Adequate Vitamin D Serum Levels Reduce the Occurrence of Age-Related

Macular Degeneration in Elderly Patients.

McKenna M. Murphy

Introduction:
According to recent findings,1-3 age-related macular degeneration (AMD) is a clinical condition in
the retina of the eyes and is the main cause of visual impairment in individuals over the age of 60. It is
characterized by the destruction of the macula, the center of the retina in the back of the eye. The macula
is responsible for central vision and its degradation can lead to blurred vision that impairs straight-forward
vision, preventing individuals from driving, reading, or moving easily. The retina is the light-sensing
portion of the eye that sends nerve signals to our brain to allow vision to occur. In the beginning stages of
AMD, the following ensues: drusen formation, lipid deposits under the retina, and changes in the retinal
pigment epithelial (RPE) cells, pigmented cell layer that nourishes retinal visual cells, occurs. Then in
later stages, geographical atrophy (GA) with slow vision loss or choroidal neovascularization (CNV),
with or without subretinal fibrosis, and fast vision loss could occur. The degree of AMD severity and
progression varies from patient to patient. Genetic, environmental, oxidative stress, and immune function
factors are considered to play a role in the development of AMD, but more research needs to be done.
In a 2015 study,4 approximately 50% of the global population faces vitamin D deficiency, and the
elderly population is no exception. Vitamin D is endogenously made in the body after
7-dehydrocholesterol is converted to precholecalciferol by ultraviolet B light from sun exposure on the
skin. The elderly may face atrophic skin changes, lifestyle changes that decrease sun exposure, and/or
lack of dietary vitamin D intake that may hinder this pathway. Other findings3 explain that vitamin D is a
steroid hormone that circulates in the blood and binds to vitamin D receptors (VDR) to counteract
inflammation, fibrosis, oxidative stress, and angiogenesis. This leads to the idea that vitamin D deficiency
may play a role in AMD as it counteracts some of its major symptoms. The purpose of this paper is to
determine whether the environmental factor, high serum vitamin D, reduces the occurrence of age-related
macular degeneration in elderly patients.
Methods:

Research for this article was done through the University of North Floridas library database
using the search engine UNF OneSearch. Topics dealing with vision were considered after vitamin C and
night vision research was explored, but the need for a more unique topic led to articles of macular
degeneration and low serum vitamin D. Search terms included: vitamin D deficiency, macular
degeneration, AMD, age-related macular degeneration, calcitriol, elderly, and sun exposure. After a
number of hours of collecting and reading abstracts, four primary articles were chosen from reputable
journals. The four articles included two observational cross-sectional studies, one animal research study,
and one population-based cohort study. All studies, except the animal study, dealt with older populations,
AMD, and vitamin D. The animal study offered a possible genetic explanation for varying vitamin D
serum levels that may have a correlation to AMD. Journals used were Investigative Ophthalmology &
Visual Science, Plos One, Experimental Eye Research, and Journal Of Nutrition. All articles were written
in 2013 or later, making them extremely relevant and up-to-date.
Main findings:
An observational cross-sectional study1 explores vitamin D and macular thickness in the elderly.
The purpose was to determine if low serum 25-hydroxyvitamin D (25OHD) was associated with macular
thickness among older populations that did not have AMD. Sixty-two older French community-dwellers
were separated into two groups based on 25OHD levels (insufficient < 50 nmol/L or sufficient 50
nmol/L). Optical coherence tomography was used to measure macular thickness with normal values being
267.74 m for males, and 255.60 m for females. Results showed that the mean serum 25OHD was 61.2
26.3 nmol/L. The 17 members in the vitamin D insufficient group had a smaller macular thickness of
232.9 40.4 m compared to the sufficient group at 253.3 32.1 m macular thickness. This showed
true after adjustment of potential confounders. In the end, low serum vitamin D was associated with
reduced macular thickness. This may be a risk factor of AMD. A limitation to the study was that only 62
participants were used. Also, the seniors were relatively healthy, as only 17 were found to have

insufficient vitamin D. This may not be representative of the entire senior population and more research
needs to be done. This study is significant because macular thickness may be a major factor in the
development of AMD, and this study encourages the idea that vitamin D insufficiency may lead to AMD,
not vice versa.
Research2 explored 25OHD levels in elderly patients with AMD and the Clinical Age-Related
Maculopathy Staging (CARMS) system was used to classify elderly patients with or without subretinal
fibrosis through a single-center cross-sectional study. The study included 178 participants over a
20-month period and each participant was classified into one of five CARMS groups based on AMD
severity. CARMS 1 had no drusen formation and CARMS 5 patients had exudative AMD. Differences in
plasma 25-hydroxyvitamin D2 and D3 were determined in the subgroups as well as between patients in
CARMS 5 with or without subretinal fibrosis using liquid chromatography-tandem mass spectrometry.
Results in CARMS group 5 showed subretinal fibrosis occurred significantly more often with much lower
concentrations of 25OHD than in cases with high 25OHD concentrations (47.2 mmol/L vs. 75.6 nmol/L).
This study shows an association may exist between subretinal fibrosis in patients with exudative AMD
and poor serum vitamin D status. However, no observations were made between vitamin D status and
CARMS groups 1-5 without subretinal fibrosis. This may indicate that 25OHD levels may only affect
subretinal fibrosis in AMD patients and may not have any impact on other symptoms or onset of AMD in
elderly patients. Further research needs to be explored.
Based on 2013 research,3 25OHD may decrease the activity of HTRA1 promoter in the rhesus
monkey. This may explain vitamin Ds role in AMD. One AMD disease-related area in humans is 10q26
and includes two genes: ARMS2 and HTRA1. HTRA1 is associated with drusen formation as it may
promote the single-nucleotide polymorphism (SNP) rs196357513 (found inside a gene at a site at which
more than one nucleotide is found in a population) and thus may increase the likelihood of AMD. In this
study, nine binding sites for the vitamin D-dependent transcription factor vitamin D receptor in the rhesus

HTRA1 promoter were identified and one is removed by the rs196357513-risk allele. A luciferase assay
in transiently transfected ARPE19-cells was done to find the SNP rs196357513 effects on 25OHD of the
rhesus monkeys HTRA1 gene. Results showed the rs196357513 allele had significant reductions after
25OHD was incorporated. So in summation, HTRA1 may activate SNP rs196357513 that leads to drusen
formation in the retina which is strongly correlated to AMD occurrence. Vitamin D may act to reduce
HTRA1 activity and thus may lead to a reduction in AMD occurrence. This study is limited because
humans may have different genes than rhesus monkeys that may affect outcomes. However, if this holds
to be true in humans, finding the cure for AMD is one step closer.
A population-based cohort study4 explores factors that lead to 25OHD deficiency and its
associations with AMD in the elderly through a population-based cohort study. Subjects were chosen
from an ongoing population-based study [Three-City (3C) Study] on the vascular risk factors for
dementia. Six hundred and ninety-seven elderly residents of Bordeaux, France, had 25OHD levels
assessed and were placed into one of three groups: <25 nmol/L (deficiency), 2549 nmol/L
(insufficiency) at a participant percentage of 27.3% and 55.9%, or $50 nmol/L (sufficiency). Participants
were classified as no AMD, early AMD, or late AMD. Participants were initially recruited between
1999-2001 and were assessed every two years from baseline. Results showed that 25OHD was
significantly associated with older age, females, lack of movement, no vitamin D supplementation, high
cholesterol, fibrate usage, low alcohol intake, and season of blood sampling. Adjustment for these
covariates and other potential confounders was done. In summation, no significant associations were
found between AMD and 25OHD insufficiency or deficiency, However, this study does show a high
prevalence of vitamin D deficiency in the elderly, which may lead to bone deterioration and other health
problems.
A contradiction exists between two studies.1,2 Vitamin D may play a role in AMD beyond the
formation of subretinal fibrosis as the macula tends to shrink in the absence of sufficient vitamin D levels.

This may be due to the lack of macular thickness being a potential confounder in a different studys
research2 and the shrinking may be due to the increased amounts of subretinal fibrosis, but more research
needs to be done. However, both studies report that low vitamin D levels have a strong correlation with
AMD in the elderly. Another study3 offers an explanation behind this correlation. It may not be about the
elderly community or about humans in general, but it offers a genetic explanation about how vitamin D
may inhibit the HTRA1 gene to hinder drusen formation in the retinas to help promote strong central
vision. A 2015 study4 offers an opposing view in that vitamin D may have no association with AMD. This
study had a much larger elderly human participant pool in comparison to other studies. This study should
be taken into major consideration because many of the other studies showed correlations with symptoms
or various forms of AMD, while this study looked at direct linkage of vitamin D serum levels and AMD
prevalence. In comparison, this study had a limitation. There were a small number of subjects with
25OHD sufficiency. This could be a problem because statistical results may not have been able to detect a
potential protective effect of high vitamin D serum levels and AMD.
Conclusion:
There is unclear evidence that the environmental factor, low serum vitamin D, increases the
occurrence of age-related macular degeneration in elderly patients. It is unclear if vitamin D consumed
throughout a lifetime had a major role in this because study data was mainly taken from older populations
and data tended to be gathered once. More research needs to be done to prove that vitamin D plays a
significant role in AMD because a 2015 study4 offered strong evidence against this assumption by
showing that a huge French society had low vitamin D levels, but not a relevant level of AMD
occurrence. However, other studies1-3 show strong support for low serum vitamin D and AMD
occurrence, but they only deal with symptoms of AMD, such as macular thickness, subretinal fibrosis,
and drusen formation. Overall, studies showed a prevalence of poor vitamin D serum levels in the elderly.
This is important because vitamin D deficiency may lead to poor bone health and other health problems.

Doctors and dietitians should encourage elderly patients to gain more sun exposure, increase physical
activity levels, increase vitamin D food intake and to possibly consume vitamin D supplements to
promote a healthful lifestyle.

References:

1) Graffe A, Beauchet O, Fantino B, Milea D, Annweiler C. Vitamin D and Macular Thickness in

the Elderly: An Optical Coherence Tomography Study. Investigative Ophthalmology & Visual
Science. August 2014;55(8):5298-5303. Accessed April 1, 2016.
2) Singh A, Falk M, Subhi Y, Srensen T. The association between plasma 25-hydroxyvitamin D
and subgroups in age-related macular degeneration: a cross-sectional study. Plos One. July 29,
2013;8(7):e70948. Accessed April 1, 2016.
3) Pahl L, Schubert S, Skawran B, Sandbothe M, Schmidtke J, Stuhrmann M.
1,25-Dihydroxyvitamin D decreases HTRA1 promoter activity in the rhesus monkey A
plausible explanation for the influence of vitamin D on age-related macular degeneration?.
Experimental Eye Research. November 1, 2013;116:234-239. Accessed April 1, 2016.
4) Cougnard-Grgoire A, Merle B, Delcourt C, et al. Vitamin D Deficiency in Community-Dwelling
Elderly Is Not Associated with Age-Related Macular Degeneration. Journal Of Nutrition. August
2015;145(8):1865-1872. Accessed April 1, 2016.