process of primary Sjögren’s syndrome (PSS). Vitamin D supplementation is suggested for chronic autoimmune diseases. Low levels of vitamin D may be related to low-complement components and the presence of cryoglobulins in predicting the eventual development of lymphoma in patients with Sjögren’s syndrome.[9]
Our study attempts to evaluate vitamin D3 deficiency in patients with primary DES and establish an association if any.
Methods
This cross-sectional study was conducted in the outpatient department at a tertiary care hospital, on 60 subjects out of which 40 were diagnosed cases of DES and 20 were control subjects who did not have dry eye. It was a two-year study from September 2018 to September 2020. Ethical clearance was taken from the review board of the ethical committee of the institute.
Inclusion criteria included all patients aged between 18 and 45 divided into two groups; clinically proven dry eye (as diagnosed by standard clinical tests) who were in the test group, otherwise in the control group.
Dry eye secondary to ocular surgery, ocular surface pathologies like burns, chemical injury, or systemic illness were excluded.
Serum vitamin D3 levels were investigated in all patients. Data from the test group were compared to the control group to analyze any statistical significance of the prevalence of vitamin D3 deficiency in patients with dry eyes.
Written informed consent was taken before enrolling the patients in the study. An Ocular Surface Disease Index (OSDI) questionnaire was administered to all participants to assess the symptoms of dry eye and correlate them with the signs.
A complete slit-lamp examination of the lid margins, tear meniscus, conjunctiva, cornea, and tear film was done. A relevant examination of other important ocular structures was done. Following this, tests for the dry eye were performed to assess the severity.
-
Schirmer’s test: This test was performed before the other tests, as it had to be done before the instillation of anesthesia.
Measurements of <10 mm were considered to be positive.
Readings >/=10 mm were considered as negative.
Tear film break-up time (TBUT): The TBUT is the time in seconds between the last blink and the appearance of the dry spot.
A break-up time of less than 10 s was considered positive, indicative of dry eye. Greater than or equal to 10 s was considered negative.
Results
Characteristics of the study population can be seen in Table 1. Of the 60 total patients, 40 patients had dry eyes and 20 with no dry eyes. Also of the total study subjects, 26 were seen to have a deficiency of serum D3, while the rest 34 were found to have normal serum D3 levels.
Table 1.
Characteristics of the study population
| Characteristics | Number |
|---|---|
| Total number of patients | 60 |
| Test group patients (Dry eye present) | 40 |
| Control group patients (Dry eye not present) | 20 |
| Patients deficient in serum vitamin D3 | 26 |
| Patients not deficient in serum vitamin D3 | 34 |
Table 2 shows the distribution of serum vitamin D3 in the test group versus the control group. While 55% of subjects in the test group had D3 deficiency, only 20% of control subjects had the same.
Table 2.
Data qualitative analysis
| Participants with vitamin D3 deficiency | Participants with optimal vitamin D3 | Total number | |
|---|---|---|---|
| Test group | 22 (55%) | 18 (45%) | 40 (100%) |
| Control group | 4 (20%) | 16 (80%) | 20 (100%) |
| 60 |
Fig. 1 shows the mean age among the control group to be 39.6 and among the test group 37.12; not statistically different between both groups to exclude any age bias in the study.
Figure 1.
Age-wise distribution
The gender ratio was intended to be kept 1:1 in both the control and test group to exclude any gender bias in the study as can be seen in Table 3.
Table 3.
Gender-wise distribution
| Gender | Group C (n=20) | Group T (n=40) |
|---|---|---|
| Male | 10 (50%) | 19 (47.5%) |
| Female | 10 (50%) | 21 (52.5%) |
| Total | 20 (100%) | 40 (100%) |
| P | 0.8558 | |
The mean OSDI score in the test group was 30.11 and 9.67 in the control group [Table 4]; statistically significant to be higher among patients with dry eye (as diagnosed with objective tests such as Schirmer and TBUT test). OSDI scores were correlating with objective test values of the Schirmer test and TBUT test. This suggests the usefulness of the OSDI index in diagnosing primary dry eye in absence of objective tests.
Table 4.
OSDI score-wise distribution
| Group C (n=20) | Group T (n=40) | |
|---|---|---|
| Mean OSDI Score | 9.67±3.39 | 30.11±8.59 |
| P | <0.0001 | |
As indicated in Fig. 2, out of 40 test group patients, 6 patients (15%) had mild dry eye, 23 patients (57.5%) had moderate dry eye, and 11 patients (27.5%) had severe dry eye; indicating moderate dry eye to be statistically commoner than the mild and severe dry eye.
Figure 2.
Severity-wise distribution of dry eye
Patients in the test group had mean Schirmer 1 values of 9.85 in the right eye and 9.85 in the left eye, patients in the control group had mean Schirmer 1 values of 18.8 in the right eye and 18.45 in the left eye, indicating no statistical difference of Schirmer 1 values among right and left eye. This can be seen in Fig. 3.
Figure 3.
Schirmer 1 test
Patients in the test group had mean Schirmer 2 values of 7.2 in the right eye and 7.25 in the left eye while patients in the control group had mean Schirmer 2 values of 15 in the right eye and 15.3 in the left eye, indicating no statistical difference of Schirmer 2 values among right and left eye in both groups. This can be seen in Fig. 4.
Figure 4.
Schirmer 2 test
Fig. 5 shows the TBUT in both groups with individual eye distribution. Patients in the test group had a mean TBUT of 7.97 in the right eye and 8.1 in the left eye, patients in the control group had a mean TBUT of 15.5 in the right eye and 15.65 in the left eye, indicating no statistical difference of TBUT values among right and left eye.
Figure 5.
TBUT-wise distribution
Mean serum vitamin D3 levels are significantly lower in the test group than in the control group with a P value <0.0001. 45% of total test group patients had serum vitamin D3 levels <10 ng/ml which suggests a strong correlation of deficiency of serum vitamin D3 in patients with primary DES [Table 5 and Fig. 6].
Table 5.
Vitamin D3-wise distribution
| Group C (n=20) | Group T (n=40) | |
|---|---|---|
| Vitamin D3 (ng) | ||
| 0-10 | 4 (20%) | 18 (45%) |
| 11-20 | 1 (5%) | 4 (10%) |
| 21-30 | 2 (10%) | 0 |
| 31-40 | 1 (5%) | 4 (10%) |
| 41-50 | 2 (10%) | 7 (17.5%) |
| 51-60 | 7 (35%) | 5 (12.5%) |
| >60 | 3 (15%) | 2 (5%) |
| Mean Vitamin D3 (ng) | 41.19±21.42 | 27.49±21.25 |
| P | <0.0001 | |
Figure 6.
Vitamin D3-wise distribution
The prevalence of the vitamin D deficient population was found to be statistically increasing with increasing levels of OSDI scores with a P value of 0.001, suggesting increasing levels of patient discomfort and other dry eye symptoms with associated vitamin D deficiency. This indicates the possible role of vitamin D as a treatment option in patients with dry eyes with high OSDI scores [Table 6 and Fig. 7].
Table 6.
Prevalence of vitamin D deficiency among different OSDI score range
| OSDI | Prevalence of Vit D3 Deficiency in the control group | Prevalence of Vit D3 Deficiency in the test group |
|---|---|---|
| 0-12 (Normal) | 30.8% | - |
| 13-22 (Mild) | 14.28% | 36.66% |
| 23-32 (Moderate) | - | 43.47% |
| 33-100 (Severe) | - | 63.63% |
Figure 7.
Prevalence of vitamin D deficiency among different OSDI score range
As seen in Fig. 8, mean serum vitamin D3 levels were significantly lower among the test group than the control group with a P value less than 0.0001. However, serum vitamin D3 levels were not found to be decreasing consistently with increasing severity of dry eye.
Figure 8.
Vitamin D3 with the severity of the dry eye
Discussion
The prevalence of male to female ratio was the same in both control and test groups; 19 males and 21 females in the test group and 10 males and 10 females in the control group. The mean age for the control group was 39.6 and the mean age for the test group was 37.12. This ruled out any gender or age-based bias for the study.
OSDI scores were significantly associated with an objective test for dry eye, Schirmer’s test, and TBUT. An OSDI scoring of 67–100 which corresponds to the severe dry eye was found to correlate significantly with objective tests of dry eye (P = 0.006). Similar findings were noted by Ozcura et al.[10] who evaluated the OSDI questionnaire for the diagnosis of dry eye and found a significant inverse correlation between OSDI and TBUT scores. The mean OSDI score for the control group was 9.67 ± 3.39 and for the test group was 30.11 ± 8.59. OSDI was found to be a reliable measure of dry eye symptoms. Higher scores of OSDI, indicating severe dry eye, correlated well with diagnostic tests for dry eye.
Out of 40 test group patients, 15% had mild dry eye, 57.5% had moderate dry eye, and 27.5% had a severe dry eye. The mean Schirmer 1 score in the control group was 18.8 ± 2.01 for the right eye and 18.45 ± 2.06 for the left eye. The mean Schirmer 1 score in the test group was 9.85 ± 1.31 for the right eye and 9.85 ± 1.38 for the left eye. Results of the Schirmer 1 test in the test group were statistically significant to be lower than the control group with a P value < 0.0001.
The mean Schirmer 2 test in the control group was 15 ± 2.19 for the right eye and 15.3 ± 2.21 for the left eye. The mean Schirmer 2 test in the test group was 7.2 ± 1.63 for the right eye and 7.25 ± 1.61 for the left eye, being statistically significant to be lower than the control group with a P value < 0.0001.
The mean TBUT of the control group was 15.5 ± 2.41 in the right eye and 15.65 ± 2.32 in the left eye. The mean TBUT of the test group was 7.97 ± 1.34 in the right eye and 8.1 ± 1.33 in the left eye, which was statistically significant to be lower than the control group with a P value < 0.0001.
In our study, the mean serum vitamin D3 level was 41.19 ± 21.42 ng/ml in the control group and 27.49 ± 21.25 ng/ml in the test group, which was significantly lower than the test group with P value < 0.0001; more so in lower ranges of serum vitamin D3 levels. The maximum number of patients belonged to the serum vitamin D3 level of 0–10 ng/ml range, out of which 4 belonged to the control group and 18 belonged to the test group. The mean serum vitamin D3 level in mild dry eye patients was 20.66 ± 19.18 ng/ml, 31.43 ± 20.72 ng/ml in moderate dry eye patients, and 22.99 ± 23.37 ng/ml in severe dry eye patients. The correlation of the severity of dry eye with the level of serum vitamin D3 was found to be not significant. However, the prevalence of dry eye was significantly associated with low levels of serum vitamin D3 levels.
The above findings are consistent with the Turkish study[11] of 2018, in which the Schirmer I test and TBUT results in group 1 (8.5 ± 3.7 mm and 8.7 ± 0.6 s, respectively) were significantly lower compared with group 2 (16.6 ± 2.4 and 18.1 ± 0.5, respectively) (P < 0.001 for all). Tear osmolarity values, OSDI, and Oxford scale scores were significantly higher in group 1 (309 ± 9 mOsm/l, 35.78 ± 21.44, and 1.3 ± 0.9, respectively) compared with group 2 (295 ± 10 mOsm/l, 18.69 ± 17.21, and 0.4 ± 0.8, respectively) (P < 0.001 for all).
Results were also consistent with the Turkish study[12] of 2013, in which the mean TBUT were 5.18 ± 2.15 and 7.36 ± 3.10 and Schirmer scores were 12.18 ± 6.44 and 18.57 ± 8.99 mm in the study and control groups, respectively. TBUT scores and Schirmer 1 results of the study group were significantly lower than the control group (P = 0.01 and 0.007, respectively). The mean vitamin D levels were 11.50 ± 1.8 ng/ml in the study group and 32.8 ± 8.72 ng/ml in the control group (P = 0.001).
Unlike the Korean[13] and Australian[14] interventional study of 2018, in which vitamin D3 supplements were given to patients with a refractory dry eye and TBUT and tear secretion test showed an improvement at 2 and 6 weeks after vitamin D supplementation compared to pretreatment values (P < 0.05 for all, paired t-test), our study being cross-sectional analysis of a set of patients, cannot comment upon effectiveness and treatment possibility of dry eye with vitamin D3 supplements. Conjunctival congestion and corneal dryness were the most common signs observed. 65.6% of the patients with conjunctival congestion showed evidence of dry eye. The association between dry eye and conjunctival congestion was found to be statistically highly significant (P = 0.001). Our findings correspond to those of Srinivas et al.[15] who also found an increased incidence of bulbar hyperemia in women with dry eye. It may be used as one of the diagnostic signs for screening for evidence of dry eye instead of directly performing the tests. Corneal dryness, though noted to be high in our study, is subject to inter-observer variability and not recommended. We could not find other studies looking for signs of dry eye performed recently.
Conclusion
In our study, vitamin D3 deficiency was found to be more prevalent among patients with dry eyes than patients who did not have dry eyes, indicating a possible association between vitamin D3 deficiency and dry eye. However, serum vitamin D3 levels were not consistent with the severity of dry eye. The possibility of vitamin D3 deficiency as an etiological factor of dry eye and the therapeutic effect of vitamin D3 supplements in DES needs to be further explored with a larger sample study. OSDI index can be utilized as a reliable tool to diagnose dry eye, as it was consistent with subjective findings of dry eye.
Study limitations
Our study is limited by a small study sample and by the virtue of being a cross-sectional study, no follow-up was taken nor any intervention was done. The therapeutic effectiveness of vitamin D3 supplements cannot be commented upon to establish a causal association.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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