Ocular Immunology and Inflammation

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

Vitamin D and Ocular Inflammation

Emmett T. Cunningham Jr, Lucia Sobrin, Anthony J. Hall & Manfred Zierhut

To cite this article: Emmett T. Cunningham Jr, Lucia Sobrin, Anthony J. Hall & Manfred Zierhut
(2020) Vitamin D and Ocular Inflammation, Ocular Immunology and Inflammation, 28:3,
337-340, DOI: 10.1080/09273948.2020.1734421

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Published online: 07 Apr 2020.

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Ocular Immunology & Inflammation, 2020; 28(3): 337–340
© 2020 Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273948.2020.1734421

EDITORIAL

Vitamin D and Ocular Inflammation

1,2,3 4 5,6
Emmett T. Cunningham Jr, MD, PhD, MPH , Lucia Sobrin, MD, MPH , Anthony J. Hall, MD ,
and Manfred Zierhut, MD7

1
Department of Ophthalmology, California Pacific Medical Center, San Francisco, California, USA,
2
The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA,
3
The Francis I. Proctor Foundation, UCSF School of Medicine, San Francisco, California, USA,
4
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA,
5
Department of Surgery, Monash Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash
University, Clayton, Australia, 6Department of Ophthalmology, The Alfred Hospital, Melbourne, Australia, and
7
Centre for Ophthalmology, University Tuebingen, Tuebingen, Germany
The term vitamin D refers to a family of secosteroid In the extreme, vitamin D deficiency results in rick-
compounds derived from cholesterol that are best ets in children and osteomalacia in adults. However,
known for facilitating intestinal absorption of cal- increasing epidemiological evidence points to impor-
cium and phosphate required for normal bone devel- tant roles for vitamin D in normal functioning of the
opment and homeostasis. There are two major forms cardiovascular, nervous, endocrine, and immune sys-
of vitamin D: vitamin D2, known as ergocalciferol, tems. In fact, a number of epidemiological studies have
which is derived from plants, and vitamin D3, associated vitamin D deficiency with statistically
known as cholecalciferol and which is derived from higher rates of all-cause mortality, of cancer, and of
animal tissues. Humans generate vitamin D from 7- cardiovascular, neurodegenerative, metabolic, and
dehydrocholesterol in the deep epidermis following autoimmune disease – including noninfectious uveitis
exposure to natural ultraviolet B (UVB) radiation in and scleritis.1–6,11-22 Specific forms of uveitis linked to
sunlight. In the absence of supplementation, most vitamin D deficiency include noninfectious anterior
vitamin D in humans is dermal in origin and depen- uveitis,18,19 anterior uveitis in the setting of juvenile
dent on adequate sunlight exposure, with more pig- idiopathic arthritis,17 Behçet’s-associated uveitis,15,21
mented people requiring longer exposure than those and uveitis in patients with Vogt-Koyanagi-Harada
who are lightly pigmented to achieve similar serum disease.20,22 Of note, Chiu et al.13 recently performed
levels of vitamin D. Fatty fish and fortified foods can a prospective case–control study of 151 patients with
augment skin-based synthesis, but dietary vitamin noninfectious uveitis seen at two tertiary centers in
D alone is often insufficient to achieve adequate Victoria, Australia, from January through
doses.1–6 Given indoor work-life routines and current August 2017. The researchers found that subjects
recommendations to limit unprotected sunlight expo- with active uveitis tended to have lower serum vitamin
sure, it is perhaps not surprising that billions of D levels than patients with inactive uveitis (46 vs
people around the world are believed to be vitamin 64 nmol/L; p < .001), that these levels in patients with
D deficient, defined as a serum level of less than active uveitis were lower than those observed in the
≤20 ng/mL (50 nmol/L). Although accurate esti- local non-uveitic population (46 vs 62 nmol/L), and
mates of vitamin D deficiency are not available for that both vitamin D supplementation (p = .026) and
most countries,7 a survey of 4495 US citizens tested increased sunlight exposure (p = .014) were associated
as part of a 2005–2006 National Health and Nutrition with uveitis inactivity. Equally important, however,
Examination Survey identified vitamin D deficiency was that the reduced odds of active uveitis in those
in approximately 40% of adults, with much higher with vitamin D levels ≥50 nmol/L were modest at 0.98
rates in Latinos (~70%) and African-Americans (95% CI 0.96–0.99).12 Similarly, modest reductions in
(~80%).8 Rates of vitamin D deficiency in many the risk of developing uveitis in the setting of JIA were
parts of Asia, India, The Middle East, and African identified in the prospective study by Sengler et al.17 at
are believed to be in excess of 90%.9,10 a single tertiary referral center in Berlin, Germany,

Correspondence: Emmett T. Cunningham, West Coast Retina Medical Group, 1445 Bush Street, San Francisco, CA 94109.
E-mail: emmett_cunningham@yahoo.com

337
338 E. T. Cunningham et al.
where the authors showed that JIA patients with a nor-
mal vitamin D level were less likely to develop uveitis
(OR = 0.95, 95% CI 0.91–0.99); and by Sobrin et al.,16
who performed a retrospective case–control study on
a health care claims database from a large private
insurer in the US and found that 2790 controls without
uveitis were slightly less likely to be deficient in vita-
min D than the 558 identified cases with noninfectious
uveitis (OR = 0.79, 95% CI 0.62–0.99). Three Original
Articles23-25 in this issue of Ocular Immunology &
Inflammation (OII) address the role of vitamin D in
ocular inflammation.
Rohmer et al.23 retrospectively studied serum levels
of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvi-
tamin D (1,25(OH)2D), and the 1,25(OH)2D/25(OH)D
ratio in 59 patients seen at a tertiary referral center in
Paris between January 2009, and December 2014. To
interpret the findings of this study it is important to
remember that following synthesis in the skin or diet-
ary intake, vitamin D is mostly hydroxylated in the
liver to 25(OH)D, with a small amount being further
hydroxylated under tight regulation in the kidney by
serum calcium, phosphate, and parathyroid hormone
to 1,25(OH)2D. In contrast, extrarenal hydroxylation to
1,25(OH)2D in activated macrophages is not regulated
and so the doubly hydroxylated form of vitamin
D tends to increase in granulomatous diseases such
as sarcoidosis and tuberculosis. Twenty-two of the
patients (37%) in the study by Rohmer et al. had defi-
nite, presumed, or probable sarcoidosis as defined by
the International Workshop on Ocular Sarcoidosis. The
authors found that the sarcoid cohort tended to have
lower median serum levels of 25(OH)D (34.5 vs
43.2 nmol/L; p = .02), higher median serum levels of
1,25(OH)2D (132.4 vs 108.0 pmol; p = .02), and a higher
median 1,25(OH)2D/25(OH)D ratio (4.17 vs 2.56;
p = .0007). They found further that a median 1,25(OH)
2D/25(OH)D ratio of >3.5 was associated with the
diagnosis of sarcoidosis in their clinic-based cohort
with a 68% sensitivity and 78% specificity, and that
a ratio >3.5 was much more likely to be associated
with an abnormal chest CT (OR = 5.7; p = .003), gran-
uloma formation on bronchial biopsy (OR = 14.7;
p = .007), and lymphocytosis in bronchoalveolar lavage
fluid (OR = 12.4; p = .0006). They found no association
between a 1,25(OH)2D/25(OH)D ratio > 3.5 and either
an angiotensin-converting enzyme (ACE) level >1.5
above the upper limit of normal (ULN; >78 U/L;
OR = 2.87, 95% CI 8.89–9.37) or lymphopenia (cell
count <1.5 × 109/L; OR = 1.02, 95% CI 0.72–7.20). The
authors concluded that measurement of serum 25(OH)
D and 1,25(OH)2D with calculation of the 1,25(OH)2D/
25(OH)D ratio could provide value independent of
serum ACE or absolute white blood cell count for the
diagnosis of presumed or probable sarcoidosis, parti-
cularly in patients where biopsy is either impossible or
impractical. It is important to keep in mind, however,
that in settings where the prevalence of sarcoidosis is
low, the predictive value of any of serum ACE, of
absolute white blood cell count, or of the 1,25
(OH)2D/25(OH)D ratio as surrogates of more defini-
tive radiographic or tissue-based diagnoses of sarcoi-
dosis will decrease dramatically.
Maciejewski et al.24 studied 107 patients with thyr-
oid-associated orbitopathy (TAO) and 130 control
subjects seen at a referral center in Poznan, Poland,
to determine whether polymorphisms in the vitamin
D receptor (VDR) differed in their genotypic distribu-
tion across the two cohorts. The researchers used real-
time polymerase chain reaction (PCR)-based testing to
search for five specific VDR polymorphisms:
rs2228570, rs1544410, rs7975232, rs731236, and
rs11568820. Only rs2228570 showed a statistically dif-
ferent distribution, with TAO patients showing an
increased frequency of the C allele (OR = 2.05; 95%
CI 1.03–4.08; p = .04). The authors suggested that
allele C of the rs2228570 polymorphism may confer
added risk for the development of TAO, at least in
Caucasian Polish patients, and cited previously pub-
lished studies showing a correlation between vitamin
D deficiency and the development of both autoim-
mune thyroiditis and Grave’s disease as supportive
of a role for vitamin D and its signaling through the
VDR in pathogenesis of TAO. Of note, however,
p-values appear not to have been corrected for multi-
ple hypothesis testing and so should be viewed as
nominal.
Akkaya and Ulusoyl25 evaluated the serum 25(OH)D
levels in 100 patients with keratoconus and 100 non-atopic
age- and sex-matched healthy controls seen at a tertiary
referral center in Kayseri, Turkey. Keratoconus was
graded as mild (K = 43.1–46.9 D), moderate (K = 47.0–
50.0 D), or severe (K > 50.0 D), and vitamin D levels were
classified as optimal (>20 ng/mL), insufficient (11–20 ng/
mL), or deficient (≤10 ng/mL). The researchers found that
the mean serum 25(OH)D level was lower (12.18 vs
15.18 ng/ML; p < .001) and the rate of 25(OH)D defi-
ciency, defined as a vitamin D level ≤10 ng/mL, was
higher (54% vs 34%; p = .011) in patients with keratoconus
as compared to healthy controls. Multivariate logistic
regression suggested further that having vitamin
D deficiency as defined in the study increased the risk of
having keratoconus by nearly three-fold (OR = 2.9; 95% CI
1.17–6.95; p = .021). Vitamin D levels did not appear to
correlate statistically to the severity of keratoconus –
although the rate of vitamin D deficiency tended to be
highest in the severe keratoconus subgroup. The authors
suggested that an association between vitamin
D deficiency and keratoconus might support a role for
the immune system in the pathogenesis of keratoconus –
although the precise role of inflammation in the develop-
ment or progression of keratoconus remains unclear.
Together, these studies add to the growing body of
evidence linking vitamin D to ocular inflammation. The
Ocular Immunology & Inflammation
 OCULAR IMMUNOLOGY AND INFLAMMATION 339

risk effect size of vitamin D deficiency seems to be low, TABLE 1. Indications for 25(OH)D measurement (candidates
however, such that many patients with ocular inflam- for screening) to promote bone health*.
mation have normal vitamin D levels of 50 nmol/L or
greater, whereas many patients with no history of ocu- Rickets
lar inflammation are vitamin D deficient. It seems clear, Osteomalacia
therefore, that deficient vitamin D is neither necessary Osteoporosis
nor sufficient for ocular inflammation to occur. In addi- Chronic Kidney Disease
tion, although a number of randomized clinical trials Hepatic Failure
have looked to treat patients with autoimmune disease Malabsorption syndromes
with vitamin D supplementation, none to-date have Cystic Fiborosis
demonstrated a definitive therapeutic benefit. It should Inflammatory Bowel Disease
be mentioned, however, that many of these trials have Crohn’s Disease
been criticized, both for not limiting enrollment to Bariatric Surgery
patients who were clearly vitamin D deficient and for Radiation Enteritis
failing to control for either sunlight exposure or vitamin Hyperparathyrodism
D intake across the treatment arms. So, should we mea- Medications
sure serum 25(OH)D levels in our patients with ocular Antiseizure Medications
inflammation? On the pro side, testing requires a simple Glucocorticoids
blood test, many patients with ocular inflammation will AIDS Medications
be found to be deficient, and treatment is both easy and Antifungal Medications (eg, Ketoconazole)
effective with 15–30 min of unprotected mid-day sun- Cholestyramine
light exposure, a tablespoon of cod liver oil, or 800–2000 African-American and Hispanic Children and Adults
International Units of vitamin D – each daily. On the con
Pregnant and lactating women
side, even simple blood tests add cost to the already
Older Adults with a History of Falls
over-burdened medical system, most patients with
Older Adults with History of Nontraumatic Fractures
uveitis will have normal vitamin D levels, and there is
Obese Children and Adults (BMI > 30 kg/m2)
no level one evidence that supplementing those who are
Granuloma Forming Disorders
deficient will alter the incidence or course of their dis-
ease. Although somewhat dated, the Endocrine Society Sarcoidosis
published vitamin D screening guidelines from 201126– Tuberculosis
28
to promote bone health are clearly broad and include Histoplasmosis
all African-Americans and Latinos, those with a body Coccidiodomycosis
mass index (BMI) greater than 30 kg/m2, pregnant, and Berylliosis
lactating women, those with bone, renal, hepatic, or Some Lymphomas
gastrointestinal disorders, many of the elderly, many *Reproduced from Holick MF, Binkley NC, Bischoff-Ferrari
taking medications, such as corticosteroids, and patients HA, Gordon CM, Hanley DA, R.P. Heaney RP, Hassan Murad
with granuloma-forming or lymphoproliferative disor- M, Weaver CM. Evaluation, treatment, and prevention of vita-
ders (Table 1). Our view, therefore, is that 25(OH)D min D deficiency: an endocrine society clinical practice guide-
measurement, followed by supplementation as indi- line, J. Clin. Endocrinol. Metab. 2011; 96(7):1911–1930.27
cated, seems already justified in many patients with
uveitis – at least according to Endocrine Society guide-
ACKNOWLEDGMENTS
lines for the indication of bone health. In contrast, mea-
surement of the active metabolite, 1,25(OH)2D, should
The authors received no financial support for this study.
be limited to those suspected of having rickets, an
inborne error in vitamin D metabolism, advanced
renal disease,29 or perhaps as an investigational surro- DECLARATION OF INTEREST
gate screen for the presence of granuloma-forming dis-
orders as suggested by Rohmer et al.23 in this issue of The authors report no conflicts of interest. The
OII. To promote bone health for those who are vitamin authors alone are responsible for the content and
D deficient, The Endocrine Society recommended writing of the paper.
achieving serum 25(OH)D concentrations more than
30 ng/mL (>75 nmol/L), with the preferred range of
40–60 ng/mL (100–150 nmol/L) – so slightly higher FINANCIAL CONFLICTS
than the deficiency cutoff of 50 nmol/L.26–28 Those
who are overweight typically require higher doses of LS is a consultant to Clearside Biomedical, Inc., and
vitamin D than those with a normal BMI to achieve the Novartis, Inc. AJH is consultant to AbbVie, Inc., has
similar circulating levels. received research payments from Novartis, Inc., and

© 2020 Taylor & Francis Group, LLC

340 E. T. Cunningham et al.
has received lecture fees from Janssen, Inc. The other
authors have no relevant financial conflicts.
ORCID
Lucia Sobrin http://orcid.org/0000-0003-1575-0819
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Ocular Immunology & Inflammation