Lutein and Age-Related Macular Degeneration

Lutein.

Lutein and its structural isomer zeaxanthin are compounds that belong to a large class of plant pigments referred to as carotenoids. Of the two, lutein is present in a greater amount in the diet and in human blood and tissues (Johnson et al, 2000, Holden et al, 1999; Sommerberg et al, 1998; Hammond et al, 1997; Hart et al, 1995). Lutein is more polar than many other carotenoids due to the presence of hydroxyl groups on the cyclic ring structure. The relatively higher polarity of lutein compared to other carotenoids determines, in part, distinctive characteristics during absorption, transport, metabolism and uptake into tissues (Erdman et al, 1993; Castenmiller & West 1998; Parker et al, 1999). Unlike the provitamin A carotenoids, (alpha-, beta-carotene and cryptoxanthin), it cannot be converted to vitamin A. Its presence in human blood and tissues (including the macula of the eye) is entirely due to the ingestion of food or supplement sources of lutein, that is, it is not synthesized by human or animal tissue. The two foods that were found to have the highest amount of lutein are kale and spinach (Holden et al, 1999, Mangels et al, 1993). Other major sources include broccoli, peas, and brussel sprouts.

Macular Pigment.

While more than 600 carotenoids can be found in nature (Goodwin 1993) and 30-50 carotenoids are found in human serum and tissues (Parker 1993), lutein and zeaxanthin are the only carotenoids that are found in significant amounts in the macula of the eye with no more than trace amounts of other dietary carotenoids (Bone, Landrum, & Tarsis, 1985; Handelman et al, 1992; Bone et al, 1993; Schmitz et al, 1993). The macula is an area up to 5.5 mm in diameter with the fovea at its center. The fovea is located 4 mm temporally from the center of the optic disc and approximately 0.8 mm below the horizantal line. The fovea is the thinnest part of the retina and is free from blood vessels. The macular has a preponderance of cone cells and is responsible for detailed central vision.  Cones, along with rods, are photoreceptor cells that have neural connections to gather light and convert it to electrical nerve impulses, transmitted via the optic nerve. Lutein and zeaxanthin are concentrated in the central retina at the macula and are responsible for the yellow color.  The first careful characterization of the macular pigment was made by Bone et al (1985, 1988) who demonstrated that the pigment was lutein and zeaxanthin. Although the term macula lutea, or macula, originally applied to the yellow pigment, it is now commonly used to refer to the corresponding region of the retina.  This region includes the fovea, which is the region that is responsible for our highest visual acuity and which contains the highest density of cone photoreceptors (Landrum et al, 1996). Toward the periphery of the retina, the concentration of zeaxanthin declines rapidly whereas, as eccentricity increases away from the fovea, lutein becomes the dominant carotenoid (Bone et al, 1988; Landrum et al, 1999). In addition, Bone et al identified meso-zeaxanthin as another component of the macular pigment (1992). They have also provided evidence that lutein is the source of meso-zeaxanthin (ref ). The lutein concentration in the macula is more than a thousand-fold higher than the concentration in other human tissues (Schmitz et al, 1993; Hammond et al, 1997; Landrum et al, 1999). A characteristic of the macular pigment is its ability to absorb and attenuate blue light striking the retina (Brown & Wald, 1963).

Non-invasive psychophysical tests using heteroflicker photometry (Landrum et al, 1997; Hammond et al, 1997; Beatty et al, 2001) and Raman spectroscopy (Bernstein et al, 1998; 2002) are being used to measure macular pigment optical density (MPOD), which provides information on long-term intake of lutein and zeaxanthin. While these techniques offer the advantage of being non invasive measures, they are not able to distinquish between lutein and zeaxanthin in their relative contribution to macular pigment. The ability to measure macular pigment in vivo offers the opportunity to examine its relationship to health and disease. Traditionally, assessment of lutein status in humans has been via dietary or blood levels of lutein. Measures of macular pigment provide information of long-term exposure to lutein.

Dietary lutein, either in the form of green, leafy vegetables or lutein supplements can increase the amount of macular pigment. Evidence from human studies suggest that dietary intake of lutein can lead to its accumulation in the retina. Several other investigators have reported increases in serum and macular pigment levels of lutein with dietary or supplemental lutein in both healthy subjects and subjects with eye disease (Table 1). For example, in a prospective study (Hammond et al, 1997), eleven subjects modified their usual daily diets by adding 60g/d of spinach for 15 weeks (containing 11 mg lutein and 0.6 mg zeaxanthin).  Eight subjects had increases in serum lutein and macular pigment density, two subjects showed substantial increase in serum lutein but not macular pigment, and one subject showed no changes in serum lutein or macular pigment density.  Although the results were varied, augmentation of macular pigment through dietary modification appears to be possible for many people. Similar to this study, Landrum et al (1997) have found that supplementation with lutein (30 mg/d for 140 days) resulted in increased serum levels of lutein and corresponding increases in the concentration of lutein in the macula on the human eye (32). 

Age Related Macular Degeneration

Age –related macular degeneration is a disease that affects the central vision. In AMD, the light sensitive cells in the macula break down. The cause of this is unknown, but risk factors include female gender, smoking, family history, elevated blood cholesterol, and low dietary intake of lutein (Snodderly, 1995). Age-related macular degeneration is already the leading cause of blindness in the western world. Between 20 and 25 million people are affected worldwide.  This is expected to triple with the increase in the aging population in the next 30-40 years (National Statistics Office, 2002).  According to the World Health Organization, 8 million people have severe blindness due to age-related macular degeneration, excluding the countries where data are not available (WHO, 2002).  In the aging US population, AMD is a major cause of visual impairment and blindness. The prevalence of AMD increases dramatically with age. Nearly 30% of Americans over the age of 75 have early signs AMD and 7% have late stage disease, whereas the respective prevalence among people 43-54 yrs are 8 and 0.1% (Klein et al, 1992; Leibowitz et al, 1980, Ferris et al, 1984). AMD is the leading cause of blindness among the elderly in industrialized countries (Klein et al, 1992; National Advisory Eye Council, 1984. Ferris et al, 1984). Because there are currently no effective treatment strategies for most patients with AMD, attention has focused on efforts to stop the progression of the disease or to prevent the damage leading to this condition (Snodderly, 1995). One promising candidate in this regard is lutein. The lines of evidence for a role for lutein include its biologic plausibility and clinical and epidemiological observations.

The Biological Role of Lutein in the Eye.

Lutein is thought to protect the eye through two mechanisms: 1). Lutein is a blue light filter.  Macular pigment absorbs blue light as it enters the inner retinal layers thereby attenuating the intensity and potential for photo-oxidation of reactive unsaturated lipid components of photoreceptor membranes. In fact, intense light can produce damage in the retina (Young, 1994; Gottsch et al, 1990; Ham & Mueller, 1989) and sunlight exposure is a risk factor for age-related macular degeneration (Gottsch et al, 1990).; 2) Lutein is an antioxidant.  The rods and cones outer segments may be at particular risk of oxidative damage because of the high concentration of polyunsaturated fatty acids in photoreceptor outer segment membranes (Young, 1988; Weiter, 1988). Oxidative stress is high in the eye due to the intense light exposure and the high rate of oxidative metabolism in the retina. It has been shown that one of the mechanisms by which light damages the retina is by generation of free radicals that lead to peroxidation of membrane lipids (Noell, 1980; Wiegand et al, 1983). Lutein may act an antioxidant to limit the oxidant stress of the tissue that results from light and metabolism (Ham, 1983; Khachik et al, 1997; Schalch, 1992). Carotenoids are known to be powerful antioxidants (Beatty et al, 1999; Martin et al, 1999).  It has been recently shown that lutein is a somewhat better antioxidant than other carotenoids such as b-carotene (Martin et al, 1999).

Biological Evidence.   The action spectrum for light induced damage shows a distinct maximum at wavelengths between 400 and 450 nm, consistent with the absorption spectrum of macular pigment (Ham et al 1984). Lutein, being a colored compound, absorbs light and is effective in filtering blue light (400-475 nm). This ability to filter out blue light on entering the retinal tissue has the effect of decreasing the chromatic aberration associated with the lower wavelengths of visible light, i.e., the blue region of the visible spectrum. Khachik et al reported that the macular pigment consist of oxidation products of lutein (1997). The presence of oxidized metabolites suggests that the pigments are susceptible to oxidation in the tissue, or that an active metabolic process takes place, with some potential interconversions from among the reported intermediates.

The distribution of lutein and zeaxanthin in the retina suggests a possible role for lutein protecting the rods that are concentrated in the peripheral retina and for zeaxanthin (plus meso zeaxanthin) in protecting the cones that are concentrated in the central retina. Given that meso zeaxanthin is concentrated in the central retina and that the source of meso zeaxanthin is lutein (Bone et al, 1993, 1997), lutein may also be important in the protection of cones.

Clinical Evidence.  Several studies show evidence that macular pigment attenuates light damage in the human retina. It has been reported that the age-related decline of retinal sensitivity of the short-wavelength (blue) cones is reduced in areas where macular pigment levels are highest (Haegerstrom-Portnoy, 1988). Bull’s eye maculopathy, a clinical condition associated with photosensitizing drugs, is characterized by retinal degeneration in the annular pattern which surrounds but significantly spares the macula (area of greatest lutein concentration) (Bernstien & Ginsberg, 1964; Weiter et al, 1988). The photic damage from operating microscopes resulting in lesions, has the least damage in illuminated regions that overlap the macular pigment (Michels et al, 1992; Jaffe & Woods, 1988). Greater age-related loss of sensitivity to blue light in retinal regions with lower macular pigment density and in older adults with lower macular pigment density has been interpreted as further evidence of protection by macular pigment (Hammond et al, 1998). However, it should be noted that loss of sensitivity could also be due to decreased lens transmission of blue light in persons with low dietary carotenoids (Hammond et al, 1997b; Brown et al, 1999; Chasen-Taber et al, 1999; Gale et al, 2001) or to local gain changes as a result of differential filtering of light (Werner et al, 2000).

It has been reported that foveal cone and parafoveal rod visual sensitivities of older individuals are positively related to macular pigment density (Hammond et al, 1998).

Although macular pigment density has been reported to be normal I patients with age-related maculopathy (Berendschot et al, 2002)

Early photoreceptor atrophy in AMD appears later and progresses more slowly in the fovea (Sarks et al, 1988; Marmar & McNamara, 1996). Foveal sparing is also the expected consequence of selective loss or rods in AMD (Curcio et al, 1996).

The data to support a role of lutein in the prevention of AMD is mostly limited to human data. The primary reason for this is that only primates have the anatomical feature of a macula. In monkeys fed diets devoid of carotenoids for several years, levels of lutein and zeaxanthin in the macula disappear and retinal abnormalities that resemble age-related degenerative changes in humans appear (malinow e tal, 1980).

Epidemilogical Evidence. 

Epidemiologic and case-control studies suggest that the risk for AMD and advanced AMD may (refs) or may not (ref) be inversely related to lutein concentrations in the diet or plasma (and presumably in macular pigments). Other factors associated with increased risk for AMD, including smoking, female gender, and lighter eye color  are associated with reduced serum carotenoids levels and lower macular pigment density in normal human subjects (Snodderly, 1995).  In a study comparing postmortem retinas from AMD and control donors the amounts of MP in the outer portion of the retina are lower for those diagnosed with AMD (Bone et al, 2001). Lower risk for macular degeneration has been associated with the consumption of food sources of lutein (Mares-Perlman et al, 2001; Goldberg et al, 1988; Seddon et al, 1994), with level of lutein in the diet or with higher levels of lutein in the blood (EDDSC, 1992). However, these associations have not always been observed (Mares-Perlman et al, 1995; Mares-Perlman et al, 1996; VandenLanenberg et al, 1998; Sanders et al, 1993).

Investigators from the Eye Disease Case-Control (1992) reported that patients in the group with the highest level of plasma lutein/zeaxanthin (>80th percentile) had an odds ratio for AMD of 0.3 (95% CI 0.2-0.6; p=0.001).  In a subsequent study (1993), the investigators found that protection from AMD was associated with dietary intake of specific carotenoids.  In this case-control study, AMD patients and matched control subjects (who had other eye problems) were divided into five groups on the basis on their intake of various nutrients from foods.  The odds of macular degeneration were then calculated for each group.  The nutrient class that was found to have the strongest protective effect against AMD was carotenoids.  Those in the highest quintile of carotenoid intake has a 43% lower risk of developing AMD (odds ratio 0.57; 95% CI 0.35-0.92; p <0.02) compared to those in the lowest quintile.

The authors then investigated which specific carotenoids were responsible for this effect.  They divided carotenoids into five group: a-carotene, b-carotene, b-cryptoxanthan, lycopene, and lutein/zeaxanthin.  The strongest association with protection from AMD was found for lutein/zeaxanthin.  Subjects who were in the highest quintile for their intake of lutein/zeaxanthin had a 57% lower risk of advanced AMD compared to those in the lowest quintile (odds ratio 0.43; 95% CI 0.2-0.7; p <0.001).  This odds ratio was calculated from a multivariate node, indicating that the reduction in odds associated with consumption of lutein /zeaxanthin was independent of effects from other carotenoids.

A final analysis was performed by arranging the subjects on the basis of consumption of specific foods.  In a multivariate model that included consumption of broccoli, cabbage-related vegetables, carrots, spinach or collard greens, sweet potatoes, and winter squash, only consumption of spinach was associated with protection from AMD.  Subjects in the highest quintile for consumption of spinach had an 86% lower odds of advanced AMD (odds ratio 0.14; 95% CI 0.01-0.12; p <0.001).  This is noteworthy, given that spinach is a particularly rich source of lutein and zeaxanthin (Mangels, et al, 1993; Holden et al, 1999).

Not all studies have found an association between serum carotenoids and protection from AMD.  For example, a case-control study that used the population for the Beaver Dam Eye Study found no such association for lutein or zeaxanthin, but did find a weak protective effect of serum lycopene (Mares-Perlman et al, 1995). 

In general, results from observation studies are somewhat scarce but suggest a protective association of lutein with AMD or no relationship. Inconsistencies may reflect limitations in the study design (inclusion criteria, duration, clinical endpoints, amounts ingested) or differing effects of lutein during certain stages of AMD or different relationships in people who are predisposed to the disease. This may be related to a number of factors including differences in clinical endpoints, populations assessed and study design (inclusions criteria, duration, amounts ingested), difficulties in assessing dietary lutein, and the presence of disease affecting lutein status.

Intervention trials would lend strong support to a lutein/AMD relationship. This would make it possible to establish temporality and specificity in a cause-effect relationship. However, intervention trials with lutein have been primarily experimental and on a very small number of people. Lutein has not been used in a large scale intervention trial to test its efficacy in relation to AMD.  However, lutein has been used to protect visual function since the 50’s with some (but not always) success (Table 2). Visual function has been observed to improve with lutein supplementation in both healthy subjects and in patients with eye disease (Table 2).

The Safety of Lutein

Lutein intakes at levels achievable through diet are considered to be safe. There are no known reports that lutein, at any level of intake has toxic effects. With the advancement of the supplement industries, it is now possible to consume levels of lutein that are beyond typical dietary intakes. However, the results of several human intervention studies that indicate that supplementation of pharmacological doses of b-carotene (another common dietary carotenoid0, did not decrease the risk of cancer or cardiovascular disease, and might even be harmful to smokers or former asbestos workers (ATBC, 1994; Omenn et al, 1996). It is not know if there are similar risks associated with high supplemental intakes of lutein. Certainly, supplementation with high doses of lutein raises its blood levels (Table 1). For example, in a group of apparently healthy non-smokers supplemented with lutein (15 mg/day for 4 months) resulted in the presence of ester forms of lutein was found in the serum in those subjects reaching serum levels above 1.05 umol/L (Granado et al 1998) (compared this to 0.37 umol/L median value and 0.69 fir 90th percentile for the Third NHANES survey, (Ford & Giles, 2000)). The physiological significance of this in not known, particularly since the esters forms amounted to approximately 3% of the total lutein value. This observation is specific to lutein supplementation, that is, it has not been observed of other major dietary carotenoids, such as b-carotene and lycopene at supplementation at similar doses (Johnson et al, 1996, 1997a, 1997b).

Summary. The biological actions attributed to lutein (including its selective accumulation in the retina), along with the clinical and epidemiological evidence in relation to age-related macular degeneration, as prompted interesting in the role of lutein in the prevention of this major cause of blindness.

Although the epidemiology has not been entirely consistent in showing a protective association between lutein and risk of AMD, there have been no studies (case-control, clinical, epidemiologic, animal) that have shown lutein to be associated with an increased risk of AMD, or any other disease. There evidence suggests that lutein can prevent or delay the progression AMD. However, there is no evidence that suggests that lutein can cure AMD.

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Table 1 .  The effect of dietary or supplemental lutein on serum and tissues concentrations of lutein in humans. 

Table 2 .The effect of supplemental lutein on visual function in humans.

(*) Data taken from Nussbaum  et al, 1981.