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

Fig. 5. Nuclear cataract. (Courtesy of Walter Stark.)

Fig. 6. Cortical cataract. (Courtesy of Walter Stark.)

brane–SH groups involved in cation transport and permeability, and by detoxifying hydrogen peroxide and other free radicals (134).

Another important antioxidant that may protect the lens against oxidative stress is ascorbic acid (135). Ascorbic acid is actively transported from the blood into the aqueous humor, where it is found in high concentrations (135,136). Presumably, ascorbic acid also reacts with free radicals and protects the lens from oxidative damage (135,137). Catalase may also protect the lens against oxidative damage from hydrogen peroxide

Fig. 7. Subcapsular cataract. (Courtesy of Walter Stark.)

(138), and transferrin in the aqueous humor may bind iron and protect the lens from free radical damage generated by ferrous ions (139). The accumulation of protein aggregates in the lens can increase light scattering (140,141).

5.1. Nuclear Cataract

Oxidative stress in the nucleus can result in damage to lens proteins and lipids, disulfide linking of proteins, protein aggregation, and increased light scattering (133,134,142,143). An increase in lipid peroxidation and protein oxidation has been linked to impairment of glutathione-dependent reduction (134,144–146). The lens contains low molecular weight, fluorescent compounds known as UV filters that absorb UV radiation from 295 nm to 400 nm. The concentrations of UV filters, 3-hydroxykynurenine, kynurenine, and 3-hydroxykynurenine glucoside, decrease linearly with age in the human lens, and oxidized glutathione also decreases in the lens nucleus with age (Fig. 8) (144). A lower concentration of glutathione in the lens with age may allow an increased rate of posttranslational modification of crystallins (134). Impaired diffusion of glutathione in the lens may result in lowered concentration of glutathione in the lens nucleus (145) and possible covalent linking of UV filters to crystallins in the lens (144). A barrier to transport of metabolites within the lens may prevent antioxidants from reaching the lens interior and thus allow oxidation of nuclear components (146). The aggregation of minor lens constituents may contribute to the initiation of lens opacification (147). Nuclear cataract is associated with extensive hydroxylation of protein-bound amino acid residues, which suggests a role for hydroxyl radicals (148). Perhaps the strongest evidence for the role of oxidative stress in the pathogenesis of nuclear cataract comes from a study of 25 patients who were given hyperbaric oxygen therapy (149). All treated patients developed myopic refractive changes with treatment, and seven of fifteen patients with clear lens nuclei

Fig. 8. Concentrations of reduced glutathione in humans lens as a function of age. Linear regression lines shown for nucleus (solid line, solid dots) (r = −0.47, p = 0.002, n = 38) and cortex (dotted line, open dots) (r = −0.68, p < 0.0005, n = 38) of the lens. (Reprinted from ref. 144, with permission of

Investigative Ophthalmology and Visual Science.)

prior to treatment developed nuclear cataract with reduced visual acuity (149). Oxygen, in excessive amounts, can be toxic to the lens through the generation of reactive oxygen species.

5.2. Cortical Cataract

Cortical cataract is often most pronounced in the inferior nasal quadrant of the lens (92,150,151), the part of the lens most exposed to ultraviolet radiation. Cortical cataract is associated with disruption of the lens fiber cells, formation of vesicles from membrane constituents such as cholesterol and phospholipid, and protein alterations (14,152). Studies of clear human lenses show that ruptured membranes of superficial fibers appear as early as the fourth decade of life (14). Age-related cortical lens changes have been mainly attributed to membrane disorganization induced by increased oxidative stress (14). Ultravio- let-B, or shorter wavelength UV light, appears to be more damaging to the eye than UV-A (105). Other studies suggest that chronic UV-A exposure could also generate free radicals and damage the lens. On exposure to UV light >300 nm, the chromophores in the human lens appeared to initiate photooxidative processes leading to oxidation of endogenous antioxidants glutathione and ascorbate (153). Old human lens proteins absorb more UV- A than UV-B light, which has suggested that UV-A should be considered in the pathogenesis of cortical cataract (154). It is unclear why UV light exposure would cause cataract in the lens fibers that are more shielded by the pigmented iris epithelium from light exposure, especially when the pupil is constricted in bright light. With depletion of stratospheric ozone, UV-B exposure may increase, with higher risk of cortical cataracts (155).

5.3. Posterior Subcapsular Cataract

Posterior subcapsular cataract is characterized by migration of superficial epithelial cells posteriorly from the equator, with enlarged epithelial nuclei and disorganization of postequatorial nuclear rows (156). Posterior subcapsular cataract can be induced by ionizing radiation (157) and by corticosteroids. Oxidative stress can adversely affect the DNA of lenticular epithelial cells, thus giving rise to germinative epithelial cells with aberrant DNA and abnormal development (14).

5. TREATMENT OF CATARACT

Cataract is usually treated by surgical removal of the cloudy lens and implantation of an intraocular lens. The quality of cataract surgery and the quality of outcomes of cataract surgery can vary considerably. The main strategy for reducing the burden of blindness from cataract is to find interventions that can delay the onset of cataract.

6. PREVENTION OF CATARACT

6.1. Evidence From Clinical Trials for Nutritional Interventions

Several clinical trials have been conducted to determine whether nutrients, alone or in combination, can reduce the incidence of lens opacities and the incidence of cataract operations (Table 4) (158–163). These studies generally suggest that micronutrient supplementation in well nourished adults is unlikely to reduce either the incidence of cataract or the incidence of cataract surgery.

6.1.1. LINXIAN CATARACT STUDIES

The Linxian cataract studies consisted of two clinical trials (“dysplasia trial” and “general population trial”) conducted in rural communes of Linxian, China from 1986 to 1991 (158). Linxian is a county in north central China that has a high rate of esophageal cancer and high prevalence of micronutrient deficiencies, and the main objective of the studies was to determine whether vitamin/mineral supplements could reduce the risk of esophageal/gastric cancer (158). Participants also received eye examinations and cataract grading at enrollment and at the end of the trials. In the dysplasia trial, 2141 participants, aged 45 to 74 yr, were randomized to receive multivitamin/mineral supplement or placebo. In a stratified analysis, among individuals aged 65 to 74 yr there was a 36% reduction in the prevalence of nuclear cataract (OR 0.57, 95% CI 0.36–0.90), whereas among individuals aged 45 to 64 yr, there was no significant impact of multivitamin/ mineral supplementation. In the dysplasia trial, the micronutrients contained in the supplement included beta carotene, and many of the vitamins and minerals were at levels that exceeded the Recommended Dietary Allowance (RDA) for adults. For example, the study used a daily dose of zinc of 45 mg, when the RDA for men and women is 11 mg and 8 mg, respectively.

In the general population trial, individuals aged 45 to 74 yr were randomly allocated in a factorial design to examine the effects of four different vitamin/mineral combinations (vitamin A/zinc, riboflavin/niacin, vitamin C/molybdenum, and selenium/α-tocopherol/ β-carotene). The risk of nuclear cataract was reduced among those who received riboflavin/ niacin compared to those who did not receive riboflavin/niacin, with the strongest effect

found among those aged 65 to 74 yr. There was no significant effect of vitamin/mineral supplements on cortical cataract in either trial. Although the number of subjects with posterior subcapsular cataract in the general population trial was small, the data suggested that riboflavin/niacin might increase the risk of posterior subcapsular cataract. These two trials suggest that in a rural area of China with a high prevalence of micronutrient deficiencies, vitamin/mineral supplements may reduce the risk of nuclear cataracts.

6.1.2. ROCHE EUROPEAN AMERICAN CATARACT TRIAL

The Roche European American Cataract Trial (REACT) study was a randomized, double-masked, placebo-controlled clinical trial of micronutrient supplementation to prevent age-related cataract in 297 adults aged ≥40 yr in Boston and in the United Kingdom (159). Patients were recruited in outpatient ophthalmology clinics and were eligible if they had immature age-related cataract in one or both eyes. Patients in the United States were evaluated using LOCS II, and patients in the United Kingdom were evaluated using the Oxford lens grading system. The outcome measure was lens opacification as assessed by a digitized image of the lens, rather than visual function. The study began in 1990 and concluded in 1995, and the results were published in 2002 (159). Patients were randomly allocated to receive a micronutrient supplement (α-tocopherol 200 mg, ascorbic acid 250 mg, β-carotene 6 mg) or placebo. There was a small but significant effect of treatment in lowering the risk of lens opacification among patients at the US site but not the UK site after 2 yr, but after 3 yr, there was a positive effect of treatment in both study sites. The authors noted that the rate of cataract progression is nonlinear, as it tends to be faster in the later than the earlier stages (53,90), thus, long-term progression of cataract, as assessed in this study, is likely to be highly conservative (159). If the treatment effect of 1.6% per 3 yr is extended for a 21-yr period, the authors noted that the difference would be 10.2%. Even a 10% reduction in the rate of cataract progression could potentially reduce the number of cataract operations by 49% (159).

6.1.3. AGE-RELATED EYE DISEASE STUDY

The Age-Related Eye Disease Study (AREDS) was an 11-center, double-masked, clinical trial in which subjects were randomly allocated to receive antioxidants (vitamin C, vitamin E, β-carotene) or no antioxidants (160). Subjects with more than a few small drusen were also randomized to receive tablets with or without zinc and copper as part of a trial in which the outcome was age-related macular degeneration. Of 4629 participants, aged 55–80 yr who had at least one natural lens present, the antioxidant combination had no significant effect on risk of progression of lens opacities or for cataract surgery. Subjects who were using supplements at the time of enrollment were offered a commercial daily multivitamin and mineral supplement at RDA dosages to take throughout the study (Centrum, Whitehall-Robins Healthcare, Madison, NJ). Of the participants, 55% were taking supplements and almost all chose to take the commercial supplement, and an additional 15% of subjects chose to take the commercial supplement. Thus, the study provided daily multivitamin and mineral supplements to nearly 70% of the study participants, in addition to the antioxidants or no antioxidants assigned to each participant. The study showed that use of a high-dose supplement containing vitamin C, vitamin E, and β-carotene had no impact on the development or progression of cataract in a relatively well-nourished cohort of older adults, many of whom were already taking vitamins.

6.1.4. ALPHA-TOCOPHEROL BETA-CAROTENE CANCER PREVENTION TRIAL, FINLAND

In the Alpha-Tocopherol Beta-Carotene (ATBC) trial, 28,934 male smokers, aged 50– 69 yr, were randomized to receive α-tocopherol, 50 mg/d, β-carotene, 20 mg/d, both α- tocopherol and β-carotene, or placebo for 5 to 8 yr (161). During follow-up, 425 men had cataract surgery, and the number of cases of cataract surgery in the α-tocopherol, β-caro- tene, α-tocopherol plus β-carotene, and placebo groups was 112, 112, 96, and 105, respectively. Neither α-tocopherol or β-carotene supplementation affected the incidence of cataract extraction among these male smokers in Finland (161).

6.1.5. PHYSICIANS’H EALTH STUDY, USA

In this trial involving 22,071 male physicians, aged 40–84 yr, participants were randomly assigned to receive β-carotene, 50 mg on alternate days, or placebo, for 12 yr (162). The outcome measures include incident, age-related lens opacity that reduced visual acuity based on self-report confirmed by medical record review, and rate of cataract extraction. Between the β-carotene and placebo groups, the overall incidence of cataract was not significantly different (RR 1.00, 95% CI 0.91–1.09), and the overall rate of cataract extraction was not significantly different (RR 1.00, 95% CI 0.89–1.12) (162).

6.1.6. VITAMIN E, CATARACT AND AGE-RELATED MACULOPATHY TRIAL, AUSTRALIA

In this clinical trial in Melbourne, Australia, 1193 participants, aged 55–80 yr, with early or no cataract were randomized to receive either 500 IU natural vitamin E in soybean oil or placebo for 4 yr (163). The incidence and progression of cataract were assessed with clinical lens opacity grading and computerized analysis of digital lens images. The 4-yr cumulative incidence rates among those who received vitamin E and those who received placebo was 12.9% and 12.1%, respectively, for nuclear cataract (p = 0.77), 4.5% and 4.8%, respectively, for cortical cataract (p = 0.77), and 1.7% and 3.5% for posterior subcapsular cataract (p = 0.08). There was no difference in the rate of cataract extraction between the two groups. This study shows that vitamin E in a daily dose of 500 IU did not reduce the incidence or progression of nuclear, cortical, or posterior subcapsular cataracts (163).

7. CONCLUSIONS

Short-term micronutrient supplementation in well nourished adults appears to have little impact on the incidence or progression of cataract. Although some data suggest that micronutrient supplementation may have an impact on the incidence of cataract in populations with a high prevalence of micronutrient deficiencies, such as Linxian, China, there is little other data to support the idea that micronutrient supplementation will prevent the onset or progression of cataract in other developing world populations. The amount of oxidative damage to the lens during the lifetime of an individual may be cumulative, thus, supplementation with antioxidant micronutrients in later adulthood may have little impact. There is the theoretical problem of “too little, too late” for late onset of micronutrient supplementation, if the actual window for intervention is earlier in life. The cessation of smoking and avoidance of excessive lifetime UV light or sunlight exposure remain the two major strategies to reduce the risk of cataract. Several areas of research have been identified. The relationship between nutritional factors and cataract has gen-

erally been studied in populations where nutritional status is relatively good, i.e., in the United States and Europe. The relationship between nutrient deficiencies and cataract needs to be addressed in populations that actually have a relatively high prevalence of nutritional deficiencies, i.e., low income and middle income countries. Future studies should examine the effect of improving nutritional status early in life, rather than supplementing with micronutrients in middle age or later. Ideally, long-term changes in lifestyle and diet rather that supplementation would be preferred. The relationship between laboratory indicators of riboflavin status, such as erythrocyte glutathione reductase, erythrocyte flavin, or urinary flavin and risk of cataract has not been characterized. Further investigation is needed into the possible relationship between lutein and zeaxanthin and cataract. The most important nutritional intervention for the reduction of cataract may be the prevention of obesity and its associated risk of diabetes mellitus, however, further large epidemiological studies are needed to demonstrate the long-term consequences of preventing obesity and its impact on cataract. Given the relationship between dietary antioxidants and inflammation, it may be possible that the association between dietary antioxidant status and cataract in some epidemiological studies is actually reflecting the level of systemic inflammation. Further studies are needed to address the relationship between antioxidant nutritional status after taking into account the effects of inflammation, as might be reflected by elevations in acute phase proteins and proinflammatory cytokines.

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