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ScienceDirect journal homepage: www.elsevier.com/locate/survophthal

Therapeutic review

The role of omega-3 and micronutrients in age-related macular degeneration Giuseppe Querques, MD, PhD*, Eric H. Souied, MD, PhD Creteil University Eye Clinic, Cre´teil, France

article info

abstract

Article history:

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in

Received 12 October 2012

the United States, Europe, and other developed countries. Although the pathogenesis of

Received in revised form 21 January

AMD remains unclear, current evidence suggests a multifactorial aetiology. Nutrition may

2014

play an important role in the development and progression of AMD. There have been

Accepted 21 January 2014

several epidemiological studies suggesting that omega-3 fatty acids could have a protective

Available online xxx

role in AMD, but a beneficial effect remains to be demonstrated in randomized controlled trials. There also exists a substantial body of evidence suggesting that protection against

Keywords:

AMD may be provided by specific micronutrients (vitamins and minerals and antioxidants).

age-related macular degeneration

The identification of risk factors for the development and progression of AMD is of

omega-3

particular importance for understanding the origins of the disorder and for establishing

docosahexaenoic acid

strategies for its prevention. We examine the relationship between dietary omega-3 intake

polyunsaturated fatty acid

and the incidence and progression of AMD, as well as the role of omega-3 supplementation

supplementation

in the prevention of the disorder, and also explore the role of other micronutrients in AMD.

nutrition

1.

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the United States, Europe, and other developed countries. Early AMD, the most common form, involves lipid deposits (drusen) outside the retinal pigment epithelium (RPE), or pigment abnormalities in the RPE, without visible choroidal vessels, and is not associated with marked vision impairment.14,27 Late, or advanced, AMD involves progressive lipidization as well as degenerative changes of the RPE, Bruch membrane, and choriocapillaris and is usually associated with severe vision loss.14,27 Dry AMD, also referred to as geographic atrophy, starts with a sharply

ª 2014 Elsevier Inc. All rights reserved.

demarcated round or oval hypopigmented spot in which large choroidal vessels are visible. Wet or exudative AMD initiates with serous or hemorrhagic fluid that causes the neuroretina or the RPE to detach from Bruch is membrane. The prevalence of AMD is known to increase with age, with one study showing a prevalence of early AMD of approximately 30% among those aged 75 years or older,29 with a smaller percentage of individuals (6e8%) in this age group having the advanced form of AMD that includes geographic atrophy (dry AMD) and choroidal neovascularization (exudative or wet AMD). Strikingly, in the population-based Rotterdam Study, of the 825 participants aged 80 years or older, 64% showed signs of early or late AMD.14

* Corresponding author: Giuseppe Querques, MD, PhD, Professeur Associe´ des Universite´s, Praticien Hospitalier mi-temps, Service d’Ophtalmologie, Hoˆpital Intercommunal de Cre´teil, Universite´ Paris Est Cre´teil, 40 Av de Verdun, 94010 Cre´teil, France. E-mail address: [email protected] (G. Querques). 0039-6257/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2014.01.001

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The pathogenesis of AMD remains unclear, but current evidence suggests that it is most likely a multifactorial disorder, with both environmental and polygenic components.19,32,48,52 A genetic component has been demonstrated by familial aggregation and twins studies, with linkage studies also identifying several DNA regions of interest.17,19,24,28,32,46,48,55,56 Nutrition has also been shown to be associated with AMD.9,13,16,31,47,50,62 Studies have indicated that vitamin and mineral supplementation may reduce the risk for progression to the advanced forms of AMD and subsequent visual loss,2 and dietary sources of antioxidants also appear to be important,13,61 as do lutein and zeaxanthin.9,37,47,61 Moreover, numerous studies have indicated that people with dietary intakes higher in various carotenoids, antioxidants, and omega-3 fatty acids may have a lower risk of developing AMD.9,16,31,45,47,52,58,62

1.1.

The potential role of omega-3 fatty acids

Omega-3 and omega-6 fatty acids are important components of tissue lipids, particularly cell membrane phospholipids. The major dietary omega-3 polyunsaturated fatty acid is docosahexaenoic acid (DHA). This makes up only a small fraction of the fatty acids in most tissues, but is present at high levels in the retina, where it is a major structural lipid.4,33 As a result of its biophysical and biochemical properties, DHA may affect the permeability, fluidity, thickness, and lipid phase properties of the photoreceptor membrane,41 and may also be involved in signaling cascades, acting to enhance activation of membrane-bound retinal proteins, and may be involved in rhodopsin regeneration. There is evidence that tissue DHA insufficiency is associated with changes in retinal function.41 Eicosapentaenoic acid (EPA) (C20:5 u-3), the precursor to DHA as well as other major dietary omega-3 fatty acids, can exert similar actions to DHA.41 Dietary omega-3 fatty acids have also been shown to be beneficial in inflammatory diseases and where those taking omega-3 report less joint stiffness, swelling, tenderness, and fatigue.25,30,60 Dietary omega-3 fatty acids have been shown to

reduce the inflammatory response by competing with arachidonic acid metabolism and altering the eicosanoid profile. EPA and DHA have been shown to decrease CD4þ T-cell activation and cause the inflammatory environment to switch from a pro-inflammatory to an anti-inflammatory one; a mechanism by which omega-3 fatty acids can alter inflammation-related signaling cascades is through disrupting plasma membrane organization, increasing the molecular order of lipid rafts and suppressing lipid second messengers and proteins required for activation of T-cells (Fig. 1).54 These anti-inflammatory actions may be beneficial in the retina, inflammation may play a role in the development of new choroidal vessels in exudative AMD.3,13,18,35,51 Early studies investigating a potential relationship between dietary fat intake and AMD revealed that this might not be straightforward. Results of initial studies suggested that higher intake of some fatty acids, and possibly elevated blood cholesterol levels, may be related to an increased risk of AMD.49,53 More specifically, results suggested that higher intake of specific subtypes of lipids (cholesterol, monounsaturated, polyunsaturated fats, omega-6 fatty acid, linoleic acid) rather than total fat intake may be associated with a greater risk for progression of AMD. In contrast, diets high in omega-3 fatty acids and fish were found to be inversely associated with risk for AMD when intake of linoleic acid was low.49,53 Since this time, there have been several epidemiological studies suggesting that omega-3 or polyunsaturated fatty acids DHA and EPA could have a protective role in AMD, particularly exudative AMD.22 Furthermore, there is evidence to suggest that omega-3 fatty acids have cytoprotective and cytotherapeutic actions, giving rise to anti-angiogenic and neuroprotective mechanisms within the retina.41

2.

Objective and methodology

The identification of risk factors for the development of AMD is of particular importance for understanding of the origins of

Fig. 1 e The action of omega-3 fatty acids on lipid membranes and T-cell signaling processes. (Reproduced from Shaikh et al54 with permission of Elsevier.)

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the disorder and for establishing strategies for its prevention. We examine the relationship between dietary omega-3 intake and the incidence of AMD, as well as the role of omega-3 supplementation in the prevention of the disorder, and explore the role of other micronutrients in AMD.

3.

Relationship between omega-3 and AMD

Currently available data indicate that there is a relationship between AMD and plasma levels of omega-3, although its exact nature remains unclear. An early study in 65 patients with AMD and 65 matched controls failed to show any significant differences in plasma levels of retinol, a-tocopherol, carotenoids, cholesterol, polyunsaturated fatty acids, or erythrocyte phospholipids;38 most patients included in this study, however, had only drusen and/or pigment changes, with only two patients having neovascular AMD. A lack of association between plasma unsaturated fatty acid (arachidonic acid, DHA, palmitic, palmitoleic, oleic, and linoleic acids) levels and AMD was also shown in a Japanese study including only 11 patients with AMD and 10 healthy individuals.34 Interestingly, this study found that arachidonic acid and DHA levels in the red blood cell membrane (RBCM) were significantly higher in patients with AMD than in controls; in this small study the classification of AMD was not clearly defined, however.34 Initial reports of a relationship between dietary fat intake and AMD emerged in 1994 in abstract form.C The first fully published study evaluating the relationship between dietary fat intake and AMD, the Beaver Dam Eye study published in 1995, revealed that high intake of total fat, saturated fat, and cholesterol was significantly associated with increased odds of early age-related maculopathy (ARM), with a trend towards a similar effect for late AMD. In that study, consumption of oleic and linoleic acids and seafood (a source of long chain omega-3 fatty acids) was found to be unrelated to either early or late AMD;31 ARM/AMD patients were only a small subgroup of the total cohort, however (314 patients with early ARM and only 30 with late AMD), and all from a very limited geographical area; therefore, the power of the study was limited. In the Blue Mountains Eye Studyda population-based survey of ARM including a 145-item food frequency questionnaire (FFQ) in an urban population of 3,654 individuals (82.4% respondents)d72 cases of late ARM and 240 cases of early ARM were reported; a clear association was observed between higher frequency of intake of fish (once per week) and decreased risk of late ARM, compared with lower frequency of consumption (less than once per month). This cross-sectional survey, however, is subject to several types of bias; reporting, low responder rate among those with late ARM, and unmeasured or inadequate adjustment for confounders and spurious associations. Therefore, although biologically plausible, it did not prove conclusively that omega-3 fatty acid intake could protect against ARM.57 Five- and/or 10-year data from an extension of this study (n ¼ 2,454) revealed a reduced incidence of early AMD with fish consumption once a week (relative risk, 0.69), and consumption of one or two servings of nuts per week (relative

3

risk, 0.65).59 A borderline reduced risk of early AMD was seen with increased intake of total omega-3 fatty acids (p ¼ 0.04), and a trend towards reduced incidence of late AMD was seen with increased intake of long-chain omega-3 fatty acids (p ¼ 0.06). A cohort study that utilized data from the Nurses’ Health Study and the Health Professionals Follow-up Study (42,743 women and 29,746 men aged 50 years with no diagnosis of AMD with fat intake assessed by FFQ) found that both total fat intake (p ¼ 0.008) and linoleic acid (p ¼ 0.0009) intake were associated with an increased AMD risk, with the effect of total fat intake markedly reduced after adjustment for linoleic acid intake. In contrast, an inverse relationship was found between DHA intake and AMD risk (p ¼ 0.05). Participants who ate fish >4 times per week had a 35% lower risk of AMD than those who consumed it 1 time per month was protective against AMD. These findings are interesting and add to the overall evidence. Dietary assessments were performed 3 years after diagnosis, however, and so the findings may be subject to recall bias. Also, statistical power was low as the number of individuals with early and late ARM was small. Another European cross-sectional study, the EUREYE study, specifically examined the protective effect of EPA and DHA intake in 2,276 elderly subjects (65 years), and found that eating oily fish at least once a week was protective against neovascular AMD (p ¼ 0.002), as was high dietary DHA and EPA intake (p ¼ 0.01).5 This study went to great length to avoid bias by assessing diet in the previous year to remove variations from seasonality or due to ill health. A wide range of potential confounders were measured, objective diagnosis was made on rigorous analysis of digital fundus images, the number of neovascular AMD cases was large, and cases and controls were drawn from the same population. Data from the Age-Related Eye Disease Study (AREDS) have also been used to investigate the relationship between dietary fat intake and AMD. AREDS is an 11-center double-masked clinical trial, involving 3,640 participants aged 60e80 years (n ¼ 4,519) randomly assigned to receive daily oral tablets containing: 1) antioxidants (vitamin C 500 mg; vitamin E 400 IU; and beta carotene 15 mg); 2) zinc 80 mg (as zinc oxide) and copper 2 mg (as cupric oxide); 3) antioxidants plus zinc; or 4) placebo.2 The main study outcome was development of or treatment for advanced AMD. Over a mean 6.3-year follow-up, this study found that high doses of antioxidants and zinc significantly reduced the odds of developing advanced AMD in high-risk patients.2 Although the supplements given in the AREDS study did not contain omega-3 fatty acids, subjects provided estimates of habitual nutrient intake through a selfadministered semi-quantitative FFQ, and this data has been used to investigate the link between omega-3 fatty acid intake and AMD.42,43 This data revealed total dietary omega-3 fatty acid intake to be inversely associated with incidence of neovascular AMD at baseline.42 Moreover, multivariate analysis of data from a long-term follow-up of 2,132 participants of the AREDS study responding to an FFQ on intake of DHA, EPA, combined EPA þ DHA, and fish, revealed that AMD progression over more than 6 years was inversely related to EPA or EPA þ DHA only.42 Furthermore, in a nested cohort study of 1,837 individuals at moderate to high risk of AMD progression, taken from the AREDS study population, progression over 12 years was less likely in those with the highest intake of DHA, EPA or DHA and EPA than in those with lower intakes of DHA, EPA, or DHA and EPA.39,40 In a separate study of 2,924 AREDS participants at risk of AMD progression (5,146 eyes) followed for 8 years, higher intake of DHA and EPA conferred a lower risk for progression to advanced AMD, independent of AREDS supplementation.7 In a separate study of 2,531 AREDS participants (4,690 eyes), higher intake of DHA and EPA was

associated with a lower risk for progression to geographic atrophy.58 A recent study, using data from the Melbourne Collaborative Cohort Study, indicated that high levels of omega-3 fatty acid intake were inversely associated with prevalence of early AMD although a similar protective effect was not seen with increased fish consumption (more than two servings of fish per week).11 This study used an FFQ, which has limitations due to measurement errors and the lack of differentiation between oily and non-oily fish, and this may have been the reason for the lack of correlation between omega-3 and fish effects.11 Recently, researchers assessed the relationship between dietary fat intake and AMD using data from the Women’s Health Study, in which 38,022 women without a diagnosis of AMD completed a detailed FFQ.12 During an average follow-up duration of 10 years, 235 cases of AMD were confirmed by a combination of drusen and retinal pigment epithelial changes. This study found that the highest tertiles of DHA and EPA intake were associated with lower risks of AMD than the lowest tertiles. This apparent protective effect of DHA and EPA was supported by the finding that women who consumed at least one serving of fish per week also had a lower risk of AMD than those who consumed less.12 A recent meta-analysis used pooled data from nine of the studies mentioned earlier. In this analysis, with a total of 88,974 individuals with 3,202 cases of AMD, the dietary intake of omega-3 fatty acids was associated with a reduced risk of late AMD. Moreover, fish intake at least twice a week was associated with a reduced risk of both early and late AMD.10 The authors of the metanalysis acknowledged that, despite these associations, the evidence to support routine fish consumption for AMD prevention is weak, with limited prospective studies and no randomized clinical trials.10

3.1.

Omega-3 supplementation for AMD

There have only been a few clinical trials conducted to investigate the role of omega-3 fatty acid supplementation in the prevention of AMD. The French Nutritional AMD Treatment phase 1 (NAT-1) study evaluated the feasibility of a prospective study of oral DHA and EPA supplementation in AMD.36 In this study, a group of 38 patients with drusenoid pigment epithelial detachment in one eye without choroidal neovascularization (CNV) received DHA and EPA (EPA: 720 mg/ day and DHA: 480 mg/day) or placebo for 6 months. There were significant increases in serum and RBCM EPA and DHA levels at the 6-month visit in the group receiving the oral supplement, with no changes in the control group, despite dietary recommendations. Although there were no benefits in terms of AMD progression in this study, the supplement was well tolerated. The benefits of DHA supplementation for AMD have been evaluated in the 3-year, double-blind, randomized, parallel-group NAT-2 (Nutritional AMD Treatment phase 2) study,B,58 in which patients with early AMD (drusen, no CNV) in the study eye and neovascular AMD in the fellow eye received oral DHA 840 mg/day (n ¼ 134) or placebo (olive oil; n ¼ 129). The primary endpoint was time to occurrence of CNV, and secondary measures were incidence of CNV, changes in visual acuity, occurrence and progression of drusen, and

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changes in EPA and DHA level in RBCM. At 3 years, a reduction in CNV was seen in both groups, the mean time to CNV and CNV incidence was similar, and DHA was not shown to reduce CNV progression.A,58 In a parallel-group, age- and sexmatched controlled cohort analysis comparing lipid, lipoprotein. and fatty acid profiles in 289 AMD patients from the NAT-2 study cohort with those in 102 normal sighted nonAMD elderly individuals, presence of AMD/CNV was associated with EPA/DHA, monounsaturated and essential fatty acid deficiency compared with non-AMD subjects.B,58 At the 3-year follow-up of the NAT-2 study, circulating and cellular EPA, DHA, and oleic acid increased in DHA or placebo, and lipid, lipoprotein, and fatty acid profiles normalized, suggesting that nutritional changes may be responsible for the lower overall CNV incidence in both groups.B,58 Time to occurrence and incidence of CNV in the study eye was not significantly different between the DHA (19.5  10.9 months, 28.4%, respectively) and placebo groups (18.7  10.6 months, 25.6%, respectively). In the DHA group, patients steadily achieving the highest tertile of EPAþDHA levels in RBCM had significantly lower risk (68%; p ¼ 0.047; hazard ratio ¼ 0.32 [0.10e0.99] of developing CNV over 3 years). Another small study investigating the effect of supplementation in AMD was the Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein (TOZAL) study. In this prospective, double-blind, 6-month trial, 37 subjects with at least one eye diagnosed with dry AMD were given a nutritional supplement containing vitamins A, C, E, beta-carotene, zinc oxide, copper, taurine, EPA, DHA, lutein, and zeaxanthin. Data were compared with a control cohort constructed from literature review data. Controls experienced continual worsening of best-corrected visual acuity (BCVA) at 6 months, whereas 76.7% of patients receiving the TOZAL nutritional supplement showed continual improvement or maintenance of BCVA (logMAR) over time.6 The recently published large, phase 3, Age-Related Eye Disease Study 2 (AREDS2), a follow-up study from AREDS1, evaluated the effect of carotenoids lutein and zeaxanthin as well as omega-3 fatty acids DHA and EPA on rate of progression to advanced AMD and/or moderate vision loss in people at moderate to high risk for progression.1 In contrast to evidence from most of the related literature including findings from the NAT-2 study,58 AREDS2 findings suggest that omega3 does not prevent progression of AMD1; AREDS2 and NAT-2 studies evaluate different populations, formulations of omega-3 (EPA/DHA ratio), and use different methodology, however. Furthermore, the RBCM concentrations of omega-3 appear to vary among individuals, and this was not measured in AREDS2; therefore, no adjustment was made for differences in omega-3 concentration.1 In NAT-2, additionally, a subanalysis of data according to plasma omega-3 concentration tertiles and the protective effects of omega-3 appears to be significant only in those who had actually incorporated omega-3 into the RBCM.58 In another study evaluating nutritional supplements for AMD, conducted in preparation for AREDS2,1 the increased median serum levels of omega-3 long chain fatty acids were observed after 6 months of combined supplementation of EPA and DHA with lutein and zeaxanthin.23 The effects of lutein and DHA supplementation on their serum concentrations and

5

macular pigment optical density were investigated in another study, with results suggesting that DHA may facilitate accumulation of lutein in the blood and macula, particularly in the central part of the fovea. These findings suggest a different and maybe synergistic effect of DHA and lutein on the spatial pattern of increase in macular pigment optical density.26

4.

The role of micronutrients in AMD

There exists a substantial body of clinical data suggesting that protection against AMD may be provided by specific micronutrients (vitamins and minerals and antioxidants), although much of the data is contradictory, and it remains unclear as to which nutrients may confer benefit in AMD. The relationship between dietary intake of carotenoids and vitamins A, C, and E and risk of neovascular AMD was evaluated in a total of 356 case subjects with advanced AMD and 520 age- and sexmatched controls.47 This study found a higher dietary intake of carotenoids to be associated with lower AMD risk, particularly for lutein and zeaxanthin. This was supported by inverse associations between AMD and several food items rich in carotenoids such as spinach or collard greens. Intakes of retinol, vitamin E, and total vitamin C were not appreciably related to AMD. In contrast to these findings, data from the Beaver Dam Eye Study31 showed a significant, although small, inverse associations between intakes of pro-vitamin A carotenoids and dietary vitamin E and the incidence of large drusen and between zinc and the incidence of pigment abnormalities, with no significant inverse associations found between antioxidant or zinc intake and the incidence of overall early ARM.62 A potential protective effect of vitamin E in AMD also appeared in data from the Pathologies Oculaires Lie´es a` l’Age (POLA) study.16 In a study utilizing the Nurses’ Health Study and men in the Health Professionals Follow-up Study, fruit intake was inversely associated with the risk of neovascular ARM, whereas intakes of vegetables, antioxidant vitamins, or carotenoids were not strongly related to either early or neovascular ARM.9 Data from the Rotterdam Study showed dietary intake of both vitamin E and zinc to be inversely associated with incident AMD, and an above-median intake of beta carotene, vitamin C, vitamin E, and zinc was associated with a substantially reduced risk of AMD in elderly persons.14 Another study utilizing the Rotterdam Study population found that high dietary intake of antioxidant nutrients was associated with a reduction in early AMD risk in those at high genetic risk.21 An evaluation of data from AREDS revealed that dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD, geographic atrophy, and large or extensive intermediate drusen, whereas intake of other nutrients was not independently associated with AMD.44

4.1.

Controlled trials of micronutrient intake and AMD

Although these studies together suggest that there is a relationship between nutrient intake and AMD risk, the true nature of such a relationship cannot be determined without

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randomized controlled trials. The first large randomized controlled trial to demonstrate a beneficial effect of micronutrient supplementation in the progression of AMD was the AREDS study.2 In this study, a beneficial effect was observed with a combination of antioxidants and zinc compared with placebo. There have been several other controlled trials of micronutrient supplementation in AMD that have largely failed to show any marked effect on functional loss in AMD.

5.

Ongoing and future research

A search of ClinicalTrials.gov reveals numerous currently ongoing studies that are investigating the relationship between various micronutrients as well as omega-3 in the development and progression of AMD. Particularly noteworthy is a 300-patient phase III study currently underway in Canada on unilateral wet and dry AMD to investigate the effect of commercially available DHA supplements (study NCT00987129). There are also several ongoing studies investigating the role of supplementation with the carotenoids lutein and zeaxanthin (with or without omega-3), including the LUTEGA2 study being conducted to determine the long-term effect of supplementation with a fixed combination of lutein/zeaxanthin and omega-3-fatty acids in two different dosages on the optical density of macular pigment in patients with nonexudative age-related maculopathy (study NCT01648660). Despite the large body of research into the relationships between various nutritional factors and the development and progression of AMD, the true nature of these relationships is yet to be fully elucidated. A number of questions are still to be addressed, particularly those regarding the most effective “dose” of omega-3 fatty acids and the most effective ratio of omega-3 to omega-6 fatty acids, as well as the optimum combinations of various micronutrients.

6.

Conclusions

The vast majority of evidence suggesting a positive effect of dietary omega-3 intake on the development and progression of AMD comes from observational studies. Although this body of evidence is promising, a beneficial effect of omega-3 fatty acids in AMD remains to be demonstrated in randomized controlled trials. Given that the risk of taking omega-3 fatty acids from dietary fish or fish oil supplements is low, however, the potential benefits can be considered to outweigh the risks, and consumption of fish or fish oil supplements can therefore be recommended. In terms of other micronutrients, only the AREDS 2 formulation (which contained beta-carotene, vitamin C, vitamin E, and zinc) can currently be recommended to patients for reducing risk of AMD. Nutritional supplementation may provide an alternative to, or be used in conjunction with, dietary recommendations for the prevention of AMD development and progression. Improving our knowledge of the nutritional factors involved in the development and progression of AMD may be expected to allow some degree of control over risk factors for this disorder.

7.

Method of literature search

For this narrative review, a literature search of the Medline database (1970e2012) was conducted using the following key words: age-related macular degeneration, macular degeneration, retina, supplementation, vision, DHA, omega-3, and fatty acids. Manual searching of the bibliographies of selected papers was also used to identify other relevant studies suitable for inclusion based on their clinical relevance and importance. A few selected articles published before 1990 and in the 1990s were included for historical purpose, but the review is based mainly on articles published between 2000 and 2012. Additional papers were added at the authors’ discretion.

8.

Disclosures

The authors have no conflicts of interest or financial relationships related to the subject matter of the article being submitted.

Acknowledgments Medical writing assistance was provided by Andrea Bothwell and Mary Hines of inScience Communications, Springer Healthcare. This assistance was funded by Bausch & Lomb SpA.

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other cited material

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