Lutein and Ocular Diseases
By Georges Ramalanjaona, MD, DSc, FACEP, MBA
Cataract and Age-Related Macular Degeneration (AMD) are the leading causes of decreased visual acuity and legal blindness in the elderly,1 and important causes of disability.
A growing body of evidence from epidemiological and experimental studies has implicated a role for macular pigment in the protection against cataract and AMD, together known as Age-Related Degenerative Eye Diseases (AREDs).
Epidemiological studies have correlated high dietary intake of lutein with reduced risk of developing age-related cataract and AMD in persons with high serum concentrations of carotenoids.2 The macular pigment in the retina contains large amounts of a sub-class of carotenoids called xanthophylls, which includes lutein (L) and zeaxanthin (Z).3 Although modifying lifestyle, stopping smoking, and decreasing sunlight exposure may decrease the risk of developing AREDs, currently there are no accepted standard non-operative treatments for cataract and AMD.
Current clinical strategies are focused on preventing AREDs or delaying their progression. The best current evidence establishes a relationship between dietary lutein and AREDs as part of a promising strategy for the primary and secondary prevention of cataract and AMD.
Humans can only carry out limited metabolic transformation of carotenoids (from carotenes to xanthophylls). Thus, all carotenoids in humans are derived exclusively from the diet.4 Carotenoids are fat-soluble compounds, and their absorption involves solubilization in bile salts and incorporation into micelles. High dietary fat enhances plasma lutein levels and bioavailability of L and Z.5 Lutein is converted to zeaxanthin in the retina.
Carotenoids are known to influence each other’s metabolism in animals and humans. Low intake of L increases the storage of vitamin A in rat liver; large doses of beta-carotene (12-30 mg/d) given for six weeks decrease serum lutein levels; and 10 mg daily of oral lutein supplementation for three weeks increases serum levels of Z.6
In human serum, as in diet, lutein dominates over zeaxanthin in a ratio ranging from 2.7-5:1, and serum levels have been shown to be accurate biomarkers of food intake. Furthermore, increasing levels of macular xanthophylls pigment have been achieved through high dietary intake of foods rich in L and Z or by consuming purified supplements of lutein.7 Both L and Z are metabolized to oxo-lutein, Z isomers, and keto-carotenoids in the serum and macula.8 The uptake of L and Z from the serum into the retina is quite specific, unlike the other serum carotenoids that are found only in trace amount in retina. Yemelyanov et al recently isolated a xanthophyll-binding protein from human donor eyes; this work may play a key role in explaining that specificity.9
Mechanism of Action
In vitro studies have shown that L and Z function as antioxidants by quenching free radicals produced in the retina and as blue light filters, protecting underlying ocular tissues from photodamage and limiting chromatic aberration at the fovea.10
There are no current animal studies correlating dietary lutein to cataract formation and only limited data relating carotenoids to AMD. Several investigators have reported that monkeys fed a diet deficient in xanthophylls displayed depletion of their macular pigment (MP). Long-term maintenance (up to 14 years) on this diet resulted in loss of retinal pigment and epithelial and photoreceptor cell death.11
A preliminary human autopsy study has shown that retinal L and Z concentrations are 30% lower in eyes from patients with a history of AMD compared to those from age-matched control subjects without a known history of AMD.12
Two clinical studies have examined the effects of dietary lutein on macular density. Landrum et al found that in two subjects consuming an equivalent of 30 mg of free lutein daily for 140 days, MP optical density increased by 39% and 21%, respectively, within 20-40 days, and did not level off until 40-50 days after supplementation stopped.13 It was estimated that this modest period of lutein intake resulted in 30-40% reduction of blue light reaching the photoreceptors.
Another study by Hammond showed the effects of lutein-rich foods (cooked spinach and corn) on 13 subjects for 6-15 weeks.14 In eight subjects eating a diet rich in spinach or spinach and corn, serum lutein levels and MP density increased; the former remained elevated six months after the trial ended, and the latter returned to baseline.
Several clinical studies (retrospective, prospective, and randomized trials) have demonstrated the role of dietary lutein in lowering or preventing the incidence of age-related cataract and AMD. In this section, we will only report the most relevant and significant studies (see Table, below).
Recent studies on the effects of lutein on age-related degenerative eye diseases
|Mares Perlman et al2||Prospective cohort||11,919 women||5 years||
Statistically significant decrease of severe nuclear cataract.
|Lyle et al15||Prospective cohort||400 adults||5 years||
Inverse association between lutein intake and incidence of nuclear cataract.
|Brown et al16||Prospective cohort||36,644 men||8 years||
Statistically significant lowering of incidence of severe cataract.
|Chasan-Taber et al17||Prospective cohort||74,466 women||12 years||
Statistically significant decrease of advanced AMD.
|Seddon et al20||Case-control trial||876 adults||
Statistically significant decrease of advanced AMD.
|Mares Perlman et al21||Case-control trial||167 adults||
No significant association between lutein and AMD
|AREDS No. 823||Randomized, double-blind, controlled trial||3,640 adults||6.3 years||
Statistically significant reduction in visual acuity loss in antioxidant groups.
Cataract. In a large retrospective study (Level of evidence IIB, on a scale of I to III) Mares-Perlman reported that women (n = 1,919) who had the highest (by quintile) intake of lutein (median 949 mcg/d) 10 years prior to study enrollment had a 27% lower prevalence of severe nuclear cataract (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.5-1.06, P = 0.02) compared to those in the lowest quintile category (median 179 mcg/d).2 However, this inverse relationship between dietary lutein and development of nuclear sclerosis was not statistically significant in men. Among the lutein-rich foods studied, only spinach was found to be inversely associated with nuclear cataract.
Similarly, in a five-year follow-up of the Beaver Dam cohort, Lyle et al found that subjects who were in the highest quintile category of lutein intake (median 1,245 mcg/1,000 kcal) 10 years prior to baseline had a 50% lower incidence of nuclear cataract compared to sub-jects in the lowest quintile.15 Further examination of a sub-sample of 400 subjects (age 65 and older) showed an inverse slight association (although not statistically significant) between serum lutein levels and incidence of nuclear cataract equally in both genders.
Furthermore, a large long-term prospective cohort study (Level of evidence IA) of 36,644 men ages 45-75 with an eight-year follow-up showed that men in the highest quintile of L and Z intake had a 19% lower risk of severe cataract requiring extraction compared to men in the lowest fifth (relative risk [RR] = 0.81, P = 0.03).16 This lowering of risk of cataract extraction was modest, but significant in men with higher intakes of L and Z (spinach, broccoli) but not of alpha-carotene, beta-carotene, lycopene, or vitamin A after controlling other risk factors, including age and smoking. The use of cataract extraction rather than cataract diagnosis as an endpoint decreased the chance of variation in the threshold for diagnosis of disease and reduced the false-positive cases.
Similar findings were observed in another large, long-term prospective cohort study (Level of evidence IA) of 74,466 female registered nurses ages 45-71 years during a 12-year follow-up.17 Information on nutrient intake was regularly assessed by a detailed food questionnaire during these 12 years. Women in the highest intake of L and Z had a 22% decreased risk of cataract extraction compared to those in the lowest quintile (RR = 0.78, P = 0.04). This decrease in the risk of cataract was significant in women with higher food intake of L and Z (e.g., spinach and kale).
Conversely, two recent large long-term, randomized, double-blinded, placebo-controlled trials have effectively eliminated the role of other carotenoids in preventing cataract in the elderly.
First, Teikari et al studied 1,828 middle-aged smoking men supplemented with either 50 mg/d of alpha- tocopherol or 20 mg/d of beta-carotene, a combination of the two, or placebo for 5-8 years.18 Results showed that supplementation with either or both was not significantly associated with decreased prevalence of all subtypes of cataract (nuclear, cortical, and sub-capsular) or any effect on cataract severity as measured by lens opacity meter values compared to placebo.
Another recent randomized, placebo-controlled trial (n = 4,757) of high-dose supplementation with vitamins C and E and beta-carotene did not reveal any statistically significant effect in a large older adult cohort on the seven-year risk of development or progression of age-related cataract or visual acuity loss.19 These two trials pointed out that effort should be turned to other carotenoids such as lutein to prevent cataract.
AMD. Several epidemiological and prospective cohort studies have examined the role of dietary lutein or serum lutein in reducing the risk of AMD.
A large case-control trial by the Eye Disease Case Control Study (Level of evidence IIB) showed that individuals (n = 876) in the highest quintile of dietary intake of L and Z (median 5,757 IU) were 57% less likely to develop advanced AMD (OR = 0.43, 95% CI 0.2-0.7, P = 0.001) than individuals in the lowest quintile category (median 561 IU).20 Furthermore, subjects with high serum levels of L and Z (> 0.67 micromol/L) were 70% less likely to have AMD than those with lower serum levels (< 0.25 micromol/L) (OR = 0.3, 95% CI 0.2-0.6, P < 0.0001). Consumption of spinach or collard greens decreased odds of having AMD (P < 0.001).
In contrast, using a smaller sample of 167 case-control pairs from the Beaver Dam Study, Mares-Perlman found lower levels of serum L and Z among subjects with exudative AMD compared to controls.21 There was no significant association between L and Z intake and AMD.
A five-year follow-up of subjects from Beaver Dam cohort did not show any significant association between L and Z intake and specific macular lesions of late AMD.22 However, the power of this result was limited by the small number of subjects enrolled and the narrow range of serum L and Z intake.
The discrepancies between studies are partly due to differences in study design, sample size, range of serum levels of L and Z, and severity of AMD.
Finally, a recently completed large, long-term randomized, placebo-controlled trial (AREDS 8) sponsored by the National Eye Institute assessed four different antioxidant supplements for their protective effect against AMD.23 Results showed statistically significant reduction in rates of visual acuity loss (OR = 0.75, 99% CI 0.53-0.99) in the antioxidants plus zinc group compared to placebo. The authors did not specifically test lutein supplementation.
No statistically significant adverse effects were reported or associated with dietary lutein during short-term or long-term prospective studies.18,23
Contraindications and Precautions
There are no reported drug interactions or known interactions/contraindications with diseases or conditions with the use of lutein in the diet or as a supplement.24,25 Olestra, a fat substitute, decreases serum lutein concentrations in healthy subjects.26 Concomitant administration of beta-carotene may reduce bioavailability of lutein.27,28
Commercial products containing 6 mg or 20 mg of lutein are available. Supplemental esterified lutein is absorbed better when taken with high-fat (36 g) than with low-fat (3 g) meals.5
Foods containing high concentrations of lutein include cooked kale (44 mg per cup), cooked spinach (26 mg per cup), and broccoli (3 mg per cup).4 Substantial amounts of lutein and zeaxanthin (30-50%) are present in kiwi fruits, grapes, and orange juice. Dark green leafy vegetables contain 15-47% lutein.
In clinical trials, 6.9-11.7 mg of lutein per day from diet has been associated with reduced risks of developing AMD and cataract.1,2
Our current understanding of the role of lutein in age-related ocular disease stems from current epidemiological, histological, and clinical data. These studies conclude that risks of AMD and cataract appear to be significantly reduced in a safe and effective manner by a diet rich in lutein. Additional prospective epidemiological studies are needed to establish a nutrient database on content and bioavailability of lutein among various vegetables and fruits. Clinical trials confirming the specific benefits of lutein supplementation are still lacking.
Current evidence strongly supports the recommendation to consume vegetables and fruits high in lutein and zeaxanthin daily to reduce the incidence of age-related cataract and AMD. While AREDs have non-modifiable components (genetic, sex, race), an increased consumption of dietary carotenoids should be part of any successful strategy to prevent/retard degenerative eye diseases. Dietary consumption of food rich in lutein for the prevention of AREDs is recommended at this time.
Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Education, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.
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