Running head: CAROTENOID-RICH DIET AND AMD 1

Relationship between Carotenoid-Rich Diets and Age-Related Macular Degeneration (AMD)

Prevention: A Systematic Review

Amanda J. Tome

West Chester University

NTD 630 Capstone Course for Master of Science in Community Nutrition

July 28, 2017

CAROTENOID-RICH DIET AND AMD 2

Table of Contents

Table of Contents ............................................................................................................................ 2

List of Tables .................................................................................................................................. 3

List of Figures ................................................................................................................................. 3

Abstract ........................................................................................................................................... 4

Introduction ..................................................................................................................................... 5

Methods........................................................................................................................................... 6

Search Strategy ................................................................................................................... 6

Data Extraction and Quality Assessment ............................................................................ 8

Results ............................................................................................................................................. 9

Literature Search ................................................................................................................. 9

Study Design ..................................................................................................................... 11

Xanthophylls ..................................................................................................................... 22

Other Carotenoids ............................................................................................................. 23

Genetics............................................................................................................................. 24

Discussion ..................................................................................................................................... 25

Strengths and Limitations ................................................................................................. 28

Implications for Future Research and Practice ................................................................. 29

Conclusion .................................................................................................................................... 29

References ..................................................................................................................................... 30

Appendix ....................................................................................................................................... 33

A: Quality Criteria Checklist for Primary Research ......................................................... 33

B: Conclusion Grading Table .......................................................................................... 36

CAROTENOID-RICH DIET AND AMD 3

List of Tables

Table

1. Search Strategy ....................................................................................................................7

2. Screening and Selection Tool for Identifying Studies Assessing the Relationship between

a Carotenoid-Rich Diet and AMD Prevention .....................................................................8

3. Data Extraction Table of Studies Assessing the Relationship Between a Carotenoid-Rich

Diet and AMD Prevention .................................................................................................12

4. Quality Assessment of Studies Assessing the Relationship Between a Carotenoid-Rich

Diet and AMD Prevention .................................................................................................21

5. Reported Mean (or Range) of Lutein and Zeaxanthin Consumed by Study......................23

6. Reported Mean (or Range) of β-Carotene Consumed by Study ........................................24

List of Figures

Figure

1. Flow Diagram of Selection Process ...................................................................................10

CAROTENOID-RICH DIET AND AMD 4

Abstract

Objective: To determine the effect of a diet rich in carotenoids in the prevention of age-related

macular degeneration (AMD) among adults.

Methods: Scholarly, English language studies, published between May 2010 and June 2017,

were identified via MEDLINE, CINAHL, and PubMed electronic databases. Randomized

control trials or observational studies investigating the effect of carotenoids from diet on the

development of AMD among adults were included. Included studies were critically evaluated

using the Quality Criteria Checklist.

Results: Seven observational studies met the inclusion criteria and were included in this review.

All studies but one received a neutral rating. Of the five studies that investigated lutein and

zeaxanthin, three found a reduced risk of late or combined AMD among subjects with the highest

dietary intake and two only found a reduced risk among participants with genetic susceptibility.

Higher intake of lutein and zeaxanthin was associated with a reduced risk of early AMD among

CFH genotype carriers. All three studies that examined β-carotene found a reduced risk of late

or combined AMD. Only observational studies met the inclusion criteria, so a causal

relationship cannot be ascertained.

Conclusion: A carotenoid-rich diet may be associated with a reduced risk of AMD, particularly

late AMD among a general adult population and early AMD among adult CFH genotype

carriers. More research and higher quality studies are needed to definitively establish this

association and to ascertain the amount of carotenoids needed to prevent AMD.

CAROTENOID-RICH DIET AND AMD 5

Relationship between Carotenoid-Rich Diets and Age-Related Macular Degeneration (AMD)

Prevention: A Systematic Review

Age-related macular degeneration (AMD) is the leading cause of blindness among adults

aged 50 years or older in the United States (U.S.) and is responsible for 8.7% of all blindness

cases globally (National Eye Institute [NEI], 2015; Wong et al., 2014). As AMD progresses, the

macula – the central region of the retina that regulates central vision – is damaged, resulting in

vision loss (NEI, 2015). Age-related macular degeneration is categorized into three stages: (1)

early AMD, which is characterized by the presence of a several soft, small (< 63 μm diameter)

drusen – small yellow lipid deposits that form beneath the retina, one medium (63 – 124 μm

diameter) druse, or mild pigment changes to the retinal pigment epithelium (RPE); (2)

intermediate AMD, which is characterized by the presence of a several medium drusen, one large

(> 124 μm diameter) druse, and/or RPE pigment changes; and (3) late AMD, which is

characterized by the presence of a large drusen, pigment RPE degradation, and vision loss

(American Academy of Ophthalmology Retina/Vitreous Preferred Practice Pattern Panel &

Hoskins Center for Quality Eye Care, 2015; NEI, 2015). In 2010, 9.1 million Americans had

early AMD and 2.1 million Americans had late AMD; however, the prevalence of early and late

AMD are projected to double by the year 2050, to 17.8 and 5.4 million Americans, respectively

(NEI, n.d.; Rein et al., 2009). In 2004, AMD was responsible for $575 million in direct medical

costs, which does not include lost productivity, home health care costs, and long-term care

facility costs (Rein et al., 2009).

The etiology for AMD is still mostly unknown; however, scientific evidence suggests

that age, race, and genetics are dominant, non-modifiable risk factors, and that oxidative stress

plays an important role in its pathogenesis (NEI, 2015; Shaw et al., 2016). Dietary antioxidants
CAROTENOID-RICH DIET AND AMD 6

are suspected to play a role in preventing or slowing the progression of AMD because

antioxidants neutralize free radicals created by oxidative stress and the macular pigment is

comprised of lutein, zeaxanthin, and meso-zeaxanthin, carotenoids with antioxidant properties.

To date, there have been two systematic reviews investigating the role of dietary

supplements in AMD prevention and one systematic review, by Ma et al. (2011), investigating

the relationship between dietary lutein and zeaxanthin intake and AMD prevention. In their

review of studies published through April 2010, Ma et al. (2011), found that dietary lutein and

zeaxanthin did not significantly reduce the risk of early AMD but that dietary lutein and

zeaxanthin intake may prevent the risk of developing late AMD, and concluded that additional

research was needed for confirmation of their results. Therefore, the purpose of this review is to

systematically review and critically evaluate new scientific research to determine the effect of a

diet rich in carotenoids in the prevention of AMD among adults.

Methods

Search Strategy

Studies were identified by searching the electronic databases MEDLINE, CINAHL, and

PubMed, for studies published between May 1, 2010 and June 30, 2017, using various

permutations of the MeSH terms and keywords carotenoids, antioxidants, lutein, zeaxanthin,

xanthophyll, age-related macular degeneration, AMD, ARMD, age-related maculopathy, vision,

and eye health. Searches were limited to scholarly, peer-reviewed journals and those available in

the English language. The search strategy is outlined in Table 1.

CAROTENOID-RICH DIET AND AMD 7

Table 1

Search Strategy
Keyword/MeSH Terms ‘AND’ keyword/MeSH Terms
Carotenoid AMD OR age-related macular degeneration
Carotenoid Eye health OR vision
Antioxidants AMD OR age-related macular degeneration
Antioxidants Eye health OR vision
Lutein OR zeaxanthin ARMD OR age-related maculopathy
Lutein OR zeaxanthin Eye health OR vision

To minimize bias, a screening and selection tool with defined inclusion and exclusion

criteria was created and is outlined in Table 2. Every title and abstract identified via the keyword

searches was screened using the predefined inclusion and exclusion criteria. National and

international randomized control trials, cohort, cross-sectional, and case-controlled studies that

included adults over the age of 18 years were included. In vitro, animal studies, and those

including children (< 18 years) were excluded. Only studies investigating diet as the

intervention and the diagnosis or presence of AMD as the primary outcome were included;

studies investigating dietary supplements, pharmaceuticals, or medical procedures were

excluded. Full-text articles of all potentially relevant studies were obtained through the

electronic database if full-text was available or through West Chester University’s interlibrary

loan system, Iliad, and then reviewed for relevance using the screening and selection tool. All

studies that met the inclusion criteria were included in this review. References were exported

and organized using the bibliographic management software, RefWorks, and articles were

downloaded and stored in a designated file folder.

CAROTENOID-RICH DIET AND AMD 8

Table 2

Screening and Selection Tool for Identifying Studies Assessing the Relationship Between a Carotenoid-
Rich Diet and AMD Prevention
Include Exclude
Patient Population Adults (≥ 18 years) Children (<18 years)
Animals
Cells
Interventions Diet Pharmaceutical
AMD medical treatments/procedures
Dietary Supplements
Comparators No intervention/Placebo
Outcomes Diagnosis/presence of AMD Not diagnosis/presence of AMD
Study Design RCT, Cohort, Case-Controlled, Cross- Not an RCT, cohort, case-controlled, or
Sectional cross-sectional study
Language English Not English
Time May 2010 Before May 2010
Location U.S. and International

Data Extraction and Quality Assessment

Pertinent reference information, the study design, the research objective, study population

characteristics, intervention details, results and primary outcomes, limitations, and authors’

conclusions were extracted from each study. In studies reporting multiple risk estimates, the risk

estimate that adjusted for the most confounding factors was extracted for this report.

Each included study was critically evaluated using the Quality Criteria Checklist for

primary research, which assigns a grade of positive, neutral, or negative, based on four relevance

and 10 validity questions (see Appendix A). A study is classified as (a) positive, if all of the

relevance and the majority of the validity questions and specific questions are answered

positively; (b) negative, if the majority of the validity questions are answered negatively; or (c)
CAROTENOID-RICH DIET AND AMD 9

neutral, if the majority of the validity questions are answered positively but at least one of the

specific validity questions is answered negatively.

Results

Literature Search

Using a combination of keyword searches, 1752 citations were identified via the

electronic databases (Figure 1). There were 766 duplicates identified and deleted, resulting in

986 titles and abstracts to be screened. The title and abstract screening process identified 70

potential citations for inclusion, and the full-text articles were obtained. Of those 70 citations, 63

were excluded because they did not meet the specified patient population, intervention, or

outcome; therefore, 7 studies were included in this review.

CAROTENOID-RICH DIET AND AMD 10

Records identified through Additional records identified

database searching through other sources
Identification

(n = 1752) (n = 0)

Records after duplicates removed

(n = 986)
Screening

Records screened Records excluded

(n = 986) (n = 916)

Full-text articles assessed Full-text articles

for eligibility excluded(n = 63):
(n = 70)  inappropriate patient
population
Eligibility

 inappropriate
Studies included in intervention
qualitative synthesis  inappropriate
(n = 7) outcome

Studies included in
Included

quantitative synthesis
(meta-analysis)
(n = 0)
CAROTENOID-RICH DIET AND AMD 11

Study Design
The extracted study characteristics are reported in Table 3, and the quality assessment

results are shown in Table 4. Of the seven studies included in this review, one was rated as

positive and the remaining six were rated as neutral. The study designs of the included studies

vary; however, all were observational study types, as none of the RCT studies met the inclusion

criteria. There were four cohort studies (Lin et al, 2017; Mares et al., 2011; Wang et al., 2014;

Wu, Cho, Willett, Sastry, & Schaumberg, 2015), two case-control studies (Aoki et al., 2016; Ho

et al., 2011), and one cross-sectional study (Nidhi, Mamatha, Padmaprabhu, Pallavi, &

Vallikannan, 2013). Of the four cohort studies, three were prospective studies (Lin et al., 2017;

Mares et al., 2011; Wu et al., 2015). Two studies solely focused on lutein and zeaxanthin (Lin et

al., 2017; Wu et al., 2015), whereas five studies investigated various dietary components,

including carotenoids (Aoki et al., 2016; Ho et al., 2011; Mares et al., 2011; Nidhi et al., 2013;

Wang et al., 2014). Three studies also investigated the role of diet and genetics on AMD (Ho et

al., 2011; Lin et al., 2017; Wang et al., 2014), although only two genotypes, CFH and ARMSS2,

were assessed in at least two studies. Four studies investigated the effect of diet on prevention of

early AMD (Ho et al., 2011; Lin et al., 2017; Mares et al., 2011; Wang et al., 2014), one on the

prevention of late AMD (Wu et al., 2015), and two on any stage of AMD (Aoki et al., 2016;

Nidhi et al., 2013).

CAROTENOID-RICH DIET AND AMD 12

Table 3

Data Extraction Table of Studies Assessing the Relationship Between a Carotenoid-Rich Diet and AMD Prevention
Author/Year Purpose of Study Intervention Outcomes Conclusion Limitations
Study Population
Study
Design
Quality
Assessment
Rating
Lin et al., To assess the n = 10,295 Dietary No significant No suggested  Assessed
2017 relationship Caucasian or xanthophyll differences in association prevalent not
between African (lutein & odds ratio (OR) between dietary incident
Study
dietary American zeaxanthin) for early AMD xanthophyll AMD
Design:
xanthophyll adults (80% intake measured and xanthophyll intake and early  6 year
Population-
intake and Caucasian, using a validated intake (Q1 = AMD among interval
based,
prevalent early 55% female, 66-item FFQ at 1.00, Q2 & Q3 = middle-aged between
prospective
AMD using 32.8% have 2 visit 1 (1987-89) 1.07, Q4 = 1.09, Caucasian and visits 1 & 3
cohort
data from the risk alleles), and visit 3 (1993- Q5 = 1.02, p = African  Dietary
Rating: Ø Atherosclerosis aged 45-64 95) and adjusted .91) after American adults; xanthophyll
Risk in years (mean for estimated adjustments for however, more intake
Communities age 53.9±1 daily energy gender, age, research needed measured by
Study (ARIC) years), from intake smoking, caloric to explore effects FFQ
the United intake, and field of genetic  Only 1 study
Prevalent AMD
States center susceptibility & group
(soft drusen
HDL metabolism  Blinding
diameter ≥ 63 μm Greater
procedures
or loss of retinal xanthophyll
unclear
pigment intake
epithelium) significantly
determined via decreased odds
fundus of early AMD
photography at for Caucasian
CAROTENOID-RICH DIET AND AMD 13

visit 3 carriers of 1 risk

allele of CFH
rs1061170
genoptype (T3
vs T1, OR = .63,
p = .28) but not
for 0 or 2 risk
alleles, African
Americans, or
those with
ARMS2
10490924
genotype
Aoki et al., To assess the Case Subjects:Nutrient intake of OR (Q1 vs Q5) Dietary intake of  Poor
2016 relationship n = 157, 67.5%β-carotene, α- for AMD β-carotene, α- generalizabili
between male, mean tocopherol, Ω-3 significantly tocopherol, Ω-3 ty due to
Study
neovascular age 73.5±7.1 fatty acids, decreased as fatty acids, limited
Design:
AMD and years, mean vitamins C & D, intake of β- vitamins C & D, geographic
Case-Control
nutrient intake BMI 22.7±2.9, & zinc, assessed carotene (OR = & zinc are inclusion and
Rating: Ø among 58% smokers via a self- .2, p < .001), α- associated with a control
Japanese adults administered 58- tocopherol (OR decreased risk of subjects
Control
by comparing item brief dietary = 0.2, p < .001), AMD selected from
Subjects: n =
those with history Ω-3 fatty acids Hatoyama
369, 61.5%
neovascular questionnaire (OR = 0.2, p < cohort
male, mean
AMD to (BDHQ), .001), vitamin C  Case subjects
age 73.1±5.6
healthy adults compared to a 3- (OR = 0.4, p = may have
years, mean
control BMI 23.1±2.8, day food log, and .04), vitamin D changed diet
subjects 49.9% smokers analyzed using (OR = 0.4, p = after AMD
the Standard .002), & zinc diagnosis and
Tables of Food (OR = 0.1, p < not reported
Composition in .001) increased, dietary
after adjustments changes
CAROTENOID-RICH DIET AND AMD 14

Japan for gender, age,  Blinding

supplement use, procedures
and smoking and unclear
chronic disease  Intervention
histories not
sufficiently
described
Wu et al., To investigate NHS: n = Carotenoid intakeMultivariate Higher dietary  FFQ could
2015 how 52,740, mean was assessed via Relative risk intake of lutein, result in
carotenoids, age 62.2 years, a comprehensive (RR; Q1 vs Q5) zeaxanthin, and inaccurate
Study
specifically 98% FFQ, with an of advanced α-carotene nutrient
Design:
lutein and Caucasian, expanded fruit AMD reduces the long- intake
Prospective
zeaxanthin, 100% female, and vegetable significantly term risk of  Lutein and
Cohort
affect AMD mean BMI section, decreased for the advanced AMD. zeaxanthin
Rating: (+) development 26.8, 11.4% administered highest dietary Increasing evaluated
by examining smokers every 4 years intake/predicted carotenoid-rich jointly
2 ongoing beginning in plasma levels of fruit and  Subjects with
HPFS: n =
prospective 1984 and 1986 lutein/zeaxanthin vegetable intermediate
24,996, mean
cohorts, the age 63.2 years, for NHS and (RR = .59, p < consumption AMD may be
Nurses’ Health HPFS, .001), β- may reduce taking
95.8%
Study (NHS) respectively cryptoxanthin advanced AMD AREDS2
Caucasian,
and the Health (RR = 0.73, p = incidence formula
mean BMI 26, Intermediate
Professionals .002), α-carotene supplements,
5% smokers AMD (drusen
Follow-up diameter ≥ 63μm, (RR =0.69, p < which could
Study (HPFS) .001), β-carotene minimize
pigment
(RR = 0.82, p = dietary
abnormality, or
.03) effects
any noncentral
 Only 1 study
geographic No association
group
atrophy) and between
 Blinding
advanced AMD intermediate
procedures
(neovascular AMD and
CAROTENOID-RICH DIET AND AMD 15

AMD or central predicted plasma unclear

geographic levels (Q1 vs.
atrophy) Q5) of
incidence lutein/zeaxanthin
assessed via a (RR = 0.97, p =
biennial .17), β-
questionnaire and cryptoxanthin
validated by (RR = 0.90, p =
reviewing .12), α-carotene
subjects’ medical (RR = 0.98, p =
records .69), β-carotene
(RR = 0.99, p =
.88)
Wang et al., To investigate BMES: n = BMES: nutrient Pooled data Dietary lutein  Different
2014 the effect of 1854 intake assessed at adjusted for and zeaxanthin dietary
dietary intake (predominantly baseline (1992- gender, age, consumption is assessments
Study
of fish and Caucasian) 94) using a self- smoking, study correlated with a utilized
Design:
antioxidants administered site, and energy 20% reduction of among each
Population-  Control
based Cohort between Subjects: n = 145-item FFQ intake early AMD population
genetic and analyzed among adults  Limited
Pooled Data 723, mean OR for AMD
susceptibility using Australian with high- number of
Analysis age 61.3 and the highest
and AMD Tables of Food genetic-risk (2 late AMD
years, 45.1% tertile of lutein
Rating: Ø incidence Composition alleles). More cases
male, 47.9% and zeaxanthin
using data by 1990 research is  Unclear if
non-smokers, intake among
examining the needed to study groups
31.0% 2 RS: nutrient adults with 0
comparing confirm these were
genotype risk intake assessed at risk alleles (early
adults with AMD 1.47; late results. comparable
alleles baseline (1990-
AMD to  Blinding
 Case 93), using a self- AMD 0.65) and Understanding
control groups AMD procedures
Subjects: n = administered 2 risk alleles
from 2 cohort (early 0.78; late pathogenesis unclear
555, mean home checklist
studies, the requires
age 65.8 and a 170-item 0.64)
Blue incorporating
CAROTENOID-RICH DIET AND AMD 16

Mountains Eye years, 38.2% FFQ OR for AMD both genetic and
Study (BMES) male, 54.5% administered by a and ≥ 1 serving environmental
and the non-smokers, trained dietitian fish/week among factors.
Rotterdam 40.9% 2 and analyzed adults with 0
Study (RS) genotype risk using the Dutch risk alleles (early
alleles Food 1.17; late 0.91)
Composition and 2 risk alleles
RS: n = 2778
Table (early 0.89; late
 Control 0.54)
AMD assessed
Subjects: n =
using retinal OR for AMD
2006, mean
photography by and highest
age 65.01
trained specialists tertile of vitamin
years, 42.1%
during at least 1 C intake among
male, 33.0%
follow-up visit adults with 0
non-smokers,
(BMES follow- risk alleles (early
25.7% 2
ups every 5 0.91; late 0.78)
genotype risk
years; RS follow- and 2 risk alleles
alleles
ups 1997-99, (early 0.87; late
 Case
2002-04, & 0.67)
Subjects: n =
2009-11)
772, mean
age 66.18
years, 40.8%
male, 32.7%
non-smokers,
43.6% 2
genotype risk
alleles
Nidhi et al., To explore n = 3549 Socio- AMD incidence Higher intake of  1/10 of
2013 AMD demographic, decreased as carotenoids, fundus
Urban
prevalence and lifestyle factors, lutein and specifically photographs
Study subjects: n =
putative risk and medical zeaxanthin lutein and were
Design: 2641, mean
CAROTENOID-RICH DIET AND AMD 17

Cross- factors age history assessed intake increased zeaxanthin, is unreadable

Sectional associated with 59.76±8.25 via an (0-1 mg/day associated with a which may
hospital- AMD among years, 59.3% administered 3.6%, 1-2 reduced risk of have
based adults in male questionnaire mg/day 2.6%, 2- AMD. It is distorted
descriptive Southern India 3 mg/day 1.5%, important to results
Rural subjects: Nutrient intake
study who visited a > 3 mg/day 0%, identify dietary  Small
assessed via a
tertiary eye n = 908, mean p = .001) interventions to percentage of
Rating: Ø FFQ and
care center age 59.5±8.45 prevent or subjects with
analyzed using a β-carotene
years, 57.6% prolong AMD AMD
food database intake and AMD
male onset  Only 1 study
incidence (0-1
Early AMD group
mg/day 3.4%, 1-
(presence of soft  Blinding
2 mg/day 1.5%,
drusen or retinal procedures
2-3 mg/day
pigment unclear
1.7%, > 3
epithelium  Intervention
mg/day 0%, p =
abnormality) and not
.001)
late AMD sufficiently
(presence of Risk of AMD is described
neovascular or reduced by
geographic dietary intake of
atrophy) assessed lutein and
via fundus zeaxanthin (OR
photography by = 0.38, p < .001)
ophthalmologists and β-carotene
and confirmed by (OR = 0.65, p <
principal .001)
ophthalmologist

Ho et al., To investigate Control Nutrient intake of Among The risk of  Small

2011 how Subjects n = lutein/zeaxanthin, homozygous developing early percentage of
antioxidants, 1650, mean β-carotene, CFH genotype AMD among subjects in
Study
Ω-3 fatty acids, age 65.9 years, EPA/DHA, carriers, higher genetically stratified
CAROTENOID-RICH DIET AND AMD 18

Design: and zinc affect 56.7% female, vitamins A, C, intake of zinc susceptible adults analysis may
Nested case- incident early mean BMI and E, zinc, and (T1 HR = 2.25, may be reduced have skewed
control AMD among 26.5, 31.7% iron assessed, at T3 HR = 1.27, p by high dietary results
adults with non-smokers, baseline, via a = .03), β- intake of causing
Rating: Ø
genetic 44.6% non- self-administered carotene (T1 HR antioxidants, Ω-3 underestimati
susceptibility carriers of home checklist = 2.54, T3 HR = fatty acids, and on
by examining CFH Y402H (inquiring about 1.47, p = .05), zinc. Young  Possible
adults with genotype, food and EPA/DHA (T1 adults with a confounding
early AMD 67.5% non- beverages HR = 1.97, T3 genetic risk of factors as
compared to carriers of consumed two or HR = 1.30, p = AMD should individuals
control LOC387715 more times per .03), and consume with a
subjects from a A69S month over the lutein/zeaxanthin sufficient healthy diet
prospective, geneotype preceding year, (T1 HR = 2.63, amounts of most likely
population- supplement use, T3 HR = 1.72, p antioxidants, also have
Case Subjects:
based cohort and dietary = .05) reduced zinc, and Ω-3 other
n = 517, mean
study, the habits/diets and a the risk of early fatty acids potentially
age 68.1 years,
Rotterdam 170-item FFQ AMD protective
56.5% female,
Study administered by a healthy
mean BMI Among
trained dietitian lifestyle
26.2, 32.0% LOC387715
and analyzed factors
non-smokers, genotype
using the  Blinding
38.1% non- carriers, higher
electronic Dutch procedures
carriers of intake of zinc
Food unclear
CFH Y402H (T1 HR = 1.70,
Composition  Intervention
genotype, T3 HR = 1.17, p
Tables not
58.9% non- = .03) and
sufficiently
carriers of Early AMD EPA/DHA (T1
described
LOC387715 (presence of a HR = 1.59, T3
 Unclear if
A69S soft drusen or HR = 0.95, p =
participants
geneotype pigment .01) reduced the
are
abnormality) risk of early
assessed at AMD representativ
e of
baseline and 3
CAROTENOID-RICH DIET AND AMD 19

follow-up visits population

(mean follow-up
8.6 years) via
fundus
photography by a
trained grader
Mares et al., To explore the n = 1313 Dietary intake Compared to the A healthy  Poor
2011 effect of diet, (100% female, assessed at WHI lowest quintile, lifestyle generalizabili
smoking, and median BMI baseline (1994- the highest including ty to males
Study
physical 27.7, 53% non- 98) via a semi- quintile diets physical activity, and non-
Design:
activity on smokers), aged qualitative FFQ (Q5 mHEI OR = not smoking, and Caucasian
Prospective
AMD among 50-74 years and analyzed 0.54, p = .01; Q4 a healthy diet, is females
Cohort
participants of using the aMED OR = associated with  Participants
Rating: Ø the modified 2005 0.34, p = .046), lower AMD had healthier
Carotenoids in Healthy Eating physical activity prevalence lifestyles
Age-Related Index (mHEI) (Q5 MET OR = among post- than general
Eye Disease and the 0.46, p = .002), menopausal population
Study alternative and healthy women. The which may
(CAREDS) Mediterranean lifestyles (Q5 study supports have
and the Diet (aMED) HLS OR = 0.29, current weakened
Women’s p < .001) had a recommendations results
Early AMD
Health significantly to engage in low  Sample size
(presence of a
Initiative reduced risk of intensity not large
large drusen ≥
(WHI) study, early AMD after physically enough to
125 μm or retinal
who had the adjusting for activity 1-2 evaluate
pigment
lowest ( < 28th age, chronic hr/day, not variables
epithelium
percentile) and disease history, smoke, and independentl
abnormality with
highest ( > 78th smoking, and consume a y
a drusen ≥63μm)
percentile) family AMD healthy plant-  Blinding
assessed at
dietary lutein history based diet, with procedures
CAREDS
and zeaxanthin moderate and unclear
baseline (2001-
varied protein,  Unclear how
CAROTENOID-RICH DIET AND AMD 20

intake 04) via and limited fat, participants

stereoscopic sugar, refined were
fundus grain, oils, and groups/treate
photography by alcohol d
the University of
Wisconsin
Fundus
Photography
Reading Center
CAROTENOID-RICH DIET AND AMD 21

Table 4

Quality Assessment of Studies Assessing the Relationship Between a Carotenoid-Rich Diet and AMD Prevention
Author(s) Design Q1a Q2b Q3c Q4d Q5e Q6f Q7g Q8h Q9i Q10j QAk
Lin et al., 2017 Cohort Y N N/A N UC N Y Y Y Y Ø
Aoki et al., 2016 Case-Control Y Y Y N N UC Y Y Y N Ø
Wu et al., 2015 Cohort N Y N/A N N Y Y Y Y Y +
Wang et al., 2014 Cohort Y UC UC N UC Y Y Y Y Y Ø
Nidhi et al., 2013 Cross-Sectional Y Y N/A Y UC N Y Y Y Y Ø
Ho et al., 2011 Cohort Y UC Y N N N Y Y Y Y Ø
Mares et al., 2011 Cohort Y Y UC N N Y Y Y Y Y Ø
a
Q1=Question 1: Was the research question clearly stated?
b
Q2=Question 2: Was the selection of study subjects/patients free from bias?
c
Q3=Question 3: Were study groups comparable?
d
Q4=Question 4: Was method of handling withdrawals described?
e
Q5=Question 5: Was blinding used to prevent introduction of bias?
f
Q6=Question 6: Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were intervening factors
described?
g
Q7=Question 7: Were outcomes clearly defined and measurements valid and reliable?
h
Q8=Question 8: Was the statistical analysis appropriate for the study design and type of outcome indicators?
i
Q9=Question 9: Are conclusions supported by results with biases and limitations taken into consideration?
j
Q10=Question 10: Is bias due to study’s funding or sponsorship unlikely?
k
QA= quality assessment; l+=positive; m-=negative; nØ=neutral; oY=yes; pUC=unclear; qN/A=not applicable; rN=no
CAROTENOID-RICH DIET AND AMD 22

Xanthophylls

Lutein and zeaxanthin dietary intake was assessed in five of the seven included studies.

The amounts of xanthophylls reported in each study are described in Table 5. Three studies

found a reduced risk of AMD associated with higher dietary lutein and zeaxanthin intake (Nidhi

et al., 2013; Wang et al., 2014; Wu et al., 2015); two did not find an overall reduced risk except

among participants with a specific genetic risk (Ho et al., 2011; Lin et al., 2017). Higher dietary

consumption of lutein and zeaxanthin was found to reduce the risk of late AMD by 40% (RR =

0.59, p < .001; Wu et al., 2015), and early AMD among adults with 2 risk alleles of CFH and/or

ARMS2 genotype by 22% (OR = 0.78; Wang et al., 2014), and the risk of any form of AMD by

60% (OR = 0.38, p < .001; Nidhi et al., 2013). However, Lin et al. (2017) found no association

between the highest tertile dietary xanthophyll intake and early AMD among middle-aged adults

except among Caucasian carriers of one risk allele of CFH genotype (OR = 0.63, p = .28), and

Ho et al. (2011) only found a reduced risk of early AMD among carriers of CFH genotype who

consumed the highest tertile of lutein and zeaxanthin (T1 HR = 2.63, T3 HR = 1.72, p = .05).
CAROTENOID-RICH DIET AND AMD 23

Table 5

Reported Mean (or Range) of Lutein and Zeaxanthin Consumed by Study

Author(s) Groupa: Lowest Amountbd Highest Amountcd
Lin et al., 2017 (0.32-0.80 mg/1000kcal) (2.03-4.00 mg/1000 kcal)
Wu et al., 2015 Nurses’ Health Study 1.66 4.78
Group
Health Professionals 1.85 5.47
Study Group
Wang et al., 2014 Blue Mountain Eye 0.44 (0-0.64) 1.43 (1.01-4.87)
Study Group
Rotterdam Study Group 1.48 (0.10-1.92) 3.36 (2.61-32.65)
Nidhi et al., 2013 (0-1) (5-6)
Ho et al., 2011 CFH genotype 1.47 (0.08-1.90) 3.38 (2.63-17.69)
homozygous carrier
a
Studies that reported nutrient intake by group or sub-group are
b
Reported either at tertile 1 or quintile 1
c
Reported either at tertile 3 or quintile 5
d
Amounts are reported as means (ranges) in mg/day unless otherwise noted

Other Carotenoids

Three studies investigated the effect of other specific carotenoids (Aoki et al., 2016;

Nidhi et al., 2013; Wu et al., 2015), and one study investigated the effect of a healthy diet, which

is rich in fruit and vegetables and, as such, rich in carotenoids (Mares et al., 2011). Beta-

carotene was assessed in all three studies and was found to reduce the risk of AMD in all studies

to varying degrees. The amounts of β-carotene reported in each study are described in Table 6.

Higher dietary intake of β-carotene was found to reduce the risk of AMD by Aoki et al. (2016;

OR = 0.2, p < .001), Wu et al. (2015; RR = 0.82, p = .03), and by Nidhi et al. (2013; OR = 0.38,

p < .001). In addition to β-carotene, Wu et al. (2015) also investigated α-carotene and β-

cryptoxanthin and found that higher intakes of both reduced the risk of late AMD (RR = 0.69, p

< .001 and RR = 0.73, p = .002 respectively) but did not find a reduced risk for intermediate
CAROTENOID-RICH DIET AND AMD 24

AMD. Mares et al. (2011) found that the healthiest diets based on the 2005 modified Healthy

Eating Index (70-80 points) had a reduced risk of AMD (OR = 0.54, p = .01).

Table 6

Reported Mean (or Range) of β-Carotene Consumed by Study

Author(s) Groupa: Lowest Amountbd Highest Amountcd
Aoki et al., 2016 < 2.30 ≥ 6.04
Wu et al., 2015 Nurses’ Health Study 2.89 6.86
Group
Health Professionals 3.41 8.15
Study Group
Nidhi et al., 2013 (0-1) (4-5)
a
Studies that reported nutrient intake by group or sub-group are
b
Reported either at tertile 1 or quintile 1
c
Reported either at tertile 3 or quintile 5
d
Amounts are reported as means (ranges) in mg/day unless otherwise noted

Genetics

Three of the seven included studies investigated the role of diet and genetic susceptibility

on AMD prevention (Ho et al., 2011; Lin et al., 2017; Wang et al., 2014). As previously

discussed, higher dietary intake of lutein and zeaxanthin is associated with a reduced risk of

AMD among carriers with the CFH genotype but not among carriers of LOC387715 genotype

(Ho et al., 2011; Lin et al., 2017; Wang et al., 2014). Inconclusive evidence exists to determine

whether xanthophyll intake reduces the risk of AMD among carriers of ARMS2 genotype.

Wang et al. (2014) found that lutein and zeaxanthin reduced the risk of early AMD by 22%

among adults with a high genetic risk, i.e., carriers of two alleles of the CFH and/or ARMS2

genotype, but Lin et al. (2017) did not find a reduced risk among adults with ARMS2 genotype.

In addition to finding a reduced risk of AMD among CFH genotype carriers with higher

xanthophyll intakes, Ho et al. (2011) also found a reduced risk of early AMD among carriers of
CAROTENOID-RICH DIET AND AMD 25

the CFH genotype who had higher intake of β-carotene (M = 2.36 mg/day; T1 HR = 2.54, T3 HR

= 1.47, p = .05) but did not find a reduced risk of early AMD among carriers of LOC387715

genotype.

Discussion

The present systematic review evaluates the efficacy of a carotenoid-rich diet on

preventing AMD. After applying the inclusion criteria to the substantial number of search

results, only seven studies were included in this review. This number was smaller than

anticipated, considering that dietary antioxidants are suspected to play a role in AMD

pathogenesis, and the previous systematic review by Ma et al. (2011) recommended further

research; however, current research appears to be focusing on the effects of dietary supplements

on AMD pathogenesis. Notwithstanding the small number of included studies, piloting the

search keywords and searching three comprehensive electronic health databases provide

confidence that this review includes all appropriate studies.

The included studies reported carotenoid intake in different manners, which make it

difficult to analyze and compare the amount of each nutrient. Six of the studies reported

amounts as micrograms or milligrams per day (Aoki et al., 2016; Ho et al., 2011; Mares et al.,

2011; Nidhi et al., 2013; Wang et al., 2014; Wu et al., 2015); whereas Lin et al. (2017) reported

nutrient intake as micrograms per 1,000 kcal, and Wang et al. (2014), and Wu et al. (2015)

reported carotenoid amounts by population group even though the hazard risks were calculated

using pooled data. Lastly, Nidhi et al. (2013) did not report the amount of xanthophylls that was

used to calculate the odds ratio.

The studies investigating the effect of dietary lutein and zeaxanthin on preventing AMD

have produced mixed results, although all five of the studies reported a decreased risk of AMD
CAROTENOID-RICH DIET AND AMD 26

among at least one group or sub-group who consumed the highest tertile or quintile. The highest

tertile/quintile means range from 1.43 to 5.47 mg/day (Ho et al., 2011; Wang et al., 2014; Wu et

al., 2015) and the reported ranges range from 1.01 to 32.65 mg/day (Lin et al., 2017; Nidhi et al.,

2011). Two studies investigated the general population (Nidhi et al., 2013; Wu et al., 2015), and

the other three studies investigated a genetically susceptible population (Ho et al., 2011; Lin et

al., 2017; Wang et al., 2014). The twenty-year prospective cohort study, by Wu et al. (2015),

found a 40% reduced risk of late AMD among participants with the highest xanthophyll intake

but did not find an association with intermediate AMD, which is consistent with the findings of

the systematic review by Ma et al. (2012). Nidhi et al. (2013) found a 60% reduced risk of

AMD, but the researchers combined early and late stages when calculating the risk hazard due to

the small percentage of AMD cases, which prevents distinguishing how xanthophylls affect early

and late AMD and may reduce the power of the results.

All three studies that investigated the effect of dietary lutein and zeaxanthin intake and

genetic susceptibility on early AMD found a reduced risk among CFH genotype carriers (Ho et

al., 2011; Lin et al., 2017; Wang et al., 2014). Wang et al. (2014) found a 20% reduced risk of

early AMD among participants with at least 2 risk alleles of CFH or ARMS2 genotypes and the

highest dietary lutein and zeaxanthin intake. Ho et al. (2011) found a reduced risk among CFH

genotype carriers but not among LOC387715 genotype carriers, and Lin et al. (2017) only found

a reduced risk among Caucasian participants with one CFH genotype risk allele (moderate risk)

but not among African American participants, participants with ARMSS2 genotype carriers, or

Caucasian participants with 2 CFH genotype risk alleles. These results are inconsistent with the

Ma et al. (2012) review, which did not find an association between dietary lutein and zeaxanthin

and early AMD prevention; however, included studies of that review did not investigate the role
CAROTENOID-RICH DIET AND AMD 27

of genetics. Because Wang et al. (2014) combined two genotypes, it is difficult to determine if

the results were driven by one particular genotype. It is unclear why Lin et al. (2017) found a

statistically significant risk reduction among moderate risk Caucasian CFH genotype carriers and

not among high genetic risk (2 risk alleles), but it is possible that the substantially smaller

number of high genetic risk participants reduced the statistical power of their results. The ethnic

differences found by Lin et al. (2017) are difficult to compare, as that study was the only one to

investigate ethnicity as a variable, and participant representation of non-Caucasian ethnicities

was substantially limited in the other two studies investigating genetics (Ho et al., 2011; Wang et

al., 2014). Ho et al. (2011) was the only study to investigate the LOC387715 genotype, so it is

impossible to formulate a conclusion.

Higher dietary intake of β-carotene was found to reduce the risk of late or combined

AMD in all three studies that investigated it (Aoki et al., 2016; Nidhi et al., 2013; Wu et al.,

2015). The highest tertile/quintile means range from 6.04 to 8.15 mg/day (Aoki et al., Wu et al.,

2015). Wu et al. (2015) found a reduced risk only for late AMD and not intermediate AMD;

Aoki et al. (2016) only investigated late AMD; and Nidhi et al. (2013) combined early and late

AMD cases in their statistical analysis. These results are not surprising, since Ma et al. (2012)

found that high dietary intake of lutein and zeaxanthin intake prevented only late AMD and not

early AMD. Although β-carotene is a different carotenoid than lutein and zeaxanthin, all three

are common nutrients in fruit and vegetables, and it is difficult to isolate the effect of a single

nutrient when investigating diet. Wu et al. (2015), which found that α-carotene and β-

cryptoxanthin also reduced the risk of late AMD, was the only study to investigate other

carotenoids; however, Mares et al. (2011) investigated a healthy, and presumably carotenoid-

rich, diet and found a reduced risk of early AMD. Mares et al. (2011) is the only study that
CAROTENOID-RICH DIET AND AMD 28

found a reduced risk of early AMD among a general, non-genetically susceptible population,

which may be due to the poor generalizability of its sample population, as participants were

predominantly Caucasian females with healthier-than-average lifestyles.

Strengths and Limitations

The present review has a few strengths. First, all of the included studies adjusted for

confounding variables, including, age and smoking status. Second, a majority of the studies

included a large sample population and the cohort studies were of long duration.

The present review has several limitations. First, this review, including the screening and

selection process, was prepared by a single, independent researcher instead of the standard two

independent researchers, which creates a possibility for bias and erroneous application of the

inclusion criteria. It was impossible for two researchers to apply the inclusion criteria, as this

review is required to be written independently to fulfill a graduate school academic requirement.

However, application of the inclusion criteria was thoroughly discussed with the present

researcher’s academic advisor in an attempt to minimize errors and bias. Second, the present

review may be subject to publication bias, though this risk appears to be minimal, since the

review includes both positive and negative results, the results are consistent with the prior

systematic review (Ma et al., 2012), and all reviews are subject to the same publication bias. The

present review was limited to studies published in the English language, as the present researcher

can read only English, and there was insufficient time to translate any non-English articles.

Lastly, the included studies are all observational protocols, which may be subject to confounding

effects and are not of sufficiently high quality to ascertain a causal relationship; however, this

limitation has been addressed in the grading of the present review.

CAROTENOID-RICH DIET AND AMD 29

Implications for Future Research and Practice

Age-related macular degeneration is the leading cause of blindness in the U.S. among the

elderly and, as such, is a public health concern (NEI, 2015). The present review detected an

indication that dietary carotenoids may reduce the risk of late AMD among the general

population and may reduce the risk of early AMD among Caucasian CFH carriers, but more

research is warranted to investigate these relationships. Higher quality studies are recommended

to examine the relationship between dietary carotenoid consumption and the prevention of late

AMD and to investigate the relationship between genetic susceptibility, dietary carotenoids, and

early AMD prevention. Despite the need for more research, it is not unwarranted to recommend

to the public a healthy, carotenoid-rich diet, as this recommendation aligns with the current

dietary guidelines for Americans (U.S. Department of Health and Human Services & U.S.

Department of Agriculture, 2015).

Conclusion

A diet rich in carotenoids may be associated with a reduced risk of AMD, particularly

late AMD among a general adult population and early AMD among adult carriers of the CFH

genotype. More research and higher quality studies are needed to definitively establish this

association and to ascertain the amount of carotenoids needed to prevent AMD. The strength of

the studies mostly rated between fair and limited, thus earning it an overall grade of limited (see

Appendix B).

Grade: III
CAROTENOID-RICH DIET AND AMD 30

References

American Academy of Ophthalmology Retina/Vitreous Preferred Practice Pattern Panel &

Hoskins Center for Quality Eye Care. (2015, January). Age-related macular degeneration

preferred practice pattern guidelines – updated 2015. Retrieved July 15, 2017 from

https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-

2015.

Aoki, A., Inoue, M., Nguyen, E., Obata, R., Kadonosono, K., Shinkai, S., . . . Yanagi, Y. (2016).

Dietary n-3 fatty acid, α-tocopherol, zinc, vitamin D, vitamin C, and β-carotene are

associated with age-related macular degeneration in Japan. Scientific Reports, 6(1),

20723. doi:10.1038/srep20723.

Ho, L., van Leeuwen, R., Witteman, J. C. M., van Duijn, C.,M., Uitterlinden, A. G., Hofman, A.,

. . . Klaver, C. C. W. (2011). Reducing the genetic risk of age-related macular

degeneration with dietary antioxidants, zinc, and ω-3 fatty acids: The Rotterdam study.

Archives of Ophthalmology, 129(6), 758-766. doi:10.1001/archophthalmol.2011.141.

Lin, H., Mares, J. A., LaMonte, M. J., Brady, W. E., Sahli, M. W., Klein, R., . . . Millen, A. E.

(2017). Association between dietary xanthophyll (lutein and zeaxanthin) intake and early

age-related macular degeneration: The atherosclerosis risk in communities study.

Ophthalmic Epidemiology, 1-12. doi:10.1080/09286586.2017.1290259.

Mares, J. A., Voland, R. P., Sondel, S. A., Millen, A. E., Larowe, T., Moeller, S. M., . . .

Wallace, R. B. (2011). Healthy lifestyles related to subsequent prevalence of age-related

macular degeneration. Archives of Ophthalmology, 129(4), 470-480.

doi:10.1001/archophthalmol.2010.314.
CAROTENOID-RICH DIET AND AMD 31

National Eye Institute. (n.d.). Age-related macular degeneration (AMD) tables. Retrieved July

15, 2017 from https://nei.nih.gov/eyedata/amd/tables.

National Eye Institute. (2015, September). Facts about age-related macular degeneration.

Retrieved July 15, 2017 from https://nei.nih.gov/health/maculardegen/armd_facts

Nidhi, B., Mamatha, B. S., Padmaprabhu, C. A., Pallavi, P., & Vallikannan, B. (2013). Dietary

and lifestyle risk factors associated with age-related macular degeneration: A hospital

based study. Indian Journal of Ophthalmology, 61(12), 722-727. doi:10.4103/0301-

4738.120218.

Rein, D. B., Wittenborn, J. S., Zhang, X., Honeycutt, A. A., Lesesne, S. B., Saaddine, J.; &

Vision Health Cost-Effectiveness Study Group. (2009). Forecasting age-related macular

degeneration through the year 2050: The potential impact of new treatments. Archives of

Ophthalmology, 127(4), 533-540. doi:10.1001/archophthalmol.2009.58.

Shaw, P. X., Stiles, T., Douglas, C., Ho, D., Fan, W., Du, H., & Xiao, X. (2016). Oxidative

stress, innate immunity, and age-related macular degeneration. AIMS Molecular Science,

3(2), 196–221. http://doi.org/10.3934/molsci.2016.2.196.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. (2015).

2015 – 2020 Dietary Guidelines for Americans. 8th Edition. Retrieved November 10,

2016 from http://health.gov/dietaryguidelines/2015/guidelines/.

Wang, J. J., Buitendijk, G. H. S., Rochtchina, E., Lee, K. E., Klein, B. E. K., van Duijn, K. M., . .

. Klaver, C. C. W. (2014). Genetic susceptibility, dietary antioxidants, and long-term

incidence of age-related macular degeneration in two populations. American Academy of

Ophthalmology, 121(3), 667-675. doi:10.1016/j.ophtha.2013.10.017.

CAROTENOID-RICH DIET AND AMD 32

Wong, W. L., Su, X., Li, X., Cheung, C. M. G., Klein, R., Cheng, C-Y., & Wong, T. Y. (2014).

Global prevalence of age-related macular degeneration and disease burden projection for

2020 and 2040: A systematic review and meta-analysis. The Lancet Global Health, 2(2),

e106 - e116. http://dx.doi.org/10.1016/S2214-109X(13)70145-1.

Wu, J., Cho, E., Willett, W. C., Sastry, S. M., & Schaumberg, D. A. (2015). Intakes of lutein,

zeaxanthin, and other carotenoids and age-related macular degeneration during 2 decades

of prospective follow-up. JAMA Ophthalmology, 133(12), 1415-1424.

doi:10.1001/jamaophthalmol.2015.3590.
CAROTENOID-RICH DIET AND AMD 33

Appendix A

Quality Criteria Checklist for Primary Research

CAROTENOID-RICH DIET AND AMD 34
CAROTENOID-RICH DIET AND AMD 35
CAROTENOID-RICH DIET AND AMD 36

Appendix B

Conclusion Grading Table

Conclusion Grading Table of Studies Assessing the Relationship Between a Carotenoid-Rich Diet and Preventing Age-Related
Macular Degeneration (AMD)
Strength of Grades
Evidence I II III IV V
Elements
Good Fair Limited Expert Opinion Only Grade Not
Assignable
Quality Studies of strong design Studies of strong Studies of weak design No studies available No evidence
for question design for question for answering the that pertains to
Scientific question Conclusion based on question being
rigor/validity Free from design flaws, with minor usual practice, expert addressed
bias and execution methodological OR consensus, clinical
Considers design problems concerns, OR experience, opinion, or
and execution Inconclusive findings extrapolation from basic
Only studies of due to design flaws, research
weaker study bias or execution
design for question problems
Consistency Findings generally Inconsistency Unexplained Conclusion supported NA
consistent in direction among results of inconsistency among solely by statements of
Of findings and size of effect or studies with strong results from different informed nutrition or
across studies degree of association, and design, OR studies OR single medical commentators
statistical significance study unconfirmed by
with minor exceptions at Consistency with other studies
most minor exceptions
across studies of
weaker design
CAROTENOID-RICH DIET AND AMD 37

Quantity One to several good Several studies by Limited number of Unsubstantiated by Relevant
quality studies independent studies published research studies have
Number of investigators studies not been done
studies Large number of subjects Low number of
studied Doubts about subjects studied and/or
Number of adequacy of sample
subjects in Studies with negative size to avoid Type I inadequate sample size
studies results have sufficiently and Type II error within studies
large sample size for
adequate statistical power
Clinical Impact Studied outcome relates Some doubt about Studied outcome is an Objective data Indicates area
directly to the question the statistical or intermediate outcome unavailable for future
Importance of clinical significance or surrogate for the research
studied outcomes Size of effect is clinically of the effect true outcome of
meaningful interest
Magnitude of
effect Significant (statistical) OR
difference is large
Size of effect is small
or lacks statistical
and/or clinical
significance
Generalizability Studied population, Minor doubts about Serious doubts about Generalizability limited NA
To population of intervention and generalizability generalizability due to to scope of experience
interest outcomes are free from
serious doubts about narrow or different
generalizability study population,
intervention or
outcomes studied