From the Institute of Vision Research (SHB, OWK), Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea; and the Department of Food and Nutrition (H-YC), College of Human Ecology, Yonsei University, Seoul, Korea.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Oh Woong Kwon, MD, PhD, Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, 120-752 Seoul, Korea.
Histological examination showed that hard exudates in diabetic macular edema are similar to the intimal plaque observed in atherosclerotic lesions.1,2 In contrast to atherosclerotic lesions, in which lipids and macrophages accumulate in the vessel wall, accumulations of lipids and macrophages in diabetic macular edema are localized to the perivascular areas of retinal tissue.1,2
The correlation between serum lipids and atherosclerotic lipids suggests that dietary polyunsaturated fatty acids (PUFA) may significantly influence the fatty acid composition of aortic plaques.3 Epidemiological studies have shown an association between increased consumption of PUFA and reduced incidence of coronary heart disease.4 Currently, Omar (highly purified PUFA) is prescribed for the management of hypertriglyceridemia, which is a frequently coexisting condition in diabetics.5 However, whether ingested PUFA itself decreases the incidence of coronary heart disease is still under debate.4 Theoretically, an increased proportion of PUFA in lipids results in increased susceptibility to oxidative modification. This, in turn, results in lipid accumulation through uptake by macrophages and accelerates formation of atheroma.6 The modification of lipids renders them toxic to adjacent tissues.7
Hard exudates in the retina are believed to develop as a result of extravasation of lipids and proteins. Theoretically, there should be a direct correlation between dietary fatty acid composition and hard exudates. We compared the fatty acid composition of hard exudates and PL, as an objective estimation of dietary intake.
Three eyes of 2 diabetic patients with extensive hard exudates underwent pars plana vitrectomy for removal of hard exudates (Table 1).2 One day before surgery, plasma was collected from each patient. The fatty acid composition of plasma PL and hard exudates were analyzed by a thin-layer chromatography on silica gel-60 plates and gas chromatography. Retinal hard exudates are believed to develop from the extravasation of blood lipids, suggesting a correlation between blood fatty acid composition and hard exudates. Fatty acid composition of plasma PL, which reflects dietary intake weeks to months before sample collection, was used to estimate the composition of blood fats.
Table 1: Pertinent Clinical Data of Three Cases from Which the Quantity of the Extracted Hard Exudates Was Sufficient for Analysis
In these 3 patients, total PUFA contents in hard exudates were relatively well correlated with those in plasma PL (Table 2). Oxidation of lipoprotein was variable but continuous decrement of the proportion of PUFA in lipoprotein over time, and this oxidation may be affected by levels of antioxidants (e.g. vitamin E) in each case. We found that eicosapentaenoic acid (EPA, C20:5 ω3) and docosahexaenoic acid (DHA, C22:6 ω3), which are more readily oxidized than less saturated fatty acids such as linoleic acid (18:2 ω 6), were consistently lower in hard exudates than in plasma PL. Some arachidonic acid (C22:4 ω 6), a substrate in the synthesis of inflammatory mediators such as prostaglandin E2 and leukotriene C4, was still detected in hard exudates.
Table 2: The Fatty Acids Composition of Plasma Phospholipids and Hard Exudates in Each Three Cases
Although deposition and reabsorption of hard exudates is a dynamic process, the efflux of lipids is thought to be very slow. During that time, hard exudates exist under conditions of high oxidative stress. The retina is constantly surrounded by high concentrations of oxygen, and in diabetic retinopathy, the reentry of oxygen into hypoxic tissue is associated with the active generation of free radicals.
Limited visual improvement after surgery due to atrophic, degenerative changes and even formation of subretinal fibrosis may be due to surgical trauma or mechanical damage caused by exudates. The cytotoxicity and inflammatory properties of lipid peroxides may cause retinal damage, which may also contribute to limited functional recovery. In clinical observations of ETDRS, significant risk factors for subretinal fibrosis were found to be the extent of hard exudates, reported age, and elevated serum lipid level at baseline.8 All of these factors are thought to be related to an increased susceptibility to peroxidation.
Macrophages may be important in the removal of retinal hard exudates.1 Oxidized or modified lipids may block the return of these cells to systemic circulation and may also be toxic to adjacent cells, including retinal cells.7,9 Injection of lipid peroxide into the subretinal space was reported to produce a range of toxic effects.10 High doses were noticeably toxic and resulted in severe retinal and choroidal atrophy, whereas lower doses could induce choroidal neovascularization through expression of tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF).11 VEGF was also reported to be expressed in excised hard exudates of diabetic patients.2
The findings in our series suggest that dietary PUFA may influence the composition of hard exudates. This raises the question of whether dietary PUFA, especially that of DHA and EPA, might therefore influence the accumulation, removal, and modification (peroxidation) of extracellular lipid components in diabetic macular edema. Modification of dietary intake of ω-3 PUFA as a treatment for diabetic retinopathy should be evaluated with caution, prior to identification of the potential risks for extracellular PUFA in diabetic macular edema.6
- Cusick M, Chew EY, Chan C, et al. Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels. Ophthalmology. 2003;110:2126–2133. doi:10.1016/j.ophtha.2003.01.001 [CrossRef]
- Takagi H, Otani A, Kiryu J, Ogura Y. New surgical approach for removing massive foveal hard exudates in diabetic macular edema. Ophthalmology. 1999;106:249–257. doi:10.1016/S0161-6420(99)90054-4 [CrossRef]
- Felton CV, Crook D, Davies MJ. Dietary polyunsaturated fatty acids and composition of human aortic plaques. Lancet1994;344:1195–1196. doi:10.1016/S0140-6736(94)90511-8 [CrossRef]
- Harper CR, Jacobson TA. Usefulness of omega-3 fatty acids and the prevention of coronary heart disease. Am J Cardiol. 2005;96:1521. doi:10.1016/j.amjcard.2005.07.071 [CrossRef]
- Bays H. Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids. Am J Cardiol. 2006;21:71–7. doi:10.1016/j.amjcard.2005.12.029 [CrossRef]
- Song JH, Fujimoto K, Miyazawa T. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexanoic acid-containing oils. J Nutr. 2000;130:3028–303.
- Lyons TJ, Li W, Wells-Knecht MC, Jokl R. Toxicity of mildly modified low-density lipoproteins to cultured retinal capillary endothelial cells and pericytes. Diabetes. 1994;43:1090–1095. doi:10.2337/diabetes.43.9.1090 [CrossRef]
- Fong DS, Segal PP, Myers F, et al. Subretinal fibrosis in diabetic macular edema: ETDRS report 23. Arch Ophthalmol1997;115:873–877.
- Tamai K, Matsubara A, Tomida K, et al. Lipid hydroperoxide stimulates leukocyte-endothelium interaction in the retinal microcirculation. Exp Eye Res. 2002;75:69–75. doi:10.1006/exer.2002.1178 [CrossRef]
- Tamai K, Spaide RF, Ellis EA, et al. Lipid hydroperoxide stimulates subretinal choroidal neovascularization in the rabbit. Exp Eye Res. 2002;74:301–38. doi:10.1006/exer.2001.1121 [CrossRef]
- Armstrong D, Ueda T, Ueda T, et al. Lipid hydroperoxide stimulates retinal neovascularization in rabbit retina through expression of tumor necrosis factor-α, vascular endothelial growth factor and platelet-derived growth factor. Angiogenesis. 1998;2:93–104. doi:10.1023/A:1009010628371 [CrossRef]
Pertinent Clinical Data of Three Cases from Which the Quantity of the Extracted Hard Exudates Was Sufficient for Analysis
|Case||Sex/Age/Eye||Pre-op Size of Exudates (disk area)||Pre-op Visual Acuity||Post-op Best Visual Acuity (months)||Final Visual Acuity||Main Feature of Final Macula|
|3a||F/67/OD||4||FC 10 cm||20/200 (24)||20/200||Atrophy|
The Fatty Acids Composition of Plasma Phospholipids and Hard Exudates in Each Three Cases
|Fatty acids||Case 1||Case 2||Case 3|
|Plasma PL||HE||Ratio (HE%/Plasma PL%)||Plasma PL||HE||Ratio (HE%/Plasma PL%)||Plasma PL||HE||Ratio (HE%/Plasma PL%)|
|C20:5 ω 3 (EPA)||3.24||-||0.00||0.29||-||0.00||0.79||0.49||0.62|
|C22:6 ω 3 (DHA)||0.98||0.07||0.07||4.57||-||0.00||3.10||1.79||0.58|
|C18:2 ω 6 (LA)||22.52||15.88||0.71||10.24||12.15||1.19||16.51||12.33||0.75|
|C20:4 ω 6 (AA)||3.56||0.96||0.27||2.73||6.06||2.22||5.34||0.36||0.07|
|ω 3 / ω6||0.18||0.21||0.32||0||0.22||0.27|