Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20

Serum Vitamin D Levels in Patients with Acute

Anterior Uveitis

Zeynep Dadaci MD, Servet Cetinkaya MD, Nursen Oncel Acir MD, Mufide
Oncel MD & Mehmet Borazan MD

To cite this article: Zeynep Dadaci MD, Servet Cetinkaya MD, Nursen Oncel Acir MD, Mufide
Oncel MD & Mehmet Borazan MD (2016): Serum Vitamin D Levels in Patients with Acute
Anterior Uveitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2016.1139735

To link to this article: http://dx.doi.org/10.3109/09273948.2016.1139735

Published online: 22 Mar 2016.

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 Ocular Immunology & Inflammation, 2016; 00(00): 1–5
© Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.3109/09273948.2016.1139735

ORIGINAL ARTICLE

Serum Vitamin D Levels in Patients with Acute

Anterior Uveitis
1
Zeynep Dadaci, MD , Servet Cetinkaya, MD2, Nursen Oncel Acir, MD
1
, Mufide Oncel, MD
3
, and
Mehmet Borazan, MD1

1
Mevlana University School of Medicine, Department of Ophthalmology, Konya, Turkey, 2Ophthalmology
Clinics, Turkish Red Crescent Hospital, Konya, Turkey, and 3Mevlana University School of Medicine,
Downloaded by [University of California, San Diego] at 10:03 25 March 2016

Department of Clinical Biochemistry, Konya, Turkey

ABSTRACT
Purpose: To evaluate serum 25-hydroxyvitamin D levels in patients with acute anterior uveitis (AAU).
Methods: This observational case–control study involved 20 patients with AAU, and 20 consecutive, age and sex-
matched healthy subjects without any ocular or systemic diseases. Serum 25-hydroxyvitamin D was quantified
with electrochemiluminescence technique.
Results: No significant differences were found between the groups with respect to age (p = 0.185) and sex (p =
0.465). Serum vitamin D levels of the subjects with AAU (mean 5.75 ± 4.50 ng/mL, median 4.00 ng/mL, range:
3.00–19.00 ng/mL) were significantly lower than the control group (mean 12.96 ± 5.89 ng/mL, median 11.00 ng/
mL, range: 5.20–25.92 ng/mL) (p<0.001).
Conclusions: We found significantly low serum levels of vitamin D in patients with AAU, which suggest that
vitamin D deficiency may play a role in the pathogenesis of anterior uveitis. Further studies are necessary to
demonstrate the efficacy of vitamin D supplementation in the management of patients with anterior uveitis.
Keywords: Acute anterior uveitis, immune system, pathogenesis, rheumatologic diseases, vitamin D

Acute anterior uveitis (AAU), a common cause of deficiency is reported to be involved in the pathogen-
intraocular inflammation, is a potentially blinding esis of some diseases commonly associated with uvei-
disease. Although AAU is frequently considered as tis such as Vogt–Koyanagi–Harada (VKH) and Behçet
an idiopathic condition,1 a substantial portion of the disease.11,12
patients have associated systemic rheumatologic Although most cases of anterior uveitis can readily
diseases.2 It is reported that more than half of the be treated with topical corticosteroid therapy, a group
patients with AAU carries the allele human leuco- of patients with recurrent AAU or chronic uveitis may
cyte antigen (HLA) B27. However, the majority of have a worse course and regress to blindness.13 The
population positive for HLA-B27 allele will never side-effects of the treatment may give as much harm as
develop AAU.3 the disease itself, and may threaten vision by leading
Vitamin D is mainly synthesized in the skin from to cataract and glaucoma.14 Moreover, the treatment of
cholesterol upon exposure to sunlight and is well both the disease and its complications is associated
known for its effects on skeletal health and calcium with high costs. In a study from Spain, AAU was
homeostasis.4 Recently, upon the discovery of the reg- presented to be among the first three uveitis types
ulatory effects of vitamin D on the immune system,5 associated with highest costs and a burden for the
vitamin D deficiency has been associated with several National Health System.15
chronic health problems, including cardiovascular dis- Decreasing the frequency of uveitis attacks in
ease and hypertension,6 cancers,7 allergies,8,9 and auto- patients with recurrent AAU might be sight-saving.
immune rheumatologic diseases.10 Also, vitamin D Demonstration of a link between vitamin D status and

Received 5 December 2015; revised 30 December 2015; accepted 5 January 2016; published online 18 March 2016
Correspondence: Zeynep Dadaci, Department of Ophthalmology, Mevlana University School of Medicine, Aksinne M., Esmetas S., No: 16,
Meram, Konya, Turkey. E-mail: [email protected]

1
 2 Z. Dadaci et al.

AAU may provide the basis for future studies evaluat- of cellular reaction in the anterior chamber is evaluated
ing the effect of vitamin D supplementation for the by slit-lamp microscopy and graded according to the
prevention of the attacks. Therefore, we aimed to inves- number of inflammatory cells seen in a 1 × 3 mm high-
tigate serum vitamin D levels of patients with AAU and powered beam with maximum light intensity at a
compare them with healthy age- and sex-matched con- 45–60º angle. The reaction is graded as 1+ (5–10 cells),
trols in our preliminary study. We are unaware of any 2+ (10–20 cells), 3+ (20–30 cells), and 4+ (>30 cells).
previous reports demonstrating serum vitamin D levels
in patients presenting with AAU.
Biochemical Analysis

METHODS Fasting venous blood sample was obtained from each

subject from the antecubital vein into the serum
Study Population separator tubes. After centrifugation at 2000 g for 15
min serum samples were aliquoted, labeled and stored
This prospective, observational, case–control study at –20ºC for a maximum of 30 days until analysis.
comprised of 40 subjects (20 patients with idiopathic When we reached the targeted sample size, serum
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or HLA-B27-associated AAU and 20 control subjects). samples were thawed and serum 25-hydroxyvitamin
All patients were recruited in the study between May D levels were quantified with electrochemilumines-
and October 2015, and evaluated at the Mevlana cence technique on Modular Analytics E 170 analyzer
University and Turkish Red Crescent eye clinics. (Roche Diagnostics, GmbH, Germany). Measuring
Patients with signs and symptoms of acute anterior range for 25-hydroxyvitamin D was 3–70 ng/mL
uveitis (conjunctival hyperemia, pain, photophobia, (7.5–175 nmol/L). Between run precision values deter-
flare, and anterior chamber cells) without any evidence mined with analysis of serum pools were as follows:
of posterior segment inflammation were included in the 13.1% for low and 3.4% for high concentrations of 25-
AAU group. Patients with granulomatous, infective or hydroxyvitamin D, respectively.
traumatic uveitis, and known uveitic syndromes were
excluded. The control group was composed of 20 con-
secutive subjects of similar age (18–67 years) and gen- Statistical Analysis
der as the study group, with normal ocular
examination, except refractive disorders, without any Statistical analyses were performed using a statistical
history of systemic diseases, drug or dietary supple- program (SPSS version 15.0, SPSS Science, Chicago,
ment consumption. To minimize cultural influences or IL). The distribution of the numeric data was tested
geographic effects on the findings, the study was con- with the Shapiro–Wilk test. The Mann–Whitney U-
ducted in the central region of Turkey, and all partici- test was used for testing the difference between vita-
pants lived in the same region. The research protocol min D levels for both patient and control groups. The
was approved by the Mevlana University Ethics mean age of groups were compared with the Mann–
Committee (2015/154). The study was performed in Whitney U-test and the distribution of sex between
compliance with good clinical practice guidelines and the groups was compared using the χ2-test with con-
in accordance with the tenets of the Declaration of tinuity correction. All p values <0.5 were considered
Helsinki. Written informed consent was obtained from as statistically significant.
each patient prior to enrollment into the study.
Pregnant or breast-feeding women were excluded
from the study. Subjects with any ocular pathology RESULTS
other than AAU, such as allergic conjunctivitis and
dry eye syndrome, were also excluded. Subjects who In total, 20 patients with AAU (4 men, 16 women) and
were smokers and who had a history of consumption 20 control subjects (6 men, 14 women) were enrolled in
of vitamin supplements or alcohol during the 4 weeks our study. The mean ages of patients with AAU and
prior to the study, and obese patients, were also control subjects were 43.50 ± 16.25 years (range: 18–66
excluded. The associated systemic diseases and the years) and 36.30 ± 13.59 years (range: 18–68 years),
drugs of the patients with AAU were noted and respectively (Table 1). No statistically significant dif-
patients were consulted with internists for systemic ferences were found between the groups with respect
evaluation and vitamin D supplementation. to age (p = 0.185) and sex (p = 0.465).
All subjects underwent a full ophthalmologic exam- All subjects with AAU had an anterior chamber cel-
ination, including: best-corrected visual acuity (BCVA) lular reaction of grade 3+ or 4+. Serum vitamin D levels
obtained with a Snellen projection chart; refraction; slit- (mean ± SD) of the subjects with AAU (5.75 ± 4.50 ng/
lamp biomicroscopy; intraocular pressure (IOP) mea- mL, median 4.00 ng/mL, range: 3.00–19.00 ng/mL) were
surement with Goldmann applanation tonometry; and significantly lower than the control group (12.96 ± 5.89
dilated fundoscopy with a 90 Diopter lens. The intensity ng/mL, median 11.00 ng/mL, range: 5.20–25.92 ng/mL)

Ocular Immunology & Inflammation

 Vitamin D Levels in Acute Anterior Uveitis 3

TABLE 1. Demographic characteristics of the study subjects.

AAU group (n = 20) Control group (n = 20) p value

Age (years; mean ± SD) 43.50 ± 16.25 36.30 ± 13.59 0.185

Sex (male/female) 4/16 6/14 0.465

AAU, acute anterior uveitis; SD, standard deviation.

(minimum detection limit), none of the control subjects

had serum vitamin D levels of ≤3 ng/mL.
In the AAU group, most of the patients had coex-
isting rheumatologic and/or systemic diseases: eight
subjects had fibromyalgia; two had ankylosing spon-
dylitis; and one had gout. There were also seven
patients with systemic hypertension, three with dia-
betes mellitus, and two with asthma. The data of all
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patients in the AAU group are shown in Table 2.

DISCUSSION

This is a novel study evaluating the relationship

between acute anterior uveitis (idiopathic or HLA-
B27 associated) and vitamin D status. Serum levels of
FIGURE 1. Comparison of serum 25-hydroxyvitamin D (ng/ vitamin D in patients with AAU were significantly
mL) levels of patients with acute anterior uveitis (AAU group; lower than the control group. This finding may lead
n = 20) and control subjects (n = 20). The central box covers the
interquartile range, and the horizontal line indicates the median. to the development of new strategies in the manage-
The end of whiskers corresponds to the most extreme observa- ment of patients with recurrent AAU.
tions, and shapes indicate outliers. Uveitis, in general, is reported to be the cause of
about 10% of all legal blindness and may have worse
socioeconomic impact because it commonly affects
(p<0.001) (Figure 1). While 8 out of 20 patients in the younger people.16 The etiology of AAU, which is
AAU group had serum vitamin D levels of ≤3 ng/mL the most frequent form, is largely unclear. To date,

TABLE 2. Data of all patients in the acute anterior uveitis group.

Patient number Gender Age (years) Grade of AC cellular reaction Associated diseases Vitamin D levels (ng/mL)

1. F 58 +3 HT, gout 3.0

2. F 45 +4 Fibromyalgia 3.0
3. F 66 +4 HT, DM, asthma 5.0
4. F 57 +4 HT 3.0
5. F 62 +3 HT 8.0
6. F 57 +4 HT 4.0
7. M 19 +3 – 19.0
8. F 65 +4 HT, DM 3.0
9. F 43 +4 Fibromyalgia 4.0
10. M 39 +4 AS 16.6
11. F 30 +3 Fibromyalgia 5.6
12. F 25 +4 Fibromyalgia 3.0
13. F 20 +4 Fibromyalgia 3.0
14. F 18 +4 Fibromyalgia 4.8
15. M 53 +3 HT 3.4
16. F 62 +3 DM, asthma 3.0
17. F 32 +4 AS 4.6
18. F 37 +4 Fibromyalgia 7.0
19. M 50 +3 – 9.0
20. F 32 +4 Fibromyalgia 3.0

M, male; F, female; AC, anterior chamber; HT, hypertension; DM, diabetes mellitus; AS, ankylosing spondylitis.

© Taylor & Francis Group, LLC

 4 Z. Dadaci et al.

most of the studies in uveitis have focused on genes In the present study, 40% of the subjects with AAU
of the HLA system, especially HLA-B27.17,18 had fibromyalgia. We have not encountered any pre-
However, only a minority of HLA-B27-positive indi- vious studies reporting the frequency of fibromyalgia
viduals will ever develop AAU.3 Today, there is in subjects with anterior uveitis. Fibromyalgia was
growing attention to the interaction between the however, reported to associate with rheumatologic
immune and endocrine system, and vitamin D defi- diseases in the literature and the prevalence of fibro-
ciency has been reported to have a role in the patho- myalgia in patients with Behçet disease was reported
genesis of several autoimmune disorders. Serum as 37.1% in a previous study.28
levels of 1,25-dihydroxyvitamin D3, the active meta- Ours is a pioneer study demonstrating decreased
bolite of vitamin D, were found to be decreased in vitamin D levels in patients with AAU, but there are
uveitis patients with Behçet disease, VKH syndrome, some limitations that should be addressed. First, is the
and ankylosing spondylitis.11,12,19 1,25-dihydroxyvi- low study number. We have however, still demon-
tamin D3, was shown to inhibit Th1 and Th17 cells, strated an obvious difference between the serum vita-
which are believed to have an important role in the min D levels of the patients with AAU and the healthy
pathogenesis of autoimmune disorders.20,21 There controls. Second, we enrolled only subjects with idio-
are also studies demonstrating that 1,25-dihydroxy- pathic or HLA-B27 associated AAU, which is the most
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vitamin D3 could skew the T-cell response to an anti- frequent form, in our study. We did not check for
inflammatory state through inhibition of Th1 and HLA-B27 antigen and grouped the patients. Further
promotion of regulatory T cells.22 studies are necessary to demonstrate the possible asso-
Vitamin D can be obtained from the diet but it does ciation of vitamin D deficiency in other types of uveitis
not naturally occur in most food and its main source is and the efficacy of vitamin D supplementation. Third,
formation in cutaneous tissue following exposure to is that we used an electrochemiluminescence technique
ultraviolet light.4 Although our study was conducted to quantify serum vitamin D levels. This technique
in the sunny period of the year in our region (May– slightly underestimates vitamin D levels when com-
October), we detected very low levels of vitamin D, pared with the liquid chromatography–tandem mass
especially in the AAU group. This is in accordance spectrometry method.29 We believe that this underes-
with studies reporting vitamin D deficiency even in timation should not be important however, as we
sun-replete areas of the world.23 Also, a high fre- analyzed the samples of both groups at the same
quency of vitamin D deficiency and/or insufficiency time and compared the results between the groups.
is reported in healthy Turkish subjects.24 The reason Despite these shortcomings, our preliminary study
for vitamin D deficiency may be the lack of outdoor generates valuable hypotheses and provides a basis
activity, clothing or excess use of sunblock. Also, some for future studies.
medications, especially colchicine, is reported to Although the outcomes of the patients after normal-
associate with lower vitamin D levels.25 In our study, ization of their vitamin D levels were outside the scope
only one patient was using colchicine, which was pre- of the present study, none of the patients in the AAU
scribed recently. group experienced recurrence of uveitis attack after
There is considerable evidence about the immu- vitamin D supplementation during their follow-up.
nosuppressive effect of vitamin D. Vitamin D sup- We think that the positive influence of vitamin D on
plementation has been shown to provide beneficial the immune system might decrease the frequency of
effects in several autoimmune disease models in AAU attacks. We were able to find only one study in
animals.21 There are also clinical studies demon- the literature mentioning the effect of large dose vita-
strating aggravation of symptomatology in pro- min D in chronic uveitis, which was published in
found vitamin D deficiency (<10 ng/mL) and 1956.30 Further studies are necessary to define the
beneficial effect of vitamin D supplementation in role of vitamin D supplementation in the follow-up
various autoimmune diseases, including multiple of patients with AAU.
sclerosis and type 1 diabetes.26 Do et al.27 reported In conclusion, we demonstrated a dramatic differ-
that toll-like receptor (TLR)2 and TLR4 are highly ence between the serum vitamin D levels of patients
expressed in the monocytes of active Behçet disease with AAU and the control group. Although most
patients and demonstrated that vitamin D3 sup- patients with acute anterior uveitis responded well to
presses the protein and mRNA expressions of the classic treatment, frequent recurrences are an
TLR2 and TLR4 in vitro. They concluded that vita- important problem with an increased risk of morbidity
min D may be used as a therapeutic option in related with both the disease itself and the treatment.
Behçet disease. This immunosuppressive effect of Further studies are necessary to determine whether
vitamin D might explain the development of auto- vitamin D supplementation can decrease the frequency
immune diseases in its deficiency. Supportively, we of the attacks, which might prove to be a very valuable
demonstrated very low levels of vitamin D in and easy method for saving the vision of patients with
patients with AAU in our study. recurrent acute anterior uveitis.

Ocular Immunology & Inflammation

 Vitamin D Levels in Acute Anterior Uveitis 5

DECLARATION OF INTEREST 15. Adán-Civera AM, Benítez-Del-Castillo JM, Blanco-Alonso

R, et al. Burden and direct costs of non infectious uveitis
in Spain. Reumatol Clin. 2015;Oct 17.
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alone are responsible for the content and writing of the uveitis in blindness: a literature survey. Br J Ophthalmol.
paper. 1996;80:844–848.
17. Wakefield D, Chang JH, Amjadi S, et al. What is new HLA-
B27 acute anterior uveitis? Ocul Immunol Inflamm.
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