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Pathophysiology of NPDR
Diabetic retinopathy (DR) is a common ocular manifestation of systemic diabetes resulting from microvascular damage to the retinal vasculature1. Early stages of DR are typically classified as nonproliferative diabetic retinopathy (NPDR), further divided into mild, moderate, and severe stages.1
Chronic hyperglycemia from diabetes leads to tissue damage from various mechanisms.1 Microaneurysms are the earliest clinically evident stage of diabetic retinopathy; they result from advanced glycation-end products (AGEs) damaging basement membranes and other blood vessel wall components, including pericytes.1
Pericytes are cells within retinal capillary walls that provide physical strength and biochemical support to underlying endothelial cells.1 Damaging these cells weakens capillary endothelial cells, leading to localized outpouchings in capillary walls or microaneurysms.1 Microaneurysms (MAs) often rupture, causing hemorrhages in the deep retina, referred to as dot and blot hemorrhages on exam.1
Weakening of vessel wall integrity also leads to changes in vascular caliber, like in venous beading characterized by alternating areas of dilation and constriction of retinal veins.2 Intra-retinal microvascular abnormalities (IRMAs) are another example of blood vessel changes.4
Elevated levels of circulating glucose also result in oxidative stress and increased inflammatory factors, like protein kinase C (PKC), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-8, and IL-1.1,5 This activation of pro-inflammatory compounds leads to leukostasis and leukocyte adhesion, which are driving factors of capillary occlusion, especially when combined with endothelial damage.1 Cotton-wool spots (CWS) are visible signs of infarction of the retinal nerve fiber layer due to capillary occlusion.1
As capillary occlusion worsens, retinal ischemia occurs, leading to endothelial cell and neuroglial cell injury.1 Loss of neural retina cells results in inner retinal thinning.1 Retinal ischemia or hypoxia also triggers the upregulation of neovascular factors, like vascular endothelial growth factor (VEGF).1 VEGF has several effects, including elevating local inflammatory factors, angiogenesis, and increasing vascular permeability and local inflammatory infiltrates.1
Vascular permeability and breakdown of the blood-retina barrier increase over time with DR due to chronic inflammation and vascular damage, eventually leading to fluid leakage into the retina.1, 5 When the fluid buildup occurs in the macula, termed diabetic macula edema (DME), it can cause significant central vision impairment.1
DME can be seen at any stage of DR and sometimes progresses independently of other DR findings.2 The pathogenesis of DME is not well understood, but it likely involves all of the pathways previously mentioned, including angiogenesis, inflammation, and oxidative stress.5 Protein deposits from this edema lead to waxy, yellow findings referred to as hard exudates.1 DME is classified based on whether the edema involves the 1 mm center subfield zone.
In general, diabetic retinopathy initially presents with nonproliferative abnormalities, like MAs and dot and blot hemorrhages. As the disease worsens, fundus exam findings may include cotton-wool spots, hard exudates, venous beading, and IRMAs.1 DME can occur at any time, with severity potentially following an independent course to other NPDR findings.2
References
- Fontes ML, Falcao MF, Rosas V, et al. Diabetic retinopathy pathophysiology. EyeWiki. https://eyewiki.aao.org/Diabetic_Retinopathy_Pathophysiology
- Wong TY, Sun J, Kawasaki R, et al. Guidelines on Diabetic Eye Care: The International Council of Ophthalmology Recommendations for Screening, Follow-up, Referral, and Treatment Based on Resource Settings. Ophthalmology. 2018;125:1608-1622.
- Adapted from Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17:20-33.
- Shimouchi A, Ishibazawa A, Ishiko S, et al. A proposed classification of intraretinal microvascular abnormalities in diabetic retinopathy following panretinal photocoagulation. Invest Ophthalmol Vis Sci. 2020;61:34.
- Kusuhara S, Fukushima Y, Ogura S, et al. Pathophysiology of diabetic retinopathy: The old and the new. Diabetes Metab J. 2018;42:364-376.
- Columbia University. Edward S. Harkness Eye Institute. Diabetic Macular Edema. https://www.columbiaeye.org/sites/default/files/pictures/dmeb.jpg
- Cabrera A, Mankad RN, Marek L, et al. Genotypes and phenotypes: A search for influential genes in diabetic retinopathy. Intl J Mol Sci. 2020;21:2712.
All URLs accessed 5/9/22.
