Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

From ref. 269, with some values rounded for clarity.

to discriminate between forms of vitamin E in the packaging of chylomicrons. RRR-α- tocopherol appears to be better absorbed than other forms of vitamin E (220). The absorption of vitamin E has been variously reported to range from 15% to 85% (270–272), and the proportion of vitamin E that is absorbed decreases with increasing intake of vitamin E (273,274).

The liver takes up chylomicron remnants which contain vitamin E. Vitamin E is secreted from the liver in very low-density lipoproteins (VLDLs), and α-tocopherol is the only form of vitamin E to be resecreted by the liver (275). Hepatic α-tocopherol transfer protein transfers α-tocopherol between liposomes and microsomes (276). The major lipoprotein in VLDLs is apolipoprotein B-100, which is retained as VLDLs are catabolized by lipoprotein lipase to form LDLs and HDLs. LDLs interact with receptors for apolipoprotein B in peripheral tissues (276). High concentrations of α-tocopherol are found in adipose tissue, the adrenal glands, liver, and skeletal muscle. More than 90% of the vitamin E in the human body is found in fat droplets in adipose tissue (277).

5.4.6. FUNCTION OF VITAMIN E

The main function of vitamin E appears to be as an antioxidant which protects membranes and lipoproteins against excessive lipid peroxidation. No specific, required metabolic function has yet been identified for vitamin E. Vitamin E appears to protect polyunsaturated fatty acids within membrane phospholipids and plasma proteins by scavenging peroxyl radicals (276,278). Lipid oxidation can occur during normal aerobic metabolism and during disease processes. Polyunsaturated fatty acids can give up loosely bound hydrogen to highly reactive free radicals, thus becoming fatty acid radicals. Fatty acid radicals take up oxygen and become peroxyl radicals, where they can attack further polyun-

Fig. 13. Absorption, storage and metabolism of α-tocopherol.

saturated fatty acids. Vitamin E protects polyunsaturated fatty acids against autoxidation by breaking this chain by trapping peroxyl radicals and yielding a stable lipid hydroperoxide molecule:

polyunsaturated fatty acids + free radical (R•) → fatty acid radical (R•)

fatty acid radical (R•) + O2 → peroxyl radical (ROO•)

peroxyl radical (ROO•) + vitamin E → lipid hydroperoxide (ROOH) + vitamin E radical (O•)

In the absence of vitamin E, the chain reaction can continue with autoxidation of polyunsaturated fatty acids:

peroxyl radical (ROO•) + polyunsaturated fatty acids → lipid hydroperoxide (ROOH) + fatty acid radical (R•)

fatty acid radical (R•) + O2 → peroxyl radical (ROO•)

One tocopherol molecule can protect about 100 molecules of polyunsaturated fatty acids from autoxidative damage, and biological membranes usually contain about 1% as many molecules of vitamin E per molecules of polyunsaturated fatty acids (276). Other activities of vitamin E may include scavenging of singlet oxygen (279).

5.4.7. REQUIREMENTS FOR VITAMIN E

The dietary reference intakes for vitamin E have been determined recently (220) (Table 8). The Adequate Intake (AI) is the recommended level of intake for infants. The Estimated Average Requirement (EAR) is the daily intake value that is estimated to meet the requirement of half of the healthy individuals in a group. The Recommended Dietary Allowance (RDA) is defined as the EAR plus twice the coefficient of variation (CV) to cover 97– 98% of individuals in any particular group.

200 Handbook of Nutrition and Ophthalmology

Table 8

Dietary Reference Intakes for Vitamin E (mg/d of α-Tocopherol)

AI, Adequate Intake; EAR, Estimated Average Requirement; RDA,

Recommended Dietary Allowance. Based on ref. 220.

5.4.8. EPIDEMIOLOGY OF VITAMIN E DEFICIENCY

Clinical vitamin E deficiency is rare in humans. Premature infants are at higher risk of vitamin E deficiency, which can result in a hemolytic anemia. Among older infants, children, and adults, overt vitamin E deficiency is rare. Individuals who may be at higher risk of vitamin E deficiency are those with malabsorption syndromes, pancreatic insufficiency, short bowel syndrome, and abetalipoproteinemia, an inborn error of metabolism (see Chapter 12, Subheading 2). A genetic abnormality in α-tocopherol transport protein has been described (280).

5.4.9. ASSESSMENT OF VITAMIN E STATUS

The most commonly used laboratory test for the assessment of vitamin E status is the measurement of plasma α-tocopherol concentrations by high-performance liquid chromatography (281). Vitamin E deficiency has been defined as a plasma concentration of α-tocopherol <11.6 μmol/L (<5.0 μg/dL). The plasma α-tocopherol (μmol/L) to plasma cholesterol (mmol/L) ratio has also been advocated for identifying vitamin E deficiency, with a ratio <2.2 indicating risk of vitamin E deficiency (281). Dietary vitamin E intake is difficult to assess from food frequency questionnaires because the source of oil used in food preparation is often unknown, and this uncertainty may add to measurement error for vitamin E status from dietary surveys (282). Smoking does not appear to influence plasma vitamin E concentrations (283).

5.4.10. CLINICAL MANIFESTATIONS OF VITAMIN E DEFICIENCY

Vitamin E deficiency is characterized by a peripheral neuropathy with degeneration of large-caliber axons in the sensory neurons, loss of deep tendon reflexes, skeletal myopathy, and a pigmented retinopathy (284).

5.4.11. ROLE OF VITAMIN E IN THE RETINA

Photoreceptor outer segments are rich in polyunsaturated fatty acids, thus, there has been great interest in the potential role of α-tocopherol as an antioxidant in the retina. α-toco- pherol appears to be almost equally distributed between the retina, retinal pigment epithe-

lium, and choroid, and these layers combined contain about 2.9 mg α-tocopherol per 100 g wet weight (285). The adult human eye does not appear to be especially enriched in α- tocopherol compared with other tissues of the body such as adipose tissue, liver, or brain (285). Vitamin E concentrations were examined in a study of 70 eyes from donors aged 9 to 104 yr (286). Higher vitamin E concentrations were found in the retinal pigment epithelium than the retina, and no differences were found in vitamin E concentrations of the retinal pigment epithelium between the macula and peripheral regions (286). The amount of vitamin E in the retina was lower in the macula compared with the peripheral region (286). In contrast, the concentrations of vitamin E were measured from the foveal center to the periphery of the retinas of rhesus monkeys, and the highest concentrations of vitamin E were found in the foveal center with a minimum near the foveal crest (287).

Studies in animal models suggest that retinal pathology results from experimental vitamin E deficiency. In primates fed a vitamin E-deficient diet, a macular degeneration developed after 2 yr (288). The macular degeneration was characterized by degeneration of photoreceptor outer segments and a massive accumulation of lipofuscin in the pigment epithelium (288), a condition similar to that described in vitamin E-deficient dogs (289). The disruption of photoreceptor outer segments was attributed to increased lipid peroxidation (288). Weanling rats that were raised with a diet deficient in vitamins A and E lost 92% of rod nuclei at 35 wk, compared with losses of 34% and 20% among rats raised on diets deficient in vitamin A or E alone, respectively (290). Vitamin E deficiency resulted in the extensive deposition of lipofuscin deposits in the retinal pigment epithelium. Combined antioxidant deficiency produced by diets deficient in vitamin E, selenium, chromium, and sulfur amino acids resulted in loss of photoreceptor cells and pathological changes in the retinal pigment epithelium (291). In rats deprived of dietary vitamin E, the depletion of vitamin E from rod outer segments and retinal pigment epithelium took considerably longer than it did for other ocular tissues or for blood and other organs (292). These findings suggested that vitamin E concentrations are conserved in the retina relative to other tissues and blood (292).

Experimental animal models show that additional dietary vitamin E does not protect the retina against light damage, which is contrary to the idea that vitamin E might protect photoreceptor outer segments from photochemical damage. In albino rats, vitamin E and selenium-supplemented animal showed marked light damage effects compared with vitamin E and selenium-deficient animals (293). Vitamin E supplementation did not protect the retina against damage from cyclic light exposure in rats (244). In adult humans, it is unclear whether vitamin E supplementation can increase vitamin E concentrations in the retina. Premature infants are born with lower concentrations of vitamin E in the retina, but supplementation with vitamin E did not result in much elevation of vitamin E in the retina (295). Recently, a large randomized, double-masked, placebo-controlled clinical trial in Australia showed that daily supplementation with vitamin E had no impact on the incidence of early age-related macular degeneration (262). 1193 healthy participants between 55 and 80 yr of age received vitamin E, 500 IU, or placebo, daily for 4 yr. The incidence of early age-related macular degeneration was 8.6% and 8.1% in the vitamin E and placebo groups, respectively (RR 1.05, 95% CI 0.69–1.61). The incidence of late agerelated macular degeneration was 0.8% and 0.6% in the vitamin E and placebo groups, respectively (RR 1.36, 95% CI 0.67–2.77). These findings are consistent with observational studies that have shown that vitamin E status is not associated with age-related

with antioxidants (vitamin C 500 mg, vitamin E 400 IU, β-carotene 15 mg) plus zinc (80 mg zinc oxide) and copper (2 mg cupric oxide) could reduce the development of agerelated macular degeneration (307). This clinical trial has provided the most definitive evidence to date that antioxidants and zinc may play a role in the pathogenesis of agerelated macular degeneration. The clinical trial involved four treatment groups in a 2 H 2 factorial design: antioxidants, zinc, antioxidants + zinc, and placebo. The primary outcome measures of the trial were (1) progression to advanced age-related macular degeneration, and (2) at least a 15-letter decrease in visual acuity score. The mean follow-up in the study was 6.3 yr. There were originally 4757 participants enrolled in the trial, and the participants were divided into four categories at enrollment, based on the severity of their clinical disease: (1) no age-related maculopathy, (2) mild or borderline age-related maculopathy consisting of multiple small drusen, single or nonextensive intermediate drusen, pigment abnormalities, or a combination of these, with visual acuity of 20/32 or better in both eyes, (3) at least one large druse, extensive intermediate drusen, geographic atrophy not involving the center of the macula, or a combination of these, and visual acuity of 20/32 or better in at least one eye, and (4) visual acuity of 20/32 or better and no advanced age-related macular degeneration (geographic atrophy involving the macula or evidence of choroidal neovascularization) in the study eye, and the fellow eye with lesion of advanced age-related macular degeneration or visual acuity less than 20/32 and age-related macular degeneration abnormalities sufficient to explain reduced visual acuity as determined by examination of photographs at the reading center (306). The supplements in the study used nutrients at 5–15 times the RDA.

The results of this large study showed that supplementation with antioxidants plus zinc was protective against the development of advanced age-related macular degeneration (OR 0.72, 99% CI 0.52–0.98). When stratified analyses were restricted to the higher risk subjects, antioxidants plus zinc (OR. 0.66, 99% CI 0.47–0.91) or zinc (OR 0.71, 99% CI 0.52–0.99) were associated with reduced odds of developing advanced age-related macular degeneration. Antioxidants with zinc were also associated with a reduced risk of moderate visual loss (OR 0.73, 99% CI 0.54–0.99) (Fig. 14) (306). The investigators conclude that adults over 55 yr of age who have at least one large druse or noncentral geographic atrophy in one or both eyes, or those with advanced age-related macular degeneration in one or both eyes, should consider taking an antioxidant supplement plus zinc such as that used in the study (307). Contraindications to these high-dose supplements include smoking. It has been estimated that 8 million people aged 55 yr or older in the United States have monocular or binocular intermediate or monocular advanced age-related maculopathy (308). In the next 5 yr, an estimated 300,000 people with age-related maculopathy would avoid advanced age-related maculopathy and any associated vision loss if they received antioxidant supplementation (308).

9. CONCLUSIONS

Significant progress has been made in the last two decades in our understanding of the pathogenesis of age-related maculopathy and age-related macular degeneration. Dietary modification and antioxidant nutritional supplementation show promise as approaches to the prevention of visual loss from age-related macular degeneration. The Age-Related Eye Disease Study demonstrated that a supplement high in antioxidants could reduce the

Fig. 14. Probability of visual acuity loss by treatment group in the Age-Related Eye Disease Study. (Reprinted from ref. 306. Copyright © 2001, American Medical Association. All rights reserved.)

progression of age-related macular degeneration. Further research is needed to confirm the various hypothesized roles for macular pigment in the retina, including reduction of oxidative stress and improvement in visual acuity. It is still not known whether dietary modification or antioxidant nutritional supplementation at early stages of age-related macular degeneration will reduce the risk of progression of disease. Such studies would require extremely large sample sizes and long-term follow-up. Binding proteins and transport proteins for macular pigment must be characterized, and the origin of macular pigment needs to be verified. Further work is needed to elucidate the role, if any, of minor carotenoids in the retina. Clinical trials needed to determine whether dietary interventions with xanthophylls can protect against age-related macular degeneration. A new nationwide

study sponsored by the National Institutes of Health, Age-Related Eye Disease Study 2 (AREDS-2) will evaluate lutein and zeaxanthin and omega-3 fatty acids in the reduction of rise to progress to advanced age-related macular degeneraion. New methods are needed which can objectively measure macular pigment in vivo in the retina without relying on response of subjects. Further studies are needed to determine why women are apparently at higher risk for age-related macular degeneration. Further studies are needed to determine whether lutein and zeaxanthin in the retina can actually inhibit lipid peroxidation. The relationship between antioxidant nutritional status, systemic inflammation, and risk of age-related macular degeneration requires further elucidation.

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