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

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Table 1

Risk Factors for Diabetic Retinopathy

•Longer duration of diabetes

•Poor glycemic control

•Hypertension

•Elevated serum lipid levels

•Anemia

is higher among people with type 1 diabetes compared with type 2 diabetes. In the WESDR, the overall incidence of any diabetic retinopathy was 40.3% over a 4-yr interval. Among people with mostly type 1 diabetes, the incidence was 50.9%, and among people who were diagnosed after age 30, 47.4% of those insulin and 34.4% of those not taking insulin had developed retinopathy by 4 yr of follow-up (5).

2.2. Risk Factors for Diabetic Retinopathy

Several epidemiological risk factors have been identified for diabetic retinopathy (Table 1).

2.2.1. DURATION OF DIABETES

The length of time a person has had diabetes is a major risk factor for the development of diabetic retinopathy, as shown in the WESDR (3,4) and other large cohort studies, such as the Pittsburgh Diabetic Morbidity and Retinopathy Studies (6) and a study of 339 patients in Denmark (7).

2.2.2. GLYCEMIC CONTROL

In the Diabetes Control and Complications Trial, a study of 1441 patients with insulindependent diabetes mellitus, aged 13–39 yr, intensive treatment (self-administration of insulin at least three times a day by injection or pump, with doses adjusted based on blood monitoring with the goal of normoglycemia) slowed progression of retinopathy compared with conventional treatment (8). The cumulative 8.5-yr progression of retinopathy was 54.1% with conventional treatment and 11.5% with intensive treatment (8). Participants in this trial were informed of the benefits of intensive therapy. They were then followed by their own physicians, and follow-up showed that the reduction in risk of progression of retinopathy with intensive therapy persisted for at least 4 yr beyond the trial (9,10). In the UK Prospective Diabetes Study of 3867 newly diagnosed patients with type 2 diabetes, intensive blood glucose control with sulphonylureas or insulin significantly reduced the risk of microvascular complications, including need for retinal photocoagulation (11).

2.2.3. HYPERTENSION

In a recent clinical trial involving nineteen hospital-based clinics in the United Kingdom, 758 patients with hypertension and type 2 diabetes mellitus were allocated to a tight blood pressure control program with angiotensin-converting enzyme inhibitor or β-blockers as the main therapy, and 390 were allocated to a less tight blood pressure control program (12). The median follow-up to the end of the trial, death, or the last date at which vital status

was known was 8.4 yr. The tight blood pressure control group showed fewer microaneuryms, hard exudates, and cotton-wool spots at follow-up and were less likely to undergo photocoagulation (12). The cumulative incidence of blindness in one eye was 3.1 per 1000 patient-years in the tight blood pressure control group and 4.1 per 1000 patientyears in the control group (relative risk [RR] 0.76, 95% confidence interval [CI] 0.29- 1.99, p = 0.046). In the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial, subjects were stratified into hypertensive and normotensive subjects and were randomized to intensive or moderate control of blood pressure. Intensive control of blood pressure did not influence progression of diabetic retinopathy during 5 yr of follow-up in the hypertensive group (13), but in the normotensive group, intensive control of blood pressure retarded the progression of diabetic retinopathy (14). In the Steno-2 Study, eighty patients with microalbuminuria and type 2 diabetes were randomly assigned to receive intensive treatment for control of blood pressure, reduction of serum cholesterol and triglycerides, light-moderate exercise, smoking cessation, and aspirin therapy, and eighty patients were referred to their general practitioner (15). During mean follow-up of 7.8 yr, the patients who received intensive therapy had a lower risk of diabetic retinopathy (hazard ratio [HR], 0.42, 95% CI 0.21–0.86) (15). These three clinical trials suggest that aggressive control of hypertension in patients with type 2 diabetes can reduce progression of diabetic retinopathy.

2.2.4. SERUM LIPID LEVELS

Elevated serum cholesterol levels have been associated with severity of hard retinal exudates in diabetic retinopathy (16,17), and elevated serum triglyceride levels were associated with increased risk for high-risk proliferative diabetic retinopathy (18).

2.2.5. ANEMIA

A low hematocrit was associated with an increased risk of developing high-risk proliferative diabetic retinopathy in the Early Treatment Diabetic Retinopathy Study (ETDRS) (18). In a cohort of 1691 diabetic patients in Finland, anemia, defined as hemoglobin <12 g/dL, was associated with an increased risk of having any retinopathy (odds ratio [OR] 2.0, 95% CI 1.2–3.3) (19). In a stratified analysis involving people with retinopathy who had low hemoglobin levels, there was an increased risk of having severe retinopathy compared to mild retinopathy (OR 5.3, 95 CI 2.3–12.6) (19). The study from Finland did not classify anemia according to the World Health Organization criterion of <12 g/dL for women and <13 g/dL for men. The investigators concluded that diabetics with normocytic anemia had an increased risk of retinopathy, especially more severe retinopathy (19).

Case reports have provided anecdotal evidence that anemia may be related to diabetic retinopathy. Three patients with mild to moderate background diabetic retinopathy developed severe iron deficiency anemia and showed rapid progression to proliferative diabetic retinopathy (20). One patient with diabetic retinopathy showed resolution of microaneurysms after treatment of his iron deficiency anemia with blood transfusions, iron supplements, and B complex vitamin supplements (21). Correction of anemia with erythropoietin therapy has also been associated with improvement in diabetic macular edema (22).

In general, studies linking anemia with diabetic retinopathy have not characterized the type or types of anemia that are associated with retinopathy, and this is an issue that is critical to understanding whether anemia plays a role in the pathogenesis of diabetic retinopathy

or is perhaps more closely related to the inflammation associated with diabetes and its associated morbidity. Among people 65 yr and older in the National Health and Nutrition Examination Survey (NHANES) III, diabetes mellitus is associated with the anemia of chronic inflammation (23). Hepcidin, a recently discovered iron regulatory hormone, is upregulated by inflammation and leads to the anemia of chronic inflammation by blocking iron absorption in the enterocytes and iron release by macrophages (24). Studies are needed to characterize hepcidin in the anemia associated with diabetes. It is likely that the anemia associated with diabetic retinopathy falls into the category of anemia of chronic inflammation, but further investigations are needed to address this hypothesis.

2.2.6. OBESITY

Obesity and overweight have been linked with diabetic retinopathy, but body mass index is also associated with other risk factors associated with diabetic complications. In a study in Croatia, obesity was associated with a high risk of retinopathy (25). In a study of 592 patients with type 1 diabetes, a higher body mass index was associated with retinopathy, but this relationship was not significant after adjusting for duration of diabetes and hemoglobin A1c (26).

3. NUTRITION AND DIABETIC RETINOPATHY

3.1. Vitamin C

A consistent relationship between vitamin C and diabetic retinopathy has not been demonstrated. Some early studies suggested that vitamin C might play a role in microvascular disease and diabetes, but findings were variable (27–33). In a study from NHANES III (1988–1994) that involved a subsample of 998 people age 40 or older who had diabetes and fundus photographs, no significant relationships were found between serum vitamin C concentrations and risk of diabetic retinopathy (34). Retinopathy in NHANES III was evaluated by nonmydriatic fundus photographs of one randomly chosen eye for all participants. Retinopathy was originally graded as no retinopathy, mild nonproliferative retinopathy, moderate nonproliferative retinopathy, and proliferative retinopathy, but was used in the analysis as any versus no retinopathy, and about 20% of the sample had any retinopathy (34). Although serum ascorbate is used to indicate vitamin C status, its use is limited because large fluctuations in serum ascorbate can occur, and a single measure reflects only recent intake rather than body stores (35). In the San Luis Valley Diabetes Study in southern Colorado, an increased dietary intake of vitamin C was associated with an increased risk of diabetic retinopathy in a cross-sectional study. The study involved 387 participants (82 with background diabetic retinopathy, 39 with preproliferative diabetic retinopathy, and 17 with proliferative diabetic retinopathy, and dietary assessment involved 24-h recall (36). There was no significant relationship between vitamin C intake and diabetic retinopathy in the Atherosclerosis Risk in Communities (ARIC) Study (37).

3.2. Vitamin E

Vitamin E is a chain-breaking antioxidant (reviewed in Chapter 3) that has been hypothesized to play a role in diabetes and diabetic retinopathy. No consistent relationship has been demonstrated between vitamin E and diabetic retinopathy in human studies. In animal studies, vitamin E-deficient rats developed retinal vascular abnormalities such as

increase in retinal capillary basement membrane thickness and accumulation of lipofuscin in capillary walls (38), and abnormal retinal blood flow in diabetic rats was reduced by vitamin E treatment (39). No significant relationship was found between intake of vitamin E and glycosylated hemoglobin among diabetic patients (40). Diabetic retinopathy was not associated with lower plasma vitamin E levels among sixty patients with diabetes (41), and a study of young type 1 diabetic patients showed not differences in serum vitamin E levels between those with retinopathy and other complications and no complications (42). Higher plasma vitamin E levels were found in patients with poor glycemic control and high lipid levels (43). In the San Luis Valley Diabetes Study, higher dietary intake of vitamin E was associated with an increased risk of retinopathy (36). No significant relationships were found between serum α-tocopherol and diabetic retinopathy in NHANES III (34) or between dietary vitamin E intake and diabetic retinopathy in the ARIC study (37).

In small pilot trials, high doses of vitamin E reduced glycosylated proteins after 1–2 mo of supplementation (44), and a modest daily dose of vitamin E reduced glycosylated hemoglobin (45). Vitamin E supplementation reduced lipid peroxidation in type 2 diabetic patients with retinopathy (46). One study showed an apparent increase in retinal blood flow in diabetic patients after high-dose vitamin E treatment (47). In the Heart Outcomes Prevention Evaluation (HOPE) study, the effect of vitamin E on cardiovascular outcomes, including myocardial infarction, stroke, mortality, and secondary outcomes that included laser therapy for diabetic retinopathy, was examined in a 2 × 2 factorial design involving ramipril, a nonsulfhydryl angiotensin-converting enzyme inhibitor, and vitamin E. Among the 3654 subjects in the study with diabetes, vitamin E did not have any significant effect on the cardiovascular outcomes or on history of laser therapy for diabetic retinopathy (48).

3.3. Zinc

The effects of zinc supplementation on markers of oxidative stress have been studied in two pilot studies in patients with diabetes. In patients with insulin-dependent diabetes with and without retinopathy, zinc supplementation reduced markers of lipid peroxidation (49). In patients with type 2 diabetes who had hemoglobin A1c >7.5%, zinc supplementation, 30 mg/d, for 6 mo decreased plasma thiobarbituric acid reactive substances, a marker for lipid peroxidation, compared with placebo (50).

3.4. Healthy Dietary Pattern

A recent study of 407 men and women with diabetes in Australia suggested that a pattern of dietary intake consistent with a Mediterranean type of diet was protective against diabetic retinopathy (51). 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. These data are consistent with a large emerging literature that shows a Mediterranean diet is protective against diabetes (52), peripheral artery disease in diabetics (53), inflammation (54), and mortality (55), as further discussed in Chapter 10 in relation to the age-related proinflammatory state. Another large study suggests that quality of diet is related to diabetic retinopathy. Among 1041 subjects with type 1 diabetes in the Diabetes Control and Complications Trial, a high consumption of total fatty acids and low consumption of dietary fiber were each associated with a higher rate of progression of diabetic retinopathy (56).

Fig. 1. Background diabetic retinopathy. (Photo courtesy of Neil Bressler.)

4. CLINICAL FEATURES

Diabetic retinopathy is generally classified as (1) nonproliferative retinopathy, characterized by microaneuryms, blot and flame-shaped hemorrhages, and hard exudates (Fig. 1),

(2) preproliferative retinopathy, characterized by findings in (1) and in addition, by intraretinal microvascular abnormalities (IRMA), venous beading an loops, and cotton-wool spots, and (3) proliferative diabetic retinopathy, characterized by neovascularization of the retina and/or optic disc, vitreous hemorrhage, preretinal hemorrhage, fibrovascular proliferation, and retinal detachment (Fig. 2). Diabetic macular edema, or diabetic maculopathy, can result from leaking of blood vessels around the macular area. International clinical diabetic retinopathy and diabetic macular edema disease severity scales have been proposed (57). This new classification is based on five stages of severity for diabetic retinopathy (Table 2) and a classification for diabetic macular edema (Table 3). The diagnosis and evaluation of diabetes mellitus have been summarized in detail (2,58).

5. PATHOGENESIS

5.1. Diabetic Retinopathy

Many theories have been proposed for the pathogenesis of diabetic retinopathy, as recently reviewed by Robert Frank (59). The proposed mechanisms include increased production of sorbitol by aldose reductase, inflammation, reactive oxygen species (ROS), advanced glycation products, altered gene expression, increased growth hormone and insulin-like growth factor 1, upregulation of vascular endothelial growth factor (VEGF), and reduction of pigment-epithelium-derived factor (PEDF) (59). Activation of protein kinase C has also been implicated in microvascular changes in diabetes (60). None of these