Lutein and Zeaxanthin In Early AMD
AREDS identified these carotenoids as relevant to early AMD, but what are the applications?
Lauren S. Taney, MD, is a medical retina fellow at the Tufts Medical Center in Boston. Elias Reichel, MD, is professor and vice chair of ophthalmology at Tufts. Elizabeth J. Johnson, PhD, is a research scientist in the Carotenoids Laboratory in the Human Nutrition Research Center on Aging at Tufts. None of the authors reports any financial interests in any of the products mentioned in this article. Dr Reichel can be reached via e-mail at firstname.lastname@example.org.
LAUREN S. TANEY, MD · ELIAS REICHEL, MD · ELIZABETH J. JOHNSON, PhD
While the advent of intravitreal agents has revolutionized the ability to treat exudative AMD, very limited treatment options exist for patients with nonexudative AMD. As a result, interventions aimed at preventing or delaying the development of nonexudative AMD are critical.
Given the current understanding of the pathogenesis of nonexudative AMD, these interventions center on risk reduction in the form of dietary antioxidants, maintenance of a normal body weight, and smoking cessation.
AREDS AND AREDS2
In the original Age-Related Eye Disease Study (AREDS), patients considered at high risk for progression to advanced AMD were those with many medium-sized drusen, bilateral large drusen, or large drusen in one eye and advanced AMD in the fellow eye.
For this high-risk group, the study found that oral supplements, consisting of 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, 2 mg copper, and 15 mg beta-carotene, reduced the risk of progression to advanced AMD by 25% at five years.1
The AREDS2 results appeared in JAMA in May 2013.2 The study group consisted of patients aged 50 to 85 years old who were deemed to be high risk for progression to advanced AMD, according to the criteria described above.
AREDS2 sought to determine whether the addition of one of three supplemental combinations — lutein with zeaxanthin (L/Z), docosahexaenoic acid (DHA) with eicosapentaenoic (EPA), or L/Z with DHA + EPA — to the existing AREDS formulation would further reduce the risk of progression to advanced AMD.
No statistically significant reduction in progression to advanced AMD occurred in those high-risk subjects taking L/Z and/or DHA + EPA supplementation in addition to standard AREDS formulation.2
CAUSE FOR DISAPPOINTMENT?
While these results may discourage widespread use of L/Z and DHA + EPA supplementation for patients with AMD, it is important to realize the AREDS2 data apply mainly to patients with high-risk AMD features.
Other analyses of the AREDS2 data do suggest a role for L/Z in reducing AMD progression risk. A main effects analysis revealed that treatment with L/Z reduced the risk for progression to AMD by 10%, compared with no L/Z (P = .04).3
In a subgroup analysis of AREDS2, L/Z supplementation in subjects in the lowest quintile for dietary intake of L/Z showed a protective effect for progression to advanced AMD (hazard ratio 0.74, P = .01).2
Additionally, post hoc subgroup analyses that compared L/Z + AREDS without beta-carotene to L/Z + AREDS with beta-carotene found an 18% lower risk for progression to advanced AMD (P = .02) and a 22% lower risk of progression for neovascular AMD (P = 0.01), favoring participants receiving L/Z + AREDS without beta-carotene.2
The potential role of L/Z in prevention of the onset and/or progression of early nonexudative AMD thus warrants further consideration. This article examines the biological basis and the evidence supporting the possible protective role of L/Z in early nonexudative AMD.
Carotenoids are pigmented molecules that plants synthesize and are essential for the absorption of light energy. Two classes of carotenoids exist: xanthophylls and carotenes.
Lutein and zeaxanthin are xanthophylls that derive entirely from the diet, while meso-Z, a stereoisomer of Z, derives from retinal L.4 Foods that are sources of L/Z include leafy green vegetables, orange/yellow fruits and vegetables, and egg yolks.5 Spinach, kale, and collard greens have high lutein content, while corn, oranges, and eggs are rich in zeaxanthin.
In the United States, the average daily intake of L/Z is less than 2.0 mg/day, while intakes of L/Z amounting to 6.0 mg/day are considered protective against AMD.6 The average daily intake of L/Z is higher in certain population subsets, such as non-Hispanic African Americans.6
A total of approximately 40 dietary carotenoids exist, of which we can detect only 14 in human blood and two in the macula: L/Z (as well as the metabolite meso-Z). Collectively, we refer to L, Z, and meso-Z as macular pigment (MP).7
The density of L, Z, and meso-Z in the human retina exceeds the concentration of these carotenoids in the serum by 1,000 to 10,000 times.8 The mechanisms of the specialized transport system that enables this density remain largely unknown.
Nevertheless, we do know that HDL primarily transports L/Z from hepatocytes to other tissues in the human body and that L/Z appear to bind selectively to xanthophyll-binding proteins in the retina and to tubulin (an element of cone axon cytoskeletons).9
Macular pigment accumulates in the Henle fiber layer of the fovea, as well as the inner plexiform layers of the parafovea.7 Z is twice as abundant than L in the fovea, whereas L is present in greater concentrations than Z in the retinal periphery, with ratios of 1:2 to 1:3 of Z to L.5 Meso-Z is also found in abundance at the fovea.
The proposed functions of macular pigment include reducing the presence of free radicals, filtering damaging blue light, and improving overall visual function.8 The high oxygen demands of the retina, an environment rich in polyunsaturated fatty acid molecules with easily accessed hydrogen atoms, frequently leads to generation of reactive oxygen intermediates (ROIs).
These ROIs include free radicals, hydrogen peroxide, and singlet oxygen, which threaten retinal and retinal pigment epithelium function. The MP molecules, L/Z, bind to ROIs and curtail damage from them.
Another protective property of L/Z relates to their absorbance spectrum. The absorbance of L/Z ranges between 445 and 472 nm.5 Wavelengths of 400-500 nm mediate retinal damage, so selective filtration of damaging wavelengths reduces the overall burden of exposure to the retina and RPE.
This characteristic blue light attenuation is the basis for measuring macular pigment optical density (MPOD) in living eyes: higher concentrations of MP in a given area of the macula directly attenuate more blue light.7
Figure. Fundus photo of the right eye with early non-neovascular (dry) AMD (A). Note the numerous yellow subretinal deposits (drusen). The right eye with advanced non-neovascular AMD (geographic atrophy) (B). Note area where RPE cells have died from apoptosis (arrowheads). The right eye (C) with neovascular or wet AMD. Note subretinal hemorrhage (arrowheads) adjacent to a choroidal neovascular membrane (arrows).
CREDIT: HINDAWI PUBLISHING
Given the proposed function of MP, adequate dietary intake of or supplementation with L/Z seems reasonable from a molecular standpoint.
L/Z AND AMD PREVALENCE
Studies that have evaluated the relationship between plasma L/Z levels and AMD prevalence include the Eye Disease Case-Control Study, 10 the Sheffield (UK) study,11 and the POLA (Pathologies Oculaires Liées à l’Age) study. 12
The Eye Disease Case-Control Study Group compared patients with advanced AMD and control subjects. The results revealed that subjects in the highest quintile for L/Z blood levels had a 43% lower risk of advanced AMD, compared with those in the lowest quintile (P = .02).10
In the Sheffield study, subjects with plasma concentrations of Z in the lowest third of the distribution had an increased risk of AMD (OR 2.0, P = .046) while patients with low plasma L levels had an elevated risk of AMD, although not statistically significant (OR 1.7, P = .120).11 In the POLA study, subjects with the highest quintile of plasma Z had a 93% reduced risk of AMD (P = .005), and subjects with high total plasma L/Z had a 79% reduced risk of AMD, compared with subjects with low total plasma L/Z (P = .004).12
LIMITATIONS AND OTHER INVESTIGATIONS
These three studies demonstrated an inverse relationship between either L or Z plasma levels and AMD risk. While pivotal in linking serum L/Z levels with AMD prevalence, it is important to recognize some limitations of these conclusions as they pertain to early AMD.
The Eye Disease Case-Control Study only examined patients with advanced AMD, while both the Sheffield and POLA studies treated patients with early and late AMD collectively (although 64 of 78 patients had early AMD in the Sheffield study and 45 of 55 had early AMD in the POLA study).
While epidemiological studies, such as those cited above, have established important relationships, studies that examine MPOD may aid in our understanding of how L/Z status may reduce risk of AMD on a molecular level.
Studies have shown that healthy eyes predisposed to AMD have less macular pigment than healthy eyes not at risk for AMD.13 Studies have also demonstrated an age-related decline in MPOD.13,14
The Macular Pigment Research Group in Ireland evaluated the relationship between L/Z and MPOD. The results of this observational study demonstrated a statistically significant positive relationships among dietary intake of L/Z, serum concentrations of L/Z, and central MPOD (P < .01). The group also showed an inverse relationship between central MPOD and age, tobacco use, and family history of AMD.15
The LUTEGA study specifically investigated the question of how L/Z supplementation impacts MPOD. This randomized, double-blind, placebo-controlled study examined antioxidant plasma levels and MPOD in patients with nonexudative AMD before and after 12 months of antioxidant supplementation.
The study randomly assigned individuals with nonexudative AMD to one of three treatment groups: 1) a daily capsule containing 10 mg L, 1 mg Z, 100 mg DHA, and 30 mg EPA; 2) a daily capsule containing 20 mg L, 2 mg Z, 200 mg DHA, and 60 mg EPA; or 3) placebo.
The results revealed that, when compared with baseline, subjects receiving 12 months of supplementation had increased plasma levels of L/Z (P < .05), as well as increased MPOD (P < .05). The higher-dose supplement did not result in statistically significant higher MPOD levels, implying that the lower dose supplement was adequate for raising MPOD levels.16
A similar study conducted in Beijing randomized patients with early AMD to receive, on a daily basis for 48 weeks, 10 mg L, 20 mg L, 10 mg L + 10 mg Z, or placebo.17 The change in MPOD compared with baseline was statistically significant for the 20 mg L (P <0.01) and 10 mg L + 10 mg Z (P <0.05) groups. The MPOD of the 10 mg L group increased but not in a statistically significant fashion.
This study also demonstrated that the magnitude of MPOD changes was correlated with the degree of improvement in visual function variables, such as reduction in log-MAR BCVA (P < 0.01) and increase in contrast sensitivity at all spatial frequencies (P < 0.01).17
Other prospective studies examining L/Z supplementation are under way. Although the final study results are not yet published, the CARMA (Carotenoids and Co-Antioxidants in Age-Related Maculopathy) study investigated the efficacy of 36-month L/Z supplementation on various visual parameters, serum L/Z concentrations, MPOD, and progression rates in early AMD subjects.18
At three sites (Boston; Bonn, Germany; and Manchester, UK), the I-team Newtricious study is under way. Patients with early nonexudative AMD are receiving daily supplementation with a dairy-based beverage containing L, Z, and DHA. Results of these and similar studies should shed additional light on the concept of L/Z supplementation, as well as refine optimal dosing regimens.
WHAT WE KNOW
While the nuances of AREDS2 support a role for L/Z in reducing the risk of progression from intermediate to late AMD, the study did not assess the role of supplementation in primary prevention of AMD or treatiment of early AMD.
Epidemiologic data and smaller-scale prospective studies have indicated that L/Z supplementation has a role in prevention of presentation or progression of early AMD. Certainly, selective concentration of L/Z in the macula, as well as the proposed functions of L/Z as antioxidants and blue light filters, lends biological plausibility to their role in AMD prevention. We can recommend daily supplementation in the form of 10 mg lutein and 2 mg zeaxanthin for appropriate patients to reduce their theoretical AMD risks.
As we make continued strides in our understanding of the genetic basis of AMD, it is important not to minimize the role that other modifiable risk factors, such as diet, may have on this multifactorial disease.
Although additional research is necessary, it does appear that lutein and zeaxanthin, in the diet or as supplements, play roles in mitigating the development or progression of early AMD. RP
1. AREDS2 Research Group, Chew EY, Clemons T, SanGiovanni JP, et al. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012;119:2282-2289.
2. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005-2015.
3. Kraderm CG. AREDS2 results. EuroTimes. 2013;18:25.
4. Johnson EJ, Neuringer M, Russell RM, Schalch W, Snodderly DM. Nutritional manipulation of primate retinas, III: Effects of lutein or zeaxanthin supplementation on adipose tissue and retina of xanthophyll-free monkeys. Invest Ophthalmol Vis Sci. 2005;46:696-702.
5. Carpentier S, Knaus M, Suh M. Associations between lutein, zeaxanthin, and age-related macular degeneration: an overview. Crit Rev Food Sci Nutr. 2009;49:313-326.
6. Johnson EJ, Maras JE, Rasmussen HM, Tucker KL. Intake of lutein and zeaxanthin differ with age, sex, and ethnicity. J Am Diet Assoc. 2010;110:1357-1362.
7. Bernstein PS, Delori FC, Richer S, van Kuijk FJ, Wenzel AJ. The value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other retinal disorders. Vis Res. 2010;5:716-728.
8. SanGiovanni J, Neuringer M. The putative role of lutein and zeaxanthin as protective agents against age-related macular degeneration: promise of molecular genetics for guiding mechanistic and translational research in the field. Am J Clin Nutr. 2012;96:1223S-1233S.
9. Li B, Vachali P, Bernstein PS. Human ocular carotenoid-binding proteins. Photochem Photobiol Sci. 2010;9:1418-1425.
10. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272:1413-1420.
11. Gale CR, Hall NF, Phillips DI, Martyn CN. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2003;44:2461-2465.
12. Delcourt C, Carrière I, Delage M, Barberger-Gateau P, Schalch W; POLA Study Group. Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age related maculopathy and cataract: The POLA Study. Invest Ophthalmol Vis Sci. 2006;47:2329-2335.
13. Bernstein PS, Zhao DY, Wintch SW, Ermakov IV, McClane RW, Gellermann W. Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients. Ophthalmology. 2002;109:1780-1787.
14. Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci. 2001;42:439-446.
15. Nolan JM, Stack J, O’connell E, Beatty S. The relationships between macular pigment optical density and its constituent carotenoids in diet and serum. Invest Ophthalmol Vis Sci. 2007;48:571-582.
16. Arnold C, Winter L, Frölich K, et al. Macular xanthophylls and -3 long-chain polyunsaturated fatty acids in age-related macular degeneration: a randomized trial. JAMA Ophthalmol. 2013;131:564-572.
17. Ma L, Yan SF, Huang YM, et al. Effect of lutein and zeaxanthin on macular pigment and visual function in patients with early age-related macular degeneration. Ophthalmology. 2012;119:2290-2297.
18. Neelam K, Hogg RE, Stevenson MR, et al. Carotenoids and co-antioxidants in age-related maculopathy: design and methods. Ophthalmic Epidemiol. 2008;15:389-401.