Effects of short-term oral vitamin A supplementation on the ocular tear film in patients with dry eye

Introduction

Vitamin A is a mixture of retinol, retinal, and retinoic acid (Figure 1) along with other components such as β-carotene.¹ The most common animal sources for vitamin A are cod liver oil, liver, butter, cheese, eggs, and fish, whereas the most common vegetable sources include sweet potato, carrot, broccoli, sweet red pepper, spinach, and lettuce. Retinol and carotene are the most common forms of vitamin A in food.² Vitamin A is essential for good vision, growth, reproduction, bone metabolism, gene transcription, and immune health.³ Moreover, vitamin A in the form of retinal combines with opsin to produce rhodopsin in the retina, which is important for both color and scotopic (low-light) vision.⁴

Figure 1 Chemical structure of vitamin A.

Vitamin A deficiency is very common in children aged <5 years. It affects around a third of the pediatric population worldwide and causes blindness in 250,000–500,000 children in developing countries each year.^5,6 A previous study found that a diet containing low levels of vitamin A was found to be the main cause for night blindness among soldiers in the American civil war.⁷ Vitamin A deficiency can also lead to corneal dryness (xerosis), keratomalacia, and corneal ulceration, which are very common in children with poor diets.⁸ The deficiency can occur as a primary or secondary deficiency. The former type is common in adults and children with an inadequate intake of vegetables, fruits, and dairy products, while the second type is associated with chronic alcoholism, smoking, and malabsorption of lipids. Furthermore, zinc is necessary for the metabolism of vitamin A, and its low uptake can lead to vitamin A deficiency.⁹ A previous study found that a supplement containing vitamin A along with zinc could lower the risk of malaria and fever in African children.⁹ Therefore, children should essentially receive a nutritional diet that contains adequate amounts of vitamin A in order to avoid health problems.^10,11

Tear film stability is very important for eyes to remain healthy and moist and to prevent dryness.^12–14 The tear film consists of mucin, water, and lipid layers;^15,16 however, its precise structure, function, and biophysical and biochemical properties are complex.^17–20 Early detection of any tear film instability is necessary for maintaining the patient’s quality of life and preventing dryness-related discomfort. Although a variety of diagnostic methods for dry eye are available, some of them are not suitable for clinical use.²¹ Dry eye should ideally be diagnosed using a combination of various tests rather than any single test. Measurement of the tear break-up time (TBUT) is one of the most common diagnostic tests for evaluation of the tear film quality.²² Meanwhile, assessment of tear film osmolarity provides information about tear dynamics and hyperosmolarity.²³ The tear ferning (TF) test is also an effective technique for assessing the quality of tears and diagnosing eye dryness.^24,25 The tear volume is most commonly measured using the Schirmer test and/or the phenol red thread (PRT) test.²⁶ In addition, evaluation of tear evaporation rate is an efficient technique to detect dry eye syndrome.²⁷ Dry eye-related questionnaires such as the McMonnies questionnaire and Ocular Surface Disease Index can be additionally used with all the above-mentioned tests.¹⁴ In the present study, we investigated the effects of short-term oral vitamin A supplementation on the quantity and quality of tears in patients with dry eye as a continuation of our extensive research on the human tear film.^28–34 The TF test based on the five-point grading scale²⁴ was used for the first time to assess the effect of short-term vitamin A supplement on the quality of tears.

Materials and methods

Subjects

This study included 30 male patients with dry eye (age range, 18–38 years; mean age, 25.2±2.8 years) who did not wear contact lenses or exhibit any systemic or ocular diseases other than dry eye. A control group including 30 age-matched men (mean age, 24.5±2.3 years) with healthy eyes was also recruited. The exclusion criteria for the control group included smokers, diabetes, and subjects who had recent ocular surgeries, consumed medication, and abnormalities of the eyelids and lashes. A slit lamp was used to examine the external and anterior portions of the eye in order to rule out ocular diseases, while the McMonnies questionnaire was used to evaluate dry eye; the cutoff score for dry eye was 14.5. All subjects received a vitamin A supplement orally at a daily fixed dose of 1,500 mg (5,000 IU) for 3 consecutive days,³⁵ between 8:00 and 9:00 am. Such a dose is considered acceptable by the National Health Institute.³⁶ Vitamin A tablets were purchased from Solgar UK Ltd. (Aldbury, Hertfordshire, UK). The PRT test was performed along with assessments of TF, tear osmolarity, and TBUT before and 24 hours after the third dose of the vitamin A supplement. The tear sample was collected prior to the PRT test to avoid bias, followed by tear osmolarity test and finally the TBUT test was conducted. A 10-minute interval was observed between the different tests.³⁰ This study followed the tenets of the Declaration of Helsinki, and written informed consent for study participation was obtained from all subjects after an explanation about the nature of the research was provided. Ethical approval was obtained from the Ethics Committee at the College of Applied Medical Sciences, King Saud University.

PRT test

The PRT test was performed once for the left eye of all subjects. A sterile cotton thread treated with the pH indicator phenol red was inserted in the lower lid and removed after 15 seconds for measurement of the red portion. The cutoff value for dry eye was <10 mm.²⁸

TF test

The TF test was performed one time for the left eye. A tear sample (1 μL) was collected from the lower meniscus of the eye using a glass capillary tube (10 μL) and was dried on a glass slide for 10 minutes (23°C, <40% humidity). Tear ferns were observed under a digital microscope (Olympus DP72, ×10 magnification; Olympus Optical Co., Ltd., Tokyo, Japan) and TF grades were assigned.²⁴

Tear osmolarity test

Tear osmolarity was measured once for the left eye using the TearLab™ osmolarity system (TearLab™ Corp., San Diego, CA, USA). A value of 298–302 mOsm/L was considered normal.²⁹

TBUT test

TBUT was measured to assess the tear film stability. Fluorescein was instilled into the subject’s left eye, and the subject was instructed to refrain from blinking while the tear film was observed. A yellow barrier filter was used to enhance the visibility of the tear film break-up. TBUT was recorded as the number of seconds that elapsed between the last blink and the appearance of the first dry spot in the tear film. The measurement was performed in both eyes three times, and the average time was recorded. The cutoff value for dry eye is <10 seconds.³⁷

Statistical analysis

All collected data were recorded in Microsoft Excel 2010 (Microsoft Office, Microsoft Corp., Redmond, WA, USA) and statistically analyzed using SPSS software, version 22 (IBM, Armonk, NY, USA).

Results

TF and PRT data for the dry eye group were not normally distributed (Kolmogorov–Smirnov test, P<0.05) and are presented as medians (interquartile ranges). In contrast, McMonnies scores, and osmolarity and TBUT values showed normal distribution (Kolmogorov–Smirnov test, P>0.05) and are presented as mean ± SDs. In the control group, TF and osmolarity data were normally distributed (Kolmogorov–Smirnov test, P>0.05), while McMonnies scores and values for the PRT test and TBUT were not normally distributed (Kolmogorov–Smirnov test, P<0.05). The TF grades, PRT, TBUT, and osmolarity values for the study and control groups are shown in Tables 1 and 2, respectively.

Table 1 TF grades, PRT test results, TBUT values, and osmolarity values for patients with dry eye who received short-term vitamin A supplementation Notes: *Statistically significant difference (P<0.05) between pre- and post-supplementation values. TF and PRT test values are presented as medians (interquartile ranges), while TBUT and osmolarity values are presented as mean ± SD. Abbreviations: PRT, phenol red thread; TBUT, tear break-up time; TF, tear ferning.

Table 2 TF grades, PRT test results, TBUT values, and osmolarity values for individuals with healthy eyes who received short-term vitamin A supplementation Notes: TBUT and PRT test values are presented as medians (interquartile ranges), while TF and osmolarity values are presented as mean ± SD. Abbreviations: PRT, phenol red thread; TBUT, tear break-up time; TF, tear ferning.

The McMonnies scores for the study and control groups were 14.3±5.5 and 6.0 (2.5), respectively. After vitamin A supplementation in the dry eye group, the TF grade was significantly decreased (before vs after: 2.4 [0.5] vs 1.4 [1.1]; Wilcoxon test, P=0.01), while the tear osmolarity value was significantly increased (before vs after: 293.0±8.9 vs 303.0±9.3; t-test, P=0.01). Although the PRT test and TBUT values were higher after supplementation than before supplementation, the differences were not significant (PRT test: Wilcoxon test, P=0.17; TBUT: t-test, P=0.49). In the control group, there were no significant differences in the TF grade (P=0.74), tear osmolarity value (P=0.55), PRT test result (P=0.48), and TBUT value (P=0.18) before and after supplementation. Figures 2 and 3 show representative images of TF obtained before and after vitamin A supplementation for a patient with dry eye and a patient with healthy eyes, respectively, while Figures 4 and 5 show side-by-side box plots for the TF grades and tear osmolarity values, respectively, before and after vitamin A supplementation in the dry eye group.

Figure 2 Images of tear ferning (TF) in the left eye that were obtained before and 24 hours after 3-day vitamin A supplementation for a patient with dry eye. Notes: (A) before vitamin A supplementation; (B) after vitamin A supplementation.

Figure 3 Images of tear ferning (TF) in the left eye that were obtained before and after vitamin A supplementation for an individual with healthy eyes. Notes: (A) before vitamin A supplementation; (B) after vitamin A supplementation.

Figure 4 A side-by-side boxplot for the TF grades before (TF1) and after (TF2) 3-day vitamin A supplementation for patients with dry eye. Note: Statistically significant value at P<0.05. Abbreviation: TF, tear ferning.

Figure 5 A side-by-side boxplot for the tear osmolarity values before (OS1) and after (OS2) vitamin A supplementation for patients with dry eye. Note: Statistically significant value at P<0.05.

Discussion

Dry eye is a complex disease with various causes, and its severity is associated with several factors.³⁸ Vitamins are important for humans, and their deficiencies can lead to various complications, one of them being dry eye. For example, vitamin A can prevent night blindness, exophthalmia, and dry eye.^39,40 In developing countries, vitamin A deficiency is the main cause for blindness among children.⁴¹ Therefore, in the present study, we examined the effects of short-term oral vitamin A supplementation on the ocular tear film in patients with dry eye in order to increase awareness about the importance of vitamin A for this patient population. We found that TF grades and tear osmolarity values improved after vitamin A supplementation in most patients with dry eye, whereas PRT test results and TBUT showed no significant changes. These results indicated that vitamin A supplementation is important for maintaining the health of the ocular tear film and can minimize the symptoms of dry eye.

Various studies have suggested an association between eye dryness and vitamin A deficiency.^7,11,42 Vitamin A is an important component for the visual pigments and the integrity of the ocular surface,⁴¹ and it is used in the treatment of peripheral vision loss, age-related macular degeneration, retinitis pigmentosa, and superior limbic keratoconjunctivitis.⁴³ Dry eye disease can result from vitamin A deficiency, with mild deficiency resulting in conjunctival changes and severe deficiency resulting in xerophthalmia.⁴⁴ A healthy and balanced diet contributes to the treatment of such diseases.⁴⁴ In one study comparing orally consumed vitamin A supplements and topically applied vitamin A eye drops for the management of eye dryness, the former were found to last for a longer duration,⁴⁵ and the authors suggested that oral supplements are more effective in the treatment of dry eye syndrome than are commercially available lubricants.⁴⁵ However, topical vitamin A can be used to regulate the proliferation of corneal epithelial cells,⁴³ and topical lubricants have been used for the treatment of keratoconjunctivitis sicca, with a previous study showing a remarkable improvement after 3 months of treatment in 81% of the subjects (n=17).⁴⁶ In another study, topical trans-retinoic acid was found to be effective in the treatment of keratoconjunctivitis sicca.⁴⁷ Thus, vitamin A not only ameliorates the symptoms of dry eye but also enhances the smoothness and stability of the ocular tear film and supports tear production.^45,48 As opposed to the above-mentioned studies, one study showed that oral omega-3 supplements were more effective than were oral vitamin A supplements for the management of dry eye syndrome.⁴⁹ Moreover, it has been shown that some eye drops cause allergy and last only for a short period of time.⁵⁰ However, preservative-free vitamin A drops are more effective than other eye drops in the management of dry eye symptoms.⁴⁴ Finally, vitamin A supplementation for 2 months was also found to be very effective in improving the visual acuity of both eyes and eliminating excessive tearing;⁵¹ therefore, patients with itchy eyes should review their dietary history to ensure adequate intake of vitamin A.⁵¹

Limitations

This study has some limitations. First, the sample size was small, which makes it difficult to generalize the study findings. Second, the supplements were taken at a fixed dose for only 3 days. Further large-scale studies with longer periods of supplementation are required to support the role of vitamin A supplementation in the stability of the ocular tear film in patients with dry eye.

Conclusion

The findings of the present study suggest that short-term oral vitamin A supplementation improves the quality, but not quantity, of tears in patients with dry eye. Thus, oral vitamin A supplementation is important for maintaining the health of the ocular tear film and can minimize the symptoms of dry eye.

Acknowledgment

This project was supported by King Saud University, Deanship of Scientific Research, Research Chairs.

Disclosure

The authors report no conflicts of interest in this work.

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