Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

In the Beaver Dam Eye Study intakes of pro-vitamin A carotenoids were inversely related with the incidence of large drusen.10

Another study showed no beneficial effect of long-term supplementation with betacarotene on the occurrence of AMD among smoking males.35

In the Blue Mountains Eye Study at 10-years follow-up higher beta-carotene intake either from diet alone or from diet and supplements combined was associated with an increased risk of AMD.12 On the other hand the Age Related Eye Disease Study (AREDS) showed a significant reduction in ARMD progression with a combination of various antioxidant supplements that included 15 mg of β-carotene daily.13 This study however, was not designed to study the role of beta-carotene supplementation alone.

The role of β-carotene on AMD has to be further defined. Furthermore, an important risk of higher risk for lung cancer has been related to high intake of β -carotene (20–30 mg/day) in smokers.36-38 These reports should be taken in consideration when prescribing supplements containing high doses of β-carotene and smokers should avoid beta-carotene supplementation.37

Lutein and Zeaxanthin

Lutein and zeaxanthin are the only carotenoids that concentrate in the macula, where they are the main components of macular pigment (MP).39-41 The concentration of lutein is greater than that of zeaxanthin in the peripheral region of the macula and zeaxanthin is more abundant in the central region. 42,43 Due to this distribution pattern in the retina it has been suggested that the

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role of lutein is focusing on protecting the rods concentrated in the peripheral retina while zeaxanthin on protecting the cones concentrated in the central retina.44,45,46

Functions of MP include quenching free radicals and thereby acting as an antioxidant to protect the macula from oxidative dam- age,47-50 filtering blue light,51 and increasing stability of lipid membranes by modifying theirs structural and dynamic properties.52

The pathogenesis of AMD is likely to involve a complex interaction of cellular and vascular factors, which may be promoted, between others, by light damage53 and oxidative stress.54 Therefore, it has been hypothesized that intake of lutein and zeaxanthin might have a protective effect on the development and/or progress of AMD.

There are currently no dietary reference intakes for carotenoids. In the United States, the average daily intake for lutein and zeaxanthin is 2.0–2.3 mg/d for men and 1.7– 2.0 mg/day for women. Lutein and zeaxanthin are present in a wide variety of plant sources, such as leafy green vegetables (kale, turnip, and spinach etc.), fruits like peaches, oranges, mangos, papaya, and kiwi, as well as a few animal sources, such as egg yolk46,55 (Figure 4).

A relative decrease of these carotenoids has been shown in eyes of patients with AMD,56 and a higher intake of lutein and zeaxanthin from foods or supplements increases serum levels of these carotenoids and macular pigment density in humans.57-59 A role for dietary intake of lutein and zeaxanthin in AMD prevention is supported further by animal models.60-62 However, studies on the association between dietary, or serum levels,

of lutein and zeaxanthin and AMD have been inconsistent.12

The Veterans LAST study (Lutein Antioxidant Supplementation Trial), a 12-month randomized trial of lutein and antioxidant supplementation in people with atrophic agerelated macular degeneration demonstrated that daily 10-mg lutein supplements, with or without additional nutrients, improved visual function.63

In the Carotenoids in Age-Related Eye Disease Study (CAREDS) that included 1787 participants it’s been demonstrated that diets rich in lutein plus zeaxanthin may protect against intermediate AMD.64

In the third national health and nutrition examination survey, a large, six-year study involving 8,222 subjects over the age of 40, higher levels of lutein and zeaxanthin in the diet were related to lower odds for pigmentary abnormalities as sign of AMD.65

In another study Gale et al. reported a significant association between low plasma levels of zeaxanthin and the presence of AMD; no such association was noted for lutein. The authors suggested that zeaxanthin might be more protective than lutein.66

In the POLA study the highest quintile of plasma zeaxanthin was significantly associated with reduced risk of AMD. AMD was significantly associated with combined plasma lutein and zeaxanthin and tended to be associated with plasma lutein.67

The Blue Mountains Eye Study at 10 years follow-up found higher dietary lutein and zeaxanthin intake reduced the risk of long-term incident AMD.12

However, In the Muenster Aging and Retina Study (MARS) the serum concentrations of lutein and zeaxanthin were not related to the prevalence of AMD.68 Additionally, several other studies have also failed to find a significant association between intake23 or

serum levels32 of lutein with zeaxanthin with AMD.

Currently, an ongoing study the AgeRelated Eye Disease Study 2 (AREDS 2), a multi-center, randomized trial will attempt to assess the effects of oral supplementation of macular xanthophylls (lutein and zeaxanthin) and/or long-chain omega-3 fatty acids on the progression to advanced age-related macular degeneration (AMD).69 Enrollment for this study concluded in June 2008 and approximately 4000 participants will be followed between five and six years.

Omega-3 Fatty Acids

There is an increasing interest regarding the role of omega-3 Fatty acids (omega-3FAs) on the retinal function and more specifically on the incidence of AMD.

Omega-3FAs include alphalinolenic acid (a short-chain omega-3 fatty acid), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) (both long chain omega-3 fatty acids). Alpha-linolenic acid (LNA) is the dietary precursor to both DHA and EPA.70,71

Omega-3FAs are found in seafoods, some plants, and some livestock rations. Fish oils are the only concentrated source of EPA and DHA (Figure 5). The major omega-3FA in plants is LNA.70

Very high levels of DHA are present in the retina, specifically in the disk membranes of the outer segments of photoreceptor cells72 suggesting that DHA has an important functional role in the retina, although its exact role is not well understood. 73

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Figure 5: Omega-3FAs are found in sea foods while fish oils are the only concentrated source of docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) (both long chain omega-3 fatty acids).

Omega-3 FAs demonstrate various properties in relation to retinal function. DHA influences the biophysical properties of membranes via its high polyunsaturation and may help to create a membrane that accommodates the dynamic behavior of rhodopsin during the photoreceptive process.74 DHA also may play a role in modulating G protein– coupled signaling pathways that are involved in visual transduction.75 Furthermore, EPA affects lipoprotein metabolism and decreases the production of compounds that exert pro-inflammatory cellular actions like cytokines, interleukin 1 and tumor necrosis factor.76 Considering the possible role of inflammation in the pathogenesis of AMD, it has been hypothesized that EPA may be a protective factor in this disease. 77

Several animal studies have shown that dietary deprivation of docosahexaenoic acid (DHA), results in abnormal electroretinograms, visual impairment, loss in rod

phototransduction sensitivity and delay in rod recovery that is accompanied by lower retinal levels of DHA phospholipids.78-80

Several studies reported a protective role of omega-3 FAs regarding the incidence or the progression of AMD.

The Report No. 23 of the Age-Related Eye Disease Study (AREDS) suggested that dietary omega-3 long-chain polyunsaturated fatty acid intake was associated with a decreased risk of progression from bilateral drusen to central geographic atrophy.81

Report 20 from the Age-Related Eye Disease Study (AREDS) describes a 40% to 50% reduced likelihood of having neovascular AMD among participants who reported the highest levels of omega-3 FA consumption.82

The US Twin Study of Age-Related Macular Degeneration concluded that increased intake of omega-3 FA and fish, particularly for 2 or more servings per week and reduced risk of AMD.83

In the Eye Disease Case Control Study, higher intake of omega-3 fatty acids or fish was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an omega-6 fatty acid. Conversely, neither omega-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake. 84

In the Blue Mountains Eye Study 40% reduction of incident early AMD was associated with fish consumption at least once a week, whereas fish consumption at least 3 times per week could reduce the incidence of late AMD.85

In the Nurses’ Health Study and the Health Professionals Follow-up Study that included 42,743 women and 29,746 men aged of more than 50 years, DHA had a modest inverse relation with AMD and more than 4 servings of fish per week was associated with a 35% lower risk of AMD.86

further elucidate the role of omega-3 FA on AMD (http://www.areds2.org).87

Cofactors of Antioxidant Enzymes

Zinc

The retina and choroid contain the highest concentrations of zinc of any tissue in the human body88. Zinc is a cofactor for many enzymes, including copper-zinc superoxide dismutase and is involved in the regulation of catalase activity, two important antioxidant enzyme systems in the retina.89-91 Zinc is also a cofactor for vitamin A metabolism and is essential for the synthesis of retinol binding protein.92

It has been demonstrated that zinc protects against oxidative damage in cultured human retinal pigment epithelial cells.93 Furthermore, several animal model studies support a protective role for zinc in AMD.91,94 Low levels of zinc in parenteral nutrition in humans led to reversible changes in the electroretinogram.95

In a laboratory investigation of eighty-eight donor eyes it was found that levels of zinc and copper on retinal pigment epithelium

and choroid complex were reduced in AMD eyes suggesting that metal homeostasis plays a role in AMD and in retinal health. 96 However, epidemiologic studies on the association between zinc intake and AMD have been inconsistent.

Stur M. et al. in a 2-year, double-masked, randomized, placebo-controlled study that included 112 participants concluded that oral zinc substitution has no short-term effect on the course of age-related macular degeneration in patients who have an exudative form of the disease in one eye.97

Cho E. et al. followed 66,572 women and 37,636 men without AMD at baseline for 10 years and 8 years respectively and concluded that moderate zinc intake, either in food or in supplements, was not associated with a reduced risk of AMD.90

On the other hand, however, other studies have reported a protective effect from zinc

on AMD.10,12-14,23,98,99

In the 10-year follow-up Blue Mountains Eye Study report, participants in highest decile of total zinc intake (15.8 mg/day) were found to be significantly less likely to develop early or any AMD compared with the remaining population.12

In a recent randomized, prospective, placebo-controlled clinical trial of a novel zinc-monocysteine (ZM) compound it was found that 25 mg of ZM twice daily was well tolerated and was associated with improved macular function in comparison to a placebo in persons with dry AMD.99

The epidemiologic Beaver Dam Eye Study evaluated zinc intake and macular pigmentary changes and found less prevalent and less newly developed pigmentary abnormalities in participants with higher levels of zinc intake.10

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In the Rotterdam Study that included about 5000 participants at risk of AMD at baseline, a high dietary intake of zinc combined with beta-carotene, vitamins C and E was associated with a substantially reduced risk of AMD in elderly persons.14

The AREDS included about 80 mg of zinc per day in two of their regimens. One of the four arms of the study supplemented zinc only. In this group the probability of a defined AMD or visual acuity event at 5 years’ follow-up was decreased by 6.2 and 3.6% compared to placebo. However, combination with antioxidants further improved the outcome.13

Copper

Copper has also a high concentration on retinal pigment epithelium and is a coenzyme for antioxidant enzyme superoxide dismutase, which may play a role in AMD development.100 Furthermore, copper is involved in the metabolism of the RPE.101 Levels of copper and zinc in the human retina has been associated with cadmium levels a toxic metal with no known physiological function that interferes with copper and zinc metabolism and accumulates in human retinal tissues during aging and might play a role in AMD.92

Copper and zinc levels have been found to be reduced in the retinal pigment epithelium and choroid complex zinc in AMD eyes.96

However, clinical studies in humans evaluating copper and AMD are limited. A study suggested a relationship between serum ceruloplasmin, a multifunctional, copper-binding alpha-globulin, trace metals, and the tissue alterations associated with macular degeneration.102 Copper has been included into the

AREDS treatment arms receiving zinc, not for a potential benefit preventing progression of AMD, but to prevent possible zinc-induced copper deficiency anemia.

Nutritional Risk Factors and AMD

Dietary Fat Intake

It has been suggested that high dietary fat intake may increase the risk for AMD with various mechanisms. Dietary fat has been associated with atherosclerosis and could therefore have a negative effect on blood supply in the choroid and retina. Additionally, increased deposition of fat in Bruch’s membrane could adversely affect exchange of nutrients and waste products to and from the retinal pigment epithelium. Finally, high levels of fatty acids might increase oxidative damage due to high susceptibility of fatty acids to oxidation especially under high oxygen tension and light exposure as found in the macula.4

Several clinical studies have shown an adverse effect of specific fat intakes on AMD.84,86,103-105 Types of dietary fats that are particularly related to an increased risk of progression or development of AMD are saturated, monounsaturated, polyunsaturated, transunsaturated fats and linolenic acid. 84,90,103

Seddon J. M. et al. in a multicenter study that among individuals with the early or intermediate stages of AMD, demonstrated that high intake of specific types of fat-- including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid, was associated with increase risk of progression to advanced AMD.84

In the in the Nurses’ Health Study and the Health Professionals Follow-up Study total fat intake was positively associated with risk of AMD.86

The Beaver Dam Eye Study evaluated several aspects of dietary fat intake. Participants with high intake of saturated fat and cholesterol were associated with increased risk for early age-related maculopathy.104

On the other hand, in the Third National Health and Nutrition Examination Survey AMD was not significantly associated with dietary fat intake.106

There is increasing evidence for a correlation of dietary fat intake and serum cholesterol levels to AMD.84,90,105 The Eye Disease CaseControl Study showed people with increased serum cholesterol level to be compared to people with low levels of serum cholesterol at higher risk for neovascular AMD.107

Several studies indicated that statins used to lower LDL serum cholesterol levels to prevent cardiovascular events, could reduce the risk of especially neovascular AMD.108-110 In the Beaver Dam Eye Study however, no association was found between statin use and incident or progression of AMD over a five-year period.111, 112

Alcohol

It have been suggested that alcohol consumption may have may have both harmful and protective effects on AMD. Alcohol is a known neurotoxin that can result in oxidative brain damage113 and thus in heavy amounts may be expected to have an adverse effect on the retina. However, moderate consumption is associated with decreased platelet

aggregation, lower serum fibrinogen levels, lower C-reactive protein concentrations and higher high-density lipoprotein levels114 all of which may be protective for AMD.115-117

Chong EW et al. in a systematic review and meta-analysis of observational studies regarding alcohol consumption and the risk of AMD found that heavy alcohol consumption (more than three standard drinks per day) is associated with an increased risk of early AMD.116

The first National Health Nutrition and Examination Survey (NHANES-1) found that moderate wine consumption was associated with decreased probability of developing AMD.118

In the Blue Mountains Eye Study, no relationship was found between beer or wine intake and early or late AMD, but an increased risk of early AMD was found among those who drank spirits.119

In the Beaver Dam Eye Study, alcohol consumption was not related to the 15-year cumulative incidence of AMD.120

In conclusion there is currently insufficient evidence regarding the associations between moderate alcohol consumption or different alcoholic beverages and AMD. However, patients seeking advice on AMD prevention should be encouraged to stop heavy alcohol consumption.116

Nutrition and Diabetic

Retinopathy

Diabetic retinopathy is a leading cause of visual loss and blindness. The prevalence of

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diabetes and consequently its complications as RD is projected to increase worldwide as a result of changing of dietary patterns leading to an obesity epidemic. 121,122

Prospective, randomized, long-term clinical trials have demonstrated that tight glycemic control is a key issue in the treatment for diabetic retinopathy.123-126

More precisely, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), showed a strong stepwise relation between glycosylated hemoglobin and the incidence and progression of diabetic retinopathy.127

Intensive insulin treatment, as practiced in the Diabetes Control and Complication Trial, demonstratedstatisticallysignificantreductions in the incidence of (27%) and in progression (76%) of retinopathy.128 Additionally, in the United Kingdom Prospective Diabetes Study (UKPDS) intensive blood-glucose control substantially decreased the risk of microvascular complications by 25%.129

Appropriate diet in addition to medical treatment is essential to obtain a tight glycemic control. It has been advocated that low glycaemic index diet could lessen risk of diabetic complications.130 Recently, it’s been promoted that a low-fat vegan diet appeared to improve glycemia and plasma lipids more than did conventional diabetes diet recommendations131 while increase intakes of carbohydrate, fiber, and several micronutrients.132

A study of 407 diabetic patients in Australia suggested that a Mediterranean-Greek type of diet was protective against diabetic retinopathy.133 The Mediterranean diet is characterized by a high intake of vegetables, legumes, fruits and nuts, cereals, and olive

oil, a moderate intake of dairy products, and a low intake of meat and poultry (Figure 6).

Recently, have been suggested that synergies between carotenoids are implicated in diabeticretinopathy,independentofestablished risk factors and it has been indicated that dietary modulation of retinopathy risk may be possible by increasing intakes of luteinand lycopene-rich foods.134

However the best dietary regimen for the prevention and treatment of diabetes mellitus and its complications it has not been yet accurately determined.135,136

The role of micronutrients supplementation in reducing the risk of development of diabetic retinopathy has gained increasing attention last years. 137-139 Oxidative stress is increased in the retina in diabetes.140,141 The possible sources of increased oxidative stress might include increased generation of free radicals or impaired anti-oxidant defence system. Thus, supplementation with anti-oxidants represents an achievable adjunct therapy that may potentially help preserve vision in diabetic patients.142

Dietary supplementation with various antioxidants has provided encouraging results in experimental models of diabetic retinopathy.142-149

In a recent study, supplementation of taurine in diet of diabetic rats led to lower expression of glial fibrillary acid protein (GFAP) and vascular endothelial growth factor (VEGF) that play a significant role to pathogenesis of diabetic retinopathy. This may have prospective implications of using taurine to treat complications in diabetic retinopathy.148

In a study on diabetic rats Zinc showed beneficial in both controlling hyperglycemia and the protection of the retina against oxidative stress and development of diabetic retinopathy.145

Additionally a positive role of vitamin E was demonstrated by several animal studies150, 151 that may inhibit progression of diabetic retinopathy by prevention of diabetesinduced abnormal retinal blood flow.152

Benfotiamine (a vitamin B1 derivative) was demonstrated experimentally to inhibit progression of diabetic microangiopathy by various mechanisms and might have a role in the prevention and/or treatment of diabetic retinopathy.147,153,154

In another animal study was demonstrated thatthelong-termadministrationofalpha-lipoic acid supplementation has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively

modified DNA and nitrotyrosine in the retina and suggested that may help to prevent vision loss in diabetic patients.146

Another animal study concluded that a mixture of antioxidants including Trolox, alpha-tocopherol, N-acetyl cysteine, ascorbic acid, beta-carotene, and selenium can inhibit the development of the early stages of diabetic retinopathy.144

A recent study interestingly demonstrated that Age-Related Eye Disease Study-based (AREDS) micronutrients that that were shown to reduce the risk of development of AMD inhibit the development of diabetic retinopathy in rodents by inhibiting oxidative and nitrative stress.149

Despite the very encouraging results of animal studies regarding the role of micronutrients on reducing the risk of development of diabetic retinopathy existing human clinical trials and epidemiologic studies have been less conclusive.155-158

ambiguous.159-162 A large scale, long term epidemiologic study (NHANES III) that involved 998 diabetic found no significant relationship between serum vitamin C concentrations and risk of diabetic retinopathy.156 Additionally, in the Atherosclerosis Risk in Communities (ARIC) Study that involved 387 participants no significant relationship found between vitamin C intake and diabetic retinopathy.155 However the San Luis Valley Diabetes Study demonstrated a risk of increased severity of diabetic retinopathy related to an increase dietary intake of vitamin C.157

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Several clinical studies evaluated the role of vitamine E in diabetes and diabetic retinopathy.155-158, 163 In a large epidemiologic study that involved 3,654 diabetics vitamin E did not found to have any significant effect on history of laser therapy for diabetic retinopathy. 158 Furthermore, no significant relationships were found between serum α-tocopherol and diabetic retinopathy in NHANES III156 or between dietary vitamin E intake and diabetic retinopathy in the ARIC study.155 On the other hand, in the San Luis Valley Diabetes Study, higher dietary intake of vitamin E was associated with an increased risk of retinopathy.157 Contrarily, a small prospective study of 36 type I diabetics concluded that oral vitamin E treatment appears to be effective in normalizing retinal hemodynamic abnormalities and suggested that vitamin E supplementation may provide an additional benefit in reducing the risks for developing diabetic retinopathy.163

Another nutritional elements that was studied in clinical studies is zinc and chromium suggesting a potential beneficial antioxidant effect on diabetic patients of the individual and combined supplementation of these elements that might influence the course of diabetic retinopathy.164-166

More studies are warranted in order to clarifytheroleofmicronutrientsdietarysupplements on diabetic retinopathy and although its use in some cases might be potentially helpful it is not currently recommended.4

Nutrition and Retinal Vascular Diseases

Nutritional elements have been recently recognized as important risk factors in the

pathogenesis of various retinal vascular diseases. More specifically,nutritionalrelatedentities that are related to retinal vascular diseases include hyperhomocysteinemia, disorders of iron metabolism and lipid abnormalities.

Hyperhomocysteinemia is associated in several studies with retinal vascular disease, including central retinal vein occlusion, branch retinal vein occlusion, and central retinal artery occlusion.1,167-173

Several studies have shown that serum or plasma total homocysteine concentrations can be reduced to normal following folate supplementation or a combination of folate and other B vitamin supplements.174-176

In a study on retinal vein occlusions, Hansen et al.177 decreased significantly plasma homocysteine in all hyperhomocysteinemic patients by prescribing 5 mg daily of folic acid over at least 2 weeks. Cahill et al.171 concluded assessment of plasma homocysteine and folate levels should be considered for ocular vasculopathic patients. They hypothesized that reduction of plasma homocysteine level by folate supplementation could decrease the occurrence of the disease in the fellow eye or other systemic vascular events and recommended 400μm of oral folates daily for patients with elevated plasma homocysteine and low folate levels. However, others consider that there is currently not enough evidence for such a recommendation to be established as a general rule.178

Finally, it worth mentioning that many studies 179-183 demonstrated that dietary interventions with vegetables, fruits, wholegrain bread, eggs, chicken, fish, milk and breakfast cereals (Figure 7) were related to an increased folate intake and inversely associated with serum homocysteine levels; thus might potentially contribute to the effort of lowering homocysteine levels on ocular vasculopathic patients.

Other nutrition related diseases that are associated less frequently with vascular retinal diseases include iron deficiency and hyperlipidemia.

Iron deficiency has been related to with background retinopathy,184,185 venous stasis retinopathy186, central retinal artery occlusion,187 central retinal vein occlusion.188,189

Foods that are rich in iron include liver, beef, veal, fish, eggs, soya bean, broccoli and green beans (Figure 8).

Hyperlipidemia can be the cause of lipemia retinalis due to elevated triglycerides in the retinal and choroidal circulation.190

Lipemia retinalis usually improves with a reduction in fat intake and other therapies aimed at reducing triglycerides.191 Patients should be advised to lower their intake of egg yolks, whole-milk dairy products, and red meat, and substitute fruits, vegetables, and whole-grain food products. Coconut oil, palm oil, and hydrogenated vegetable oils should be replaced in cooking with olive oil or non-hydrogenated vegetable oils.1