Nutrition and Ophthalmology Part I: Macular Degeneration

Nutrition and Ophthalmology Part I: Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly Americans.( 1) A quarter of those over sixty-five years of age and a third over seventy-five have at least prodromal signs of AMD.( 2, 3) Conventional allopathic therapies help only a small percentage of AMD patients, though recent nutritional research appears to offer much hope.( 4)

Macular Degeneration and Antioxidants

Susceptibility to oxidative damage appears to be linked to the etiology of AMD.( 5) UV light from the sun can create singlet oxygen radicals which damage fatty acids within the retina. In animal studies, antioxidants protect the retina, probably by decreasing singlet oxygen. When animals are supplemented with antioxidants, they have a lower risk for retinal degeneration.( 6)

West, et al. reported that higher serum levels of antioxidants are associated with lower risk of AMD in humans.( 7) Though they claimed that this association did not extend to "supplements," no data were provided. Without details regarding which supplements were considered, what doses had been taken and for what duration in time, this claim tells us little about the relationship between supplements and AMD.

In 1993, the Eye Disease Case-Control Study Group found people (n=421) in the top quintile of "antioxidant index" -- a composite of serum levels for carotenoids, vitamin C and E, and selenium -- had an odds ratio for AMD of only 0.3 (95% CI=0.1-0.7), an association that was highly significant (P

Workers from the University of Illinois School of Public Health studied the relationship between dietary intake of fruits and vegetables high in beta-carotene and AMD risk, reporting an inverse association.( 10) The protective effect may have been due in part to beta-carotene itself. However, fruit and vegetables containing significant beta-carotene frequently have even higher levels of two other antioxidants which, until recently, have been mostly ignored in both epidemiologic and case-control studies dealing with antioxidants.

Lutein and Zeaxanthin

Lutein and zeaxanthin are carotenoids recently available as supplements. Spinach and kale contain very high levels of both of these antoxidants.( 11) Lutein and zeaxanthin selectively concentrate in the macula, and both filter out visible blue light, which is probably responsible for UV-induced oxidative damage.( 12, 13) The Eye Disease Case-Control Study Group report (see above) found the strength of the association between these two antioxidants and protection against AMD was as great as for beta-carotene and greater than the protective association reported for any other antioxidant studied.( 14)

Curiously, a short time before this trial was published, researchers conducting the Nurses Health Study found that eating spinach correlated better with protection from cataracts than any other food including foods high in other antioxidants.( 15) (Although cataracts have also been associated with UV-induced oxidative damage, lutein and zeaxanthin do not selectively accumulate in the lens.) In the prospective Nurses Health Study, those who ate spinach five or more times per week had approximately half the risk of forming a cataract compared with those who rarely ate spinach. This relationship was statistically significant every time spinach intake was measured. Spinach is the most commonly eaten high-lutein food in America.

In 1994, Seddon, et al. compared the diets of three hundred and fifty-six macular degeneration patients with diets from over five hundred people with unrelated eye conditions.( 16) The top quintile of total carotenoid intake associated with a 43% lower risk compared with the bottom quintile of intake, though other antioxidants were not appreciably related to macular degeneration.

These Harvard researchers then examined the effects of specific carotenoids. Some, like lycopene, were not associated with protection. High beta-carotene intake was associated with a decreased risk of AMD (RR=0.59). The top quintile of dietary lutein and zeaxanthin (a combined total of 5.8 mg per day) was linked to the greatest decrease in risk of macular degeneration (RR=0.43). An accompanying editorial claimed, "not all antioxidants are created equal" and said that the Harvard study "supports the role of specific antioxidants in preventing AMD [italics added]."( 17)

Lutein and Zeaxanthin Supplements

USDA researchers recently placed three men on a diet initially excluding high lutein foods followed by eighteen days of lutein and zeaxanthin supplementation (10 mg each).( 18) After one week, blood levels of both carotenoids increased fourfold or more showing substantial absorption with oral supplementation from non-food sources.

Researchers from the University of New Hampshire have reported a high degree of correlation between dietary and macular lutein levels.( 19) They concluded, "It appears that diet is important in determining macular pigment levels and thus diet may influence visual acuity and/or may protect the photo-receptors and pigment epithelium from damaging effect of light."

Thus we have preliminary evidence that lutein and zeaxanthin supplements absorb well and that, once absorbed, these antioxidants increase levels in the macula. Moreover, intakes of lutein and zeaxanthin correlate with protection, and both antioxidants appear to serve the purpose of protecting against the damage associated with the pathology. Finally, evidence of toxicity in humans is nonexistent nor have more thoroughly examined carotenoids been associated with any consistent toxicity.( 20)

To Supplement or Not to Supplement

So far, studies examining the relationship between lutein and zeaxanthin and protection from AMD are remarkably consistent. There remains one important missing piece -- intervention trials, optimally randomized and blinded. In the absence of such data, conventional medical catechism dictates that publicly, intervention should not yet be recommended. It seems hardly credible, however, to believe that if the grandmother of one of these researchers were going blind with AMD the researcher would not tell her to do a therapeutic trial with these supplements.

In fact, there is evidence that when allopathic physicians are squeezed between the ideology of not recommending nutritional therapy in the absence of blinded intervention trials on the one hand and real life on the other, actions and proclamations are not always in concert with each other. Following the publication of two cohort studies in the New England Journal of Medicine suggesting that vitamin E supplements dramatically reduce the risk of heart disease, leading cardiologists have said that cardiovascular patients should not be told to supplement antioxidants.( 21, 22, 23) Moreover, there are no data to suggest that cardiologists are frequently recommending antioxidants to their patients. Yet, when asked if they themselves took antioxidant supplements to prevent heart disease, nearly two-thirds of a group of seven hundred cardiologists reported that they did.( 24) It's fine that these doctors are following the Biblical dictum, "physician heal thyself," but why not heal patients, too?( 25) With a potential benefit, no apparent risk, no other treatment available for most patients, a clear mechanism of action, and an apparently consistent inverse association between lutein/zeaxanthin and AMD, why should a publicly proclaimed wait-and-see policy be tolerated when there is reason to suspect that for allopathic physicians themselves, the policy would not be enforced?

The Nature of Resistance to Supplementation

Conventional medicine often deals with therapies which carry significant risks, thus justifying a greater willingness to make type Il errors (wherein a useful therapy is discarded due to insufficient data) rather than type I errors (wherein a useless therapy is accepted on the basis of what turn out to be incorrect or insufficient data). A type I error involving a potentially toxic medicine can be tragic indeed.

Instituting a do-nothing policy with AMD, however, may well constitute a type II error in the making. If a decision to recommend not supplementing until more data are available does turn out to be a type II error, it will result in almost certain blindness for many thousands. The cost of a type I error in this instance, however, would be limited to the minor embarrassment for those of us wilting to make the suggestion, plus the cost of supplementation for patients.

Conventional medicine portrays the decision to supplement or not to supplement as a function of "science"; i.e. it is "unscientific" to recommend treatment in the absence of adequate intervention trials. This is simply not so. The policy of favoring type II rather than type I errors is a subjective call. There is nothing in science which demands that this subjective decision blindly come out in favor of type II errors regardless of the circumstances.

Zinc-Support from a Blinded Intervention Trial

Retinol dehydrogenase and superoxide dismutase (SOD) are both functional within the retina and are zinc dependent. The former enzyme affects retinol metabolism and is essential for sight. Though SOD might theoretically protect parts of the eye from oxidative damage, to what extent it protects the macula from AMD remains unknown.

Despite the limited physiologic support for such a study, researchers from Louisiana State University constructed a randomized double-blinded trial giving 80 mg of zinc or placebo for two years to one hundred and fifty-one AMD patients and used eye charts to determine visual acuity.( 26) At two years, there was 42% less visual acuity loss in the intervention group, a statistically significant difference.

As with lutein and zeaxanthin researchers, the authors of the zinc trial say that oral administration "is not now warranted." Again, the seriousness of the condition and the lack of proven effective treatments make one wonder whether the knee-jerk response -- don't try therapies without "enough" support -- is truly appropriate, especially because the available data, limited though they may be, do come from a randomized and blinded intervention trial.

In the zinc trial, significant side effects did not occur. However, decreased HDL levels and copper deficiencies sometimes result from zinc supplementation, though both may be correctable with the addition of supplemental copper.( 27)

Preventing Progression of AMD

What to do in the absence of further data? Seddon's trial reported an association between AMD and smoking, which makes physiological sense because smoke products can induce oxidative damage. Therefore, it behooves physicians to recommend that AMD patients quit smoking.

Regarding diet, it remains theoretically possible that the association between kale, spinach, collard greens, and other foods high in lutein or zeaxanthin are protective for unknown reasons -- the two antioxidants being merely markers for another yet-to-be-discovered protective agent. Therefore, it seems appropriate to encourage increased intake of these foods. Finally, until more is known, recommending supplementation with lutein, zeaxanthin, beta-carotene, and zinc (with added copper) is both justifiable and perhaps the most humane approach, even though the possibility of a type I error has not yet been ruled out.

Supplement Levels

Unfortunately, we have few guidelines regarding supplemental levels. The combined intake of 5.8 mg of lutein and zeaxanthin in the top quintile of intake in the Harvard study would seem like a minimum dose; higher levels might buy more protection and would most likely be safe. Because of the proven safety of beta-carotene, taking higher-than-dietary levels -- perhaps 25,000 IU per day -- might be suggested in the absence of more data. The 80 mg of zinc used in the intervention trial, however, may be unnecessarily high and would certainly require supplementation of several milligrams of copper to protect against induced deficiency. Only future research will help us fine-tune these doses. Until we know more, however, conservative intakes of beta-carotene, lutein, zeaxanthin, and zinc (with copper) make more sense than simply allowing macular degeneration to take its terrible course toward blindness.

(1) National Advisory Eye Council, Report of the Retinal and Choroidal Diseases Panel: Vision Research A National Plan: 1983-1987. Bethesda, MD: US Dept of Health and Human Services; 1984. National Institutes of Health publication 83-2471.

(2) Seddon JM & Hennekens CH: Vitamins, minerals, and macular degeneration. Arch Ophthalmol 112:176-79, 1994.

(3) Sighted: Foods for better vision. Tufts University Diet & Nutrition Letter 12(11): 1-2, 1995.

(4) Macular Photocoagulation Study Group: Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch Ophthalmol 109:1109-14, 1991.

(5) Young RW: Solar radiation and age-related macular degeneration. Surv Ophthalmol 32: 252-69, 1988.

(6) Katz ML, Parker KR, Handelman GJ, et al: Effects of antioxidant nutrient deficiency on the retina and retinal pigment epithelium of albino rats: a light and electron microscopic study. Exp Eye Res 34: 339-69, 1982.

(7) West S, Vitale S, Hallfrisch J, et al: Are anti-oxidants or supplements protective of age-related macular degeneration? Arch Ophthalmol 112: 222-27, 1994.

(8) Eye Disease Case-Control Study Group: Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol 111: 104-9, 1993.

(9) Blumenkranz MS, Russell SR, Robey MG, et ak Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmol 96: 552-58, 1986.

(10) Goldberg J, Flowerdew G, Smith E, et al Factors associated with age-related macular degeneration. Am J Epidemiol 128: 700-710, 1988.

(11) Micozzi MS, Beecher GR, Taylor PR & Khachik F: Carotenoid analyses of selected raw and cooked foods associated with a lower risk for cancer. J Natl Cancer Inst 82: 282-85, 1990.

(12) Bone RA & Landrum JT: Distribution of macular pigment components, zeaxanthin and lutein, in human retina. Methods Enzymol 213: 360-66, 1992.

(13) Schalch W: Carotenoids in the retina: a review of their possible role in preventing or limiting damage caused by light and oxygen. In: Emerit I, Chance B, eds. Free Radicals and Aging. Basel, Switzerland, Birkhauser Verlag pp 280-98, 1992.

(14) Blumenkranz MS, Russell SR, Robey MG, et al: Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmol 96: 552-58, 1986.

(15) Hankinson SE, Stampfer MJ, Seddon JM, et al: Nutrient intake and cataract extraction in women: a prospective study. BMJ 305: 335-39, 1992.

(16) Seddon JM, Ajani UA, Sperduto RD, et al: Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA 272:1413-20, 1994.

(17) Hankinson SE & Stampfer MJ: All that glitters in not beta-carotene. JAMA 272:1455-56 [editorial], 1994.

(18) Khachik F, Beecher GR & Smith JC: Lutein, lycopene, and the oxidative metabolites in chemoprevention of cancer. J Cellular Biochem, in press.

(19) Curran-Celentano J, Fuld K, Hammond BR & Thompson KL: Macula pigment: its relationship to dietary and serum carotene levels. FASEB Meeting, Anaheim, CA, abstract #1003, April 5-9,1992.

(20) Bendich A: The safety of B-carotene. Nutr Cancer 11:207-14, 1988.

(21) Stampfer MJ, Hennekens CH, Manson JE, et al: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 328:1444-49, 1993.

(22) Rimm EB, Stampfer MJ, Ascherio A, et al: Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 328:1450-56, 1993.

(23) Steinberg D: Antioxidant vitamins and coronary heart disease. N Engl J Med 328:1487-89, 1993.

(24) Jancin B: An antioxidant a day keeps the doctor in the pink. Family Practice News P.10, March 1, 1994.

(25) Saint Luke 4:23.

(26) Newsome DA, Swartz M, Leone NC, et al: Oral zinc in macular degeneration. Arch Ophthalmol 106: 192-98, 1988.

(27) Fosmire GJ: Zinc toxicity: Am I Clin Nutr 51:225-27, 1990 [review].

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By Steve Austin

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