Acta Ophthalmologica 2018

Review Article

The relation between dietary intake and glaucoma:

a systematic review
Wishal D. Ramdas
Department of Ophthalmology, Maastricht University Medical Center, Maastricht, The Netherlands

ABSTRACT.
Purpose: A common question of patients to their physician is what they can do surgery. However, a nonnegligible
themselves against glaucoma, except taking their daily medication. However, for number of patients continue to deteri-
orate despite an ‘adequately’ controlled
ophthalmologists, it is often hard to give their patients an advice on their dietary
low IOP. An upcoming approach for
intake. To help ophthalmologists in answering this question, an overview of the
the treatment of glaucoma is IOP-
current scientific literature on the association of nutrients with glaucoma is independent neuroprotection (Nucci
presented. et al. 2016).
Methods: A comprehensive systematic review was conducted in which articles Most medical practitioners have reg-
published up to September 2017 were identified in PubMed and reference lists. ular contact with patients who have
Nutrients were categorized into minerals and trace elements, nutrition with glaucoma. A common question
antioxidative properties and omega-fatty acids. patients with (or at risk for) glaucoma
Results: The literature search revealed a total of 407 articles of which a total of ask to their ophthalmologist is what
46 met the inclusion criteria. Most of these articles studied the effect of nutrients can they do by themselves next to just
on open-angle glaucoma. Many trace elements have been investigated in the taking their daily ophthalmic medica-
literature, but the most interesting are selenium and iron (both may increase the tion? Patients often look for alterna-
risk of glaucoma). Investigated nutrients with antioxidative properties and tives (Rhee et al. 2002). Several studies
omega-fatty acids included glutathione, nitric oxide, carotenoids, flavonoids, and suggested that nutrition might have an
omega-3 and omega-6 fatty acids. Of these, glutathione, nitric oxide, and effect on the IOP or glaucoma. With
respect to this, a few pathophysiolog-
flavonoids had a significant protective effect on glaucoma.
ical pathways implicated in glaucoma
Conclusion: Intake of selenium and iron may increase the risk of glaucoma,
can be highlighted. Nutrition may
though, only few studies have been done on this topic. Nitric oxide present in affect glaucomatous eyes through their
other dark green leafy vegetables seems to have a beneficial effect on glaucoma. antioxidative properties, their effect on
However, the evidence for an association of dietary intake with glaucoma is still the blood flow/vascular endothelium or
not strong. More (longitudinal and randomized clinical trials) studies are their neuroprotective properties.
required to make the presented findings clinically applicable. Oxidative stress occurs when more
reactive oxygen species are formed
Key words: antioxidants – dietary intake – fatty acids – glaucoma – glutathione – minerals than the antioxidative capacity of the
nitric oxide – trace elements cell can handle. This leads to damage
to the trabecular meshwork and loss of
Acta Ophthalmol. 2018: 96: 550–556 retinal ganglion cells (Izzotti et al.
ª 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd 2003, 2006; Sacc
a et al. 2005). A low
ocular (in the aqueous humour) or
doi: 10.1111/aos.13662
systemic antioxidative capacity is asso-
ciated with severe glaucomatous visual
field and is noticed by the patient. The field loss (Izzotti et al. 2003; Sacc
a
Introduction prevalence of glaucoma increases with et al. 2005; Nucci et al. 2016; Tanito
Glaucoma, a neurodegenerative eye age and is estimated at 4% in people et al. 2016). Systemic oxidative stress is
disease, is the most common cause of aged 40–80 years (Wolfs et al. 2000; also associated with decreased ocular
irreversible blindness worldwide. In Tham et al. 2014). Current treatment is blood flow (Himori et al. 2016). Of
many cases, visual symptoms arise in based on lowering the intraocular pres- interest is that two substances (timolol
an end stage when the visual field loss sure (IOP), which can be achieved by and dorzolamide) normally used to
progresses to the centre of the visual IOP-lowering drugs, laser treatment or lower the IOP from a pharmacological

550

point of view are antioxidant sub-
stances (Sacc
a et al. 2011).
The aim of this study is to present an
overview of the current scientific liter-
ature on nutrients (minerals and trace
elements, nutrition with antioxidative
properties [e.g. carotenoids and flavo-
noids], and omega-fatty acids) that are
known to have one or more of the
above-described properties and may
affect glaucoma, and to determine the
association of these nutrients with
glaucoma.
Subjects and Methods
Data search for identifying studies
A systematic review was performed
using the guidelines implied by the Pre-
ferred Reporting Items for Systematic
reviews and Meta-Analyses (PRISMA;
Liberati et al. 2009). The literature
search was conducted using the PubMed
database for articles published prior to
September 2017. The search terms used
in PubMed included (‘minerals[All
Fields] AND glaucoma[All Fields]’),
(‘diet[All Fields] AND glaucoma[All
Fields]’), (‘trace elements[All Fields]
AND glaucoma[All Fields]’), (‘carote-
noids[All Fields] AND glaucoma[All
Fields]’), (‘flavonoids[All Fields] AND
glaucoma[All Fields]’) and (‘fatty acids
[All Fields] AND glaucoma[All Fields]’).
The included entries had to have an
available abstract, which had to be in
either English or German. Further-
more, investigations had to be per-
formed in humans (or human tissue).
Studies were only eligible if they were
peer-reviewed.
From the retrieved studies, titles and
abstracts were scanned. Next, the full
text of the remaining studies was read.
In addition, the reference list from all
identified studies was scanned in a
similar fashion.
Data extraction and quality assessment
The study quality was assessed with a
tool described elsewhere (Sanderson
et al. 2007). The variables examined
included the methods for selecting study
participants, methods for measuring
exposure (nutrients) and outcome vari-
able (glaucoma), design-specific sources
of bias, statistical methods (excluding
control of confounding) and conflict of
interest. Studies on the dietary effect of
nutrition had to use (semiquantitative)
food frequency questionnaires or a
24-hr recall and/or a detailed interview.
Furthermore, studies had to use clear
criteria for defining the type of glaucoma
investigated. Included forms of glau-
coma were primary open-angle glau-
coma (POAG), primary angle-closure
glaucoma (PACG), normal-tension glau-
coma (NTG) and pseudoexfoliation
glaucoma.
Nutrients were categorized into min-
erals and trace elements, nutrients with
antioxidative properties and omega-
fatty acids. Firstly, the possible mech-
anisms regarding glaucoma of the
specific nutrient are described. Sec-
ondly, the food sources rich in the
specific nutrients are mentioned.
Thirdly, an overview of studies that
investigated the nutrient in relation to
serum or plasma levels in patients with
glaucoma is provided. Fourthly, an
overview of the studies that investi-
gated the association of the nutrient
with glaucoma is provided. Results of
retrieved studies are presented as haz-
ard ratio (HR) or odds ratio (OR) with
corresponding 95% confidence interval
(CI) if provided.
Data synthesis and analysis
As the number of studies reporting an
effect estimate of the specific nutrients
on glaucoma was too low, a meta-
analysis could not be performed.
Results
The literature search yielded a total of
407 articles from PubMed: of these 36
for ‘minerals and glaucoma’, 119 for
‘diet and glaucoma’, 87 for ‘trace
elements and glaucoma’, 51 for ‘car-
otenoids and glaucoma’, 65 for ‘flavo-
noids and glaucoma’, and 59 for ‘fatty
acids and glaucoma’. After adding
additional filters, a total of 189 articles
remained. Next, the abstracts of these
were scanned. Of the included articles,
the reference lists were scanned which
resulted in 22 additional studies. Even-
tually, a total of 46 articles were
included (Fig. 1). Most studies covered
OAG and were cross-sectional case-
control studies (Table S1).
Minerals and trace elements
The following minerals were investi-
gated in the retrieved studies: selenium
(Se), iron (Fe), calcium (Ca), lead (Pb),
Acta Ophthalmologica 2018
zinc (Zn), copper (Cu), manganese
(Mn), chromium (Cr), cobalt (Co),
molybdenum (Mo), nickel (Ni), vana-
dium (V), arsenic (As), aluminium (Al),
mercury (Hg), cadmium (Cd), stron-
tium (Sr) and magnesium (Mg). Trace
elements serve as important cofactors
for several enzymatic processes includ-
ing the elimination of reactive oxygen
species (i.e. oxidative stress).
Selenium is incorporated into seleno-
proteins, which prevent cellular dam-
age through their antioxidative
properties. Selenium is also an essential
component of the glutathione peroxi-
dase complex, which is responsible for
managing oxidative stress. Other prop-
erties are the inhibition of angiogenesis,
stimulation of apoptosis and inhibition
of cell cycle progression (reducing the
risk of several forms of cancer; King
2009). The most common source of
selenium is plant foods depending on
the soil. One study investigated the
relationship of selenium levels in
plasma and aqueous humour in 47
POAG cases and 54 controls. For their
highest tertile of plasma selenium, they
reported a high OR of POAG (OR [p-
value]: 11.3 [0.03]), whereas the OR of
the middle tertile of aqueous humour
selenium for POAG was low (OR [p-
value]: 0.06 [0.02]; Bruhn et al. 2009).
This contradiction might be explained
by that the middle tertile may represent
an optimal range of aqueous humour
selenium. If aqueous humour or tra-
becular meshwork acts like privileged
tissue (i.e. retain selenium levels in case
of selenium deficiency or supplementa-
tion), the low OR may only reflect
natural human variation and not pro-
vide relevant risk information. An
analysis of the effect of selenium on
cultured trabecular meshwork cells
showed an increased resistance to out-
flow due to elevated selenium levels
(Conley et al. 2006). A study on the
effect of selenium in pseudoexfoliation
glaucoma did not show a significant
difference in plasma levels between
cases and controls (Ceylan et al.
2013). However, a randomized clinical
trial on the effect of selenium supple-
mentation in patients with cancer
revealed an increased risk of develop-
ing glaucoma (HR [95% CI]: 1.78
[1.12–2.82]) compared to patients with-
out selenium supplementation (Lillico
et al. 2002).
Iron catalyses the generation of
reactive oxygen species (in particular
551
Acta Ophthalmologica 2018
Search term
Minerals AND glaucoma
Diet AND glaucoma
Trace elements AND glaucoma
Carotenoids AND glaucoma
Flavonoids AND glaucoma
Fatty acids AND glaucoma
Total:
After removing
duplicates*
Total: 383
Filter: Available abstract
Total: 310
Filter: Species human(-
tissue)
Total: 215
Filter: Language english
or german
Total: 189
After scanning of titles,
abstracts and full text
Total: 24
Included in the study
Total: 46
* = Search term: (minerals[All Fields] AND glaucoma [All Fields]) OR (diet[All Fields]
AND glaucoma[All Fields]) OR (trace elements[All Fields] AND glaucoma[All Fields])
glaucoma[All Fields]) OR ("fatty acids"[All Fields] AND glaucoma [All Fields])
Fig. 1. Flow diagram showing the selection process for inclusion of studies from PubMed.
hydroxyl radicals) and thus induces
oxidative stress. Chronic oxidative
stress alters intracellular iron home-
ostasis in human trabecular meshwork
cells, resulting in accumulation of iron
which may cause trabecular meshwork
cell death (Lin et al. 2010). Ferritin is
an intracellular protein that stores and
releases iron in a controlled fashion.
Rich sources of dietary iron include red
meat, lentils, beans, fish, leafy
vegetables, tofu and chickpeas. The
cross-sectional National Health and
Nutrition Examination Survey
(NHANES; N = 3833) study reported
an increased risk of self-reported glau-
coma for supplementary iron (highest
552
Results
36
119
87
51
65
59
407
After scanning of
reference lists
Additional: 22
quintile OR [95% CI]: 3.80 [1.79–
8.06]), though a clear dose–response
relation was not found (Wang et al.
2012). Regarding total and dietary iron
consumption, the same research group
reported in another study (N = 6316)
an increasing OR per quintile of total
consumption of iron, but a decreasing
OR per quintile of dietary iron (Wang
et al. 2013). In another cross-sectional
population-based study (N = 17 476),
it was shown that a high serum ferritin
level was associated with a higher risk
of glaucoma (highest quartile OR [95%
CI]: 1.89 [1.32–2.72]; Lin et al. 2014).
The retrospective cross-sectional
Kangbuk Samsung health study
(N = 164 029) found similar results in
men (highest quartile OR [95% CI]:
1.18 [1.03–1.34]; Gye et al. 2016). In
contrast, in female patients with iron
deficiency anaemia, a thinner peripap-
illary retinal nerve fibre layer was
reported compared to controls; how-
ever, it is not known whether it is the
iron deficiency or the anaemia that
caused this finding (Cikmazkara &
Ugurlu 2016).
Calcium is a frequently consumed
oxidant and may play a role in oxida-
tive stress. Furthermore, calcium
affects the trabecular meshwork and
retinal ganglion cells (He et al. 2008).
Impaired calcium regulation has been
implicated in neurodegenerative dis-
eases including eyes with glaucoma.
Well-known sources of calcium include
dairy products such as milk, seaweeds,
nuts, soybeans and tofu. The studies
from Wang reported similar results for
calcium as for iron, and thus an
increased risk of glaucoma for high
supplementary calcium (highest quin-
tile OR [95% CI]: 2.44 [1.25–4.76]), but
a rather low risk of glaucoma for a
high total and dietary calcium con-
sumption (Wang et al. 2012, 2013). Of
interest is that calcium channel block-
ers seem to increase the risk of devel-
oping glaucoma (OR [95% CI]: 1.8
[1.04–3.2]; M€ uskens et al. 2007). How-
ever, no significant association between
dietary calcium intake and OAG was
found (Ramdas et al. 2012).
Lead is a heavy metal, which is toxic
to the central nervous system and
interacts with iron, calcium and zinc
resulting in loss of neurons. Therefore,
it is of interest to assess its effect on
retinal ganglion cells. Lead can be
ingested through fruits and vegetables
contaminated by high levels of lead in
soils. A study including 98 POAG cases
and 215 controls showed a higher lead
level in women with low IOP and
POAG but not in men (Yuki et al.
2009). No differences in lead levels were
found between glaucoma cases and
controls (OR [95% CI]: 1.04 [0.84–
1.29] per lg/dl; Lin et al. 2015).
Regarding other minerals, one arti-
cle studied the association of serum
levels of zinc, copper, manganese,
chromium, cobalt, molybdenum,
nickel, vanadium, arsenic, aluminium,
mercury, cadmium and strontium in 32
patients with pseudoexfoliation syn-
drome, 30 cases with pseudoexfoliation
glaucoma and 32 controls. They found

significant higher serum levels of
manganese, molybdenum and mercury
in patients with pseudoexfoliation
(Ceylan et al. 2013). The Korea
National Health and Nutrition Exam-
ination Survey (KNHANES) reported
an association of blood levels of man-
ganese and mercury with glaucoma
(OR [95% CI]: 0.44 [0.21–0.92] and
1.01 [1.00–1.03] per lg/l, respectively),
but not for urine arsenic and blood
cadmium levels (Lin et al. 2015). The
Rotterdam study reported a harmful
effect of dietary magnesium on OAG
(highest tertile OR [95% CI]: 2.25
[1.16–4.38]). Magnesium has similar
effects as calcium channel blockers
and competes with calcium and phos-
phorus; however, no significant inter-
action between these nutrients was
found (Ramdas et al. 2012).
Nutrition with antioxidative properties
Antioxidants can be divided into two
categories: enzymatic and nonenzy-
matic. The enzymatic antioxidants
include superoxide dismutase, catalase
and glutathione peroxidase. These
enzymes are already present in the
body to scavenge the reactive oxygen
species (ROS). The nonenzymatic
antioxidants include vitamin C, vita-
min E, carotenoid and flavonoids. The
role of vitamins in glaucoma has been
described elsewhere (Ramdas, et al.
submitted). There are over 600 types
of carotenoids and 4000 types of
flavonoids.
The enzymatic antioxidants investi-
gated in relation to glaucoma include
glutathione peroxidase and nitric
oxide synthase. The former targets
reactive oxygen species (ROS), while
the latter targets reactive nitrogen
species (RNS). The deleterious effect
of ROS and RNS is ameliorated
through antioxidants.
Glutathione reduces vitamin C to the
oxidized form and is oxidized by glu-
tathione peroxidase. This reaction
requires selenium. The main role of
glutathione peroxidase is enzymatic
protection from oxidative damage.
Food sources rich in glutathione or
that stimulate glutathione production
are asparagus, avocado, spinach and
broccoli. An increase in glutathione
levels helps the productivity of the
glutathione peroxidase and vice versa.
In line with this, low plasma levels of
glutathione were found in POAG and
NTG patients compared to controls
(N = 34 POAG, 30 NTG, and 53
controls; Gherghel et al. 2005, 2013).
This finding is further supported by the
lower plasma levels of glutathione per-
oxidase found in patients with glau-
coma when compared to controls
(N = 160 vs. 31, respectively; Engin
et al. 2010). Another study in 10
POAG patients also reported lower
plasma levels of glutathione peroxidase
though not significant (Ren et al.
2006). In contrast, a significant increase
in glutathione peroxidase activity in the
aqueous humour and plasma of OAG
patients have been reported by others
(Zanon-Moreno et al. 2013; Goyal
et al. 2014). Thus, there is a discrep-
ancy over whether antioxidant enzymes
(such as glutathione peroxidase) are
increased or decreased in POAG cases.
This discrepancy might be caused by
the fact that antioxidant defence is
decreased in patients with glaucoma,
which results in an increase in the
activity of antioxidant enzymes in an
attempt to counteract the damage
caused by reactive oxygen species. No
studies were retrieved that assessed
glutathione-rich food sources in rela-
tion to glaucoma.
Nitric oxide is also known as
endothelium-derived relaxing factor
(EDRF). Ingested nitrate is turned into
the vasodilatator nitric oxide which
improves ocular blood flow (Galassi
et al. 2004; Lidder & Webb 2013; Kang
et al. 2016). Known food sources of
nitrates are dark green leafy vegetables.
Nitric oxide is also produced by the
endothelium. Abnormal function of
endothelial cells is associated with
reduced nitric oxide bioavailability.
These cells may get lost as glaucoma
progresses (Doganay et al. 2002). The
endothelium of Schlemm’s canal expe-
riences physiological shear stress which
triggers nitric oxide production (Ash-
pole et al. 2014). In the femoral artery,
it has been shown that the earlier-
mentioned glutathione may improve
endothelial dysfunction and enhance
nitric oxide availability (Prasad et al.
1999). Nitric oxide plays a role in
several neurodegenerative diseases
(Hannibal 2016). In patients with glau-
coma, diminished nitric oxide levels in
aqueous humour and compromised
ocular hemodynamics compared with
controls have been found (Doganay
et al. 2002; Galassi et al. 2004; Polak
et al. 2007). Studies on the intake of
Acta Ophthalmologica 2018
dark green leafy vegetables showed a
significant protective effect on OAG
(highest quintile OR [95% CI]: 0.82
[0.69–0.97] (Kang et al. 2016), ≥1 serv-
ing per month OR [95% CI]: 0.31
[0.11–0.91] (Coleman et al. 2008) and
>1 serving per week 0.43 [0.21–0.85]
(Giaconi et al. 2012)). However, it is
not clear whether this is due to the
nitrate or due to other antioxidants
present in these vegetables (Ramdas,
et al. submitted).
The nonenzymatic antioxidants
investigated in relation to glaucoma
include the carotenoids and the
flavonoids.
Carotenoids are organic pigments
that can be divided into xanthophylls
(hydrophilic with oxygen) and carote-
nes (hydrophobic or fat-soluble with-
out oxygen). Examples of xanthophylls
are lutein, zeaxanthin, neoxanthin, vio-
laxanthin, flavoxanthin, and alpha-
and beta-cryptoxanthin. Food sources
rich in xanthophylls include green leafy
vegetables, papaya, corn and egg yolk.
There are two primary forms of carote-
nes: alpha-carotene and the more com-
mon beta-carotene. Food sources rich
in carotenes include carrots, pumpkin,
peach, apricots and dark green vegeta-
bles. Regarding the association of
carotenoids (xanthophylls and carote-
nes) and glaucoma, no consistent
results have been published (Kang
et al. 2003; Coleman et al. 2008;
Ramdas et al. 2012). However, one
study reported a protective effect of
alpha-carotene on glaucoma (≥400 vs.
<200 lg OR [95% CI]: 0.45 [0.23–0.88];
p-trend=0.021), but not for other car-
otenoids (Giaconi et al. 2012).
Flavonoids include anthoxanthins,
flavanones, flavanonols, flavans and
anthocyanins. Flavonoids are found
in the following food sources: berries,
tea, ginkgo biloba, red wine and dark
chocolate (cocoa).
Few studies investigated the antho-
cyanins containing blackberries (black-
currants). It has been reported that
anthocyanin intake may improve visual
field indices (Shim et al. 2012). A
placebo-controlled double-masked trial
revealed that after only 2 weeks use of
blackcurrants, the IOP decreased sig-
nificantly in 12 healthy volunteers
(Ohguro et al. 2013). They also anal-
ysed the 24-month effect in OAG
patients and found both an IOP-low-
ering effect and better visual fields in
OAG patients treated with
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Acta Ophthalmologica 2018
blackcurrants compared to those not
treated with blackcurrants (Ohguro
et al. 2012, 2013). Another interesting
finding of this research group is that
endothelin-1 is decreased in OAG
patients but normalizes after consum-
ing blackcurrants. Serum levels of
endothelin-1 in placebo-treated OAG
patients remained low. The study did
not find an effect of intake of black-
currants on nitric oxide concentrations
in the 38 included patients (Yoshida
et al. 2013).
One study investigated the short-
term effect of dark chocolate rich in
flavonoids on glaucoma. They found
retinal vasodilatation in the control
group, but not in the glaucoma group.
The authors proposed that the non-
significant finding in the glaucoma
group could be related to an already
impaired endothelial function in these
patients (Terai et al. 2014). The bene-
ficial effects of flavonoids on the vas-
cular endothelial function are probably
caused by decreasing oxidative stress
and increasing nitric oxide bioavail-
ability, which lead to an improvement
of endothelium-dependent vasodilata-
tion and thus ocular blood flow
(Hermann et al. 2006).
A systematic review and meta-ana-
lysis reported a favourable effect of
flavonoids on visual fields in glaucoma
patients, but no association of flavo-
noids with IOP was found (Patel et al.
2015). A limitation of their report was
that the results were heavily influenced
by one large study (Quaranta et al.
2003; Milea & Aung 2015). The data
supports the hypothesis that the IOP-
independent effect of flavonoids is
based on its neuroprotective properties
and increase in ocular blood flow.
However, the longitudinal popula-
tion-based prospective Rotterdam
Study did not find any significant
association between flavonoids and
the risk of OAG after an average
follow-up of 9.7 years (Ramdas et al.
2012).
Omega-fatty acids
Omega-3 and omega-6 fatty acids are
among the most common fatty acids
affecting vascular properties (i.e. the
(cardio-)vascular status of patients).
Derivatives of these fatty acids are the
eicosanoids. These include the prosta-
glandin analogues, which are known
for their IOP-lowering effect
554
(Stjernschantz 2001). Dietary fatty
acids affect endogenous prostaglandin
concentrations. Food sources rich in
omega-3 and omega-6 fatty acids are
flaxseed oil, fish oil and walnuts.
Patients with glaucoma may have
reduced omega-3 levels in blood (Ren
et al. 2006). In line with this, it has
been suggested that a low intake of
omega-3 fatty acids may increase the
risk of POAG (Renard et al. 2013).
The Nurses’ Health Study and Health
Professionals Follow-up Study
(N = 116 505) and the longitudinal
SUN cohort (N = 17 128) found no
association with glaucoma for omega-3
or omega-6 fatty acids, though in both
studies, participants with high omega-
3:6 ratio had a higher risk of develop-
ing glaucoma (both for the highest
quintile: OR [95% CI]: 1.49 (1.11–
2.01); p-trend = 0.10 and HR [95%
CI]: 1.91 [1.05–3.46]; p-trend = 0.03,
respectively; Kang et al. 2004; Perez de
Arcelus et al. 2014). However, neither
the Rotterdam Study nor the study on
osteoporotic fractures in African
Americans could confirm this associa-
tion (Giaconi et al. 2012; Ramdas
et al. 2012). A randomized controlled
trial (N = 117; follow-up 2 years)
about antioxidant and omega-3 fatty
acid commercially available supple-
ments did neither find significant dif-
ferences in retinal nerve fibre layer
thickness nor in visual field indices
between participants using supple-
ments and controls (Garcia-Medina
et al. 2015).
Discussion
This review summarizes published find-
ings from the literature concerning the
association between common nutrients
and glaucoma. Most studies focused on
OAG. Interesting findings were that
selenium and iron may increase the risk
of glaucoma, glutathione plays an
important role in regulating oxidative
stress in eyes with glaucoma and nitric
oxide (especially dark green leafy veg-
etables containing high nitrate) seems
to have a beneficial effect on glaucoma.
Another promising nutrient is flavo-
noids, though, large longitudinal stud-
ies are scarce. For other nutrients, no
consistent significant association was
found.
Several studies have implicated that
nutrients affect the disease course of
common eye diseases, for example age-
related macular degeneration and cat-
aract (Mares 2004; Evans 2008). Even
the type of a person’s diet may have an
impact on eye diseases. Persons who
are vegetarian are at lower risk of
cataract than persons who eat meat
(Appleby et al. 2011). Regular intake
of a Mediterranean diet may reduce the
risk of cataract and age-related macu-
lar degeneration, and possibly glau-
coma (Mo€ıse et al. 2012; Merle et al.
2015). According to the current litera-
ture, it is obvious that oxidative stress
plays an important role in the patho-
genesis of glaucoma. Oxidative damage
is linked to two components: decreased
antioxidant defence and mitochondri-
opathy (Sacc
a et al. 2016). Systemic
oxidative stress is also associated with
decreased ocular blood flow (Himori
et al. 2016). The close relationship
between oxidative stress and blood
flow is related to the vascular perme-
ability which causes a release of
endothelin (vasoconstriction): a coun-
terpart of nitric oxide (vasodilatation).
Vasoconstriction results in ischaemia
of the trabecular meshwork, a tissue
composed of endothelial cells, which in
turn leads to a higher IOP. Blood levels
of endothelin-1 have found to be
significantly higher in patients with
POAG (Lopez-Riquelme et al. 2014).
This theory supports the association of
nitric oxide with OAG.
A healthy person with a positive
family history of glaucoma has higher
odds to develop glaucoma compared to
someone without any relative with
glaucoma. Of interest is that the pat-
tern of dietary intake of a person has a
high heritability of 30% (van den Berg
et al. 2013). Furthermore, people may
respond differently to the same diet.
This differential response can be influ-
enced by genotype as also suggested by
the Age-Related Eye Disease Study
(Awh et al. 2015; Merle et al. 2015).
For this reason, we should not only
take the physiological and metabolic
characteristics of individuals into
account but also the genetic character-
istics. For example, it has been pro-
posed that gene–gene interaction
between polymorphisms in vitamins
C, E, and glutathione-related genes
play an important role in POAG
(Zanon-Moreno et al. 2013). Espe-
cially, the glutathione S-transferases
genes (GSTM1 and GSTT1) play
important roles in cellular protection
against oxidative stress. The GSTM1

null genotype leads to loss of enzyme
activity and ultimately impedes detox-
ification increasing the risk for glau-
coma (Huang et al. 2013).
The association of nutrition with the
different forms of glaucoma seems
complex, and data on the combined/
additive effect of different nutrients on
glaucoma is scarce. Only a few studies
investigated the effect of dietary intake
of nutrients on glaucoma. Therefore,
conducting a meaningful meta-analysis
was not possible in the present review.
Another limitation is the different
methods used for assessing the expo-
sure (nutrients) and outcome (glau-
coma) across the studies (Table S1).
This makes it difficult to compare
results between studies. Furthermore,
dietary assessment methods rely on the
participant’s memory and perceptions
and face the difficulties of the extreme
day-to-day variability in human diet,
the hidden nature of many fats used for
dressing and cooking, the bias in
reporting due to social standards and
nutritional recommendations, and the
estimation of the nutritional content of
foods. However, participants’ error in
dietary reporting would result in biases
towards null associations. Further-
more, next to dietary intake, the cur-
rent review also accounts for in vitro
studies and studies on the nutritional
status of individuals.
As the aetiology of POAG remains
unclear, discoveries in cell physiology
can be assimilated from the literature
and applied to known homeostatic
mechanisms of the eye. In this way,
the possible roles of nutritional com-
ponents involved in the aetiology of
glaucoma can be described (Veach
2004). Although a nutritional supple-
ment for glaucoma might be an out-
come for persons with advanced
glaucoma, a clear effect on the disease
as in age-related macular degeneration
probably does not exist. One of the
following steps for future research may
be studies on the nutritional genomics
of glaucoma so that we may design
personalized diets for each patient in
the future. Especially, more longitudi-
nal studies and randomized clinical
trials are required to explore the role
of nutrition in glaucoma and to inves-
tigate whether nutritional supplements
can become part of the treatment of
glaucoma.
In conclusion, although there is
broad evidence that oxidative stress
plays an important role in the patho-
genesis of different types of glaucoma,
studies on the effect of dietary intake of
nutrients on glaucoma are scarce. With
our current knowledge, it is difficult to
advise a patient with glaucoma on his/
her food habits. According to the
current review, a patient with OAG
should avoid selenium and iron (e.g.
red meat) and use glutathione and
nitric oxide-rich foods (e.g. dark green
leafy vegetables). However, random-
ized clinical trials are lacking. This
review highlighted new targets and
strategies for future research aiming
to assess the influence of nutrition on
glaucoma.
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Received on June 8th, 2017.
Accepted on November 6th, 2017.
Correspondence:
Wishal D. Ramdas, MD, PhD
Department of Ophthalmology
Maastricht University Medical Center
P. Debyelaan 25, 6229 HX
Maastricht
The Netherlands
Tel: 0031 43 3 87 48 83
Emails: w.ramdas@mumc.nl;
w.ramdas@erasmusmc.nl
Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Table S1. Summary of the retrieved
studies from the systematic review in
alphabetical order.