Diabetes mellitus is a metabolic disorder caused by defects in insulin secretion (type 1), insulin action (type 2), or both. It is characterized by chronic hyperglycemia which ultimately may result in dysfunction and damage to various organ systems, including the brain, kidneys, eyes, and peripheral nerves. Diabetic retinopathy may be broadly classified in terms of the presence or absence of retinal neovascularization. The term nonproliferative diabetic retinopathy (NPDR) is used to describe intraretinal microvascular changes that occur in the early stages of diabetic retinopathy. The etiology and pathogenesis of NPDR are discussed in Chapters 65 and 67 . Proliferative diabetic retinopathy (PDR) is used to indicate the presence of newly formed vessels, fibrosis, or both, arising from the retina or optic disc and extending along the inner retinal surface and/or into the vitreous cavity. PDR may be characterized by neovascularization of the iris (NVI) as well. The focus of this chapter will be on the proliferative changes seen in these advanced stages of diabetic retinopathy.
Diabetic retinopathy is the leading cause of new cases of blindness in people aged 20–74 years in the USA. The incidence of diabetic retinopathy increases with the duration of diabetes mellitus, and it is found in the vast majority of patients who have had diabetes for 20 years or more. After 20 years of diabetes, PDR affects about 50% of patients with type 1 diabetes, 5–10% of patients with noninsulin-dependent type 2 diabetes, and 30% of patients with insulin-dependent type 2 diabetes ( Box 66.1 ). In the USA, African Americans and Hispanics have a higher prevalence of diabetes, approximately 25%, compared with 6.2% in the remainder of the population. The major risk factors for progression of diabetic retinopathy are the duration of diabetes mellitus, poor glucose control, high blood pressure, and elevated cholesterol. The Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) have demonstrated the efficacy of intensive glucose control in reducing the incidence and progression of diabetic retinopathy. However, results of these studies have also confirmed the difficulty of achieving and maintaining appropriate glycemic control over a long period. As such, recent attention has been given towards further elucidating the pathogenesis of diabetic retinopathy in an attempt to develop better, more targeted therapies for this prevalent and visually disabling condition.
Diabetic retinopathy is the leading cause of new cases of blindness in persons aged 20–74 in the USA
Incidence of diabetic retinopathy increases with duration of disease
After 20 years of diabetes, proliferative diabetic retinopathy affects:
50% of type 1 diabetes
5–10% of noninsulin-dependent type 2 diabetes
30% of insulin-dependent type 2 diabetes
Diabetic retinopathy is characterized by the appearance of microaneurysms, increased vascular permeability, occlusion of capillaries, and formation of new, abnormal vessels. There are two primary pathological features in diabetic retinopathy responsible for vision loss: diabetic macular edema (DME) and retinal neovascularization. DME is the most common cause of vision loss in diabetes and is generally associated with other nonproliferative changes. NPDR is characterized by microaneurysms, small “dot and blot” hemorrhages, “flame” hemorrhages, intraretinal microvascular abnormalities, and “cottonwool” spots. Later stages of diabetic retinopathy are characterized by the formation of new vessels on the optic nerve or in the retina which may extend along the surface of the retina and/or into the vitreous cavity. These proliferative changes occur as a programmed response to ischemia in the inner retina in an effort to improve tissue oxygenation. However, the new vessels are weak and may break, resulting in vitreous hemorrhage. Furthermore, the combination of neovascularization, fibrous tissue proliferation, and recurrent vitreous hemorrhage may lead to tractional retinal detachment ( Box 66.2 ).
The development of diabetic retinopathy is primarily related to the duration of diabetes, severity of hyperglycemia, and the existence of contributing factors such as hypertension and hyperlipidemia. Hyperglycemia is the primary pathogenic factor in the development of diabetic retinopathy. However, diabetic retinopathy may occur at higher rates in some patient groups in spite of relatively good glucose control and vice versa, suggesting that there are other contributing factors.
Siblings of individuals with diabetic retinopathy have a higher risk of developing diabetic retinopathy themselves. This risk is in addition to the baseline risk of diabetes and is greater than the expected rate of diabetic retinopathy, indicating that there is a genetic component. A variety of candidate genes have been investigated in diabetic patients and animal models, but large studies have not yet proven any direct correlation with diabetic retinopathy. The development of diabetic retinopathy is multifactorial, and as such, relevant genetic factors are probably modulated by many environmental factors as well. Recent studies have shown that polymorphisms in genes coding for intracellular adhesion molecule-1 (ICAM-1) and transforming growth factor-β are risk factors for diabetic retinopathy. The authors propose that mutations result in leukocyte activation and adhesion to the retinal vascular endothelium, leading to the development of vascular leakage and capillary closure. Larger studies are needed to evaluate further these and other possible genetic components of diabetic retinopathy.
The earliest histologic change in diabetic retinopathy is the loss of pericytes. Pericytes line the retinal vascular endothelium and provide structural support to the retinal vasculature. Loss of pericytes leads to progressive dilation of capillaries and the formation of microaneurysms. A complete discussion of the classic histologic features of NPDR can be found in Chapter 65 . PDR is characterized by the formation of new vessels which are evident histologically as thin-walled vessels devoid of pericytes.
Pathologic mechanisms in diabetic retinopathy
Several biochemical mechanisms may be responsible for the progression of diabetic retinopathy ( Figure 66.1 ). Hyperglycemia causes the formation of reactive oxygen intermediates (ROIs) and advanced glycation endproducts (AGEs). ROIs and AGEs may cause direct damage to pericytes and vascular endothelial cells and also stimulate the release of vasoactive factors. Chronic hyperglycemia also causes activation of the polyol pathway leading to increased glycosylation of cell membranes and extracellular matrix as well as the accumulation of sorbitol by increased aldose reductase expression. Glycosylation and sorbitol accumulation cause further vascular endothelial damage and dysfunction of endothelial enzymes. It is likely that activation of these pathways in association with vascular damage produces inflammation which further exacerbates the condition. Hyperglycemia may also impair autoregulation of retinal blood flow causing perfusion-related damage to endothelial cells. The ultimate effects of glucose toxicity on pericytes and endothelial cells cause impaired circulation, hypoxia, inflammation, and further activation of angiogenic stimuli. Finally, hyperglycemia also causes activation of the protein kinase C (PKC) intracellular signaling pathway. PKC influences progression of diabetic retinopathy in two ways. First, it directly promotes the activation of VEGF and other growth factors. Second, binding of VEGF to its target receptors requires the presence of the PKC signaling protein. Clinical trials investigating PKC inhibitors have demonstrated efficacy in the treatment of NPDR and further studies are ongoing.
Production of vasoactive factors
The combined effects of these pathways lead to the production of vasoactive factors such as vascular endothelial growth factor (VEGF), nitric oxide, prostacyclin, insulin-like growth factor (IGF)-1, and endothelin (ET). These vasoactive factors act in concert with hyperglycemia to produce dysfunction of pericytes and vascular endothelial cells. One mechanism by which this occurs is via VEGF stimulation of ICAM-1 expression in the retinal vasculature. ICAM-1 promotes leukocyte binding to the vascular endothelium which triggers a Fas/Fas ligand-mediated endothelial cell death and breakdown of the blood–retinal barrier. The culmination of these events leads to thrombosis and closure of retinal capillaries. Occlusion of capillaries gives rise to focal retinal ischemia and hypoxia. Local hypoxia induces further overexpression of angiogenic stimuli. In response, new vessels begin to form. However, the new vessels have reduced structural integrity including a fragile basement membrane, deficient tight junctions between endothelial cells, and lack of pericytes. The walls of the vessels are porous, allowing leakage of plasma proteins and even hemorrhage into the retina or vitreous.
In advanced PDR, the new vessels are accompanied by fibrous tissue and grow from the retinal surface into the vitreous cavity to form fibrovascular membranes. Several studies have demonstrated that the vitreous plays a role in the pathogenesis of PDR. Hyperglycemia causes changes in type 2 collagen in the vitreous, leading to liquefaction and vitreous syneresis. Additionally, hypoxia and resultant abundance of growth factors lead to a thickening of the posterior vitreous cortex. The resulting vitreous instability due to loss of the gel state without dehiscence at the vitreoretinal interface may induce retinal traction. Such traction may not only lead to retinal tears but may also contribute to the neovascular process. In support of this theory, the development of PDR is rare if the vitreous has detached completely, presumably since the scaffold for proliferating cells is removed. Liberated serum proteins such as fibronectin accumulate at the junction of attached retina and vitreous and mediate the migration and adhesion of proliferating endothelial cells. In later stages of PDR, contraction of the posterior hyaloid causes rupture of proliferating vessels, vitreous hemorrhage, and traction and/or rhegmatogenous retinal detachment.
NVI may also occur in PDR. The stimulus for the formation of NVI is the release of vasoactive factors by ischemic retina. The most common causes of NVI are central retinal vein occlusion, diabetes, and ocular ischemic syndrome. Angiogenic factors such as VEGF diffuse anteriorly into the aqueous and stimulate growth of new vessels. The new vessels begin as capillary buds at the inner circle of the iris and then extend radially forming a fine vascular network. The vessels may cross the trabecular meshwork of the angle and block aqueous outflow causing neovascular glaucoma.