The prevalence increases with the duration of diabetes. In early-onset insulin-treated subjects proliferative diabetic retinopathy is rarely seen within the first five years of diabetes, but after 15 years it is found in 25% of patients and after 20 years in more than 50%. Beyond 20 years, almost 100% of people with diabetes mellitus will develop diabetic retinopathy [152]. In late-onset diabetes retinopathy may be observed at the time the diabetes is diagnosed, but proliferative diabetic retinopathy is rare. The 10-year incidence and progression rates reflect these trends (Table 1.11). Macular edema is more common in late-onset diabetes [153]. Senilecataracts, which will not be further discussed, appear earlier in life and progress faster than in nondiabetic subjects.
Pathology
Diabetic retinopathy is a disease of the retinal vasculature. In the early stages capillary blood flow is increased. The capillary basement membrane is thickened, its composition and charge are altered, its permeability to blood-borne particles and molecules is increased, and pericytes are lost. This process is related to hyperglycemia [127,130–132] and modified by hypertension [158,159], smoking [160,161], and pregnancy [162–164].
Table 1.11 Ten years cumulative incidence of diabetic retinopathy or progression to proliferative diabetic retinopathy (PDR)
| Diabetic group | 10-Year Incidence (%) | 10-Year progression to PDR (%) |
|---|---|---|
| Younger-onset taking insulin:MaleFemaleTotal | 938589 | 293130 |
| Older-onset taking insulin:MaleFemaleTotal | 778079 | 252324 |
| Older-onset not taking insulin:MaleFemaleTotal | 696567 | 71210 |
Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy [434]
An early morphological sign is the presence of microaneurysms. These have been interpreted as abortive attempts to vascularize ischemic areas. Other early signs are intraretinal (flame-shaped or dotted) hemorrhages and lipoprotein deposits (hard exudates). They are indicative of increased capillary permeability, which could be due to modified LDL, free radical damage of endothelial cells, or AGE formation in the endothelial matrix proteins, which attract platelets and macrophages and stimulate the expression of vascular permeability factor (VPF) and other cytokines. Disruption and fenestrations of the endothelial layer and vascular proliferation may occur. Another important clinical sign of vascular permeability is focal or diffuse macular edema.
A later morphological sign is capillary closure. This may be caused by the activated hemostasis with expression of adhesion molecules in platelets and leukocytes as well as by procoagulatory changes of the endothelium and matrix areas exposed to the blood flow because of endothelial disrupture.
Capillary closure is followed by ischemia, which is a potent trigger of new vessel formation. This process is normally suppressed by collagen IV, but it is stimulated by collagen fragments, fibronectin, and local growth factors such as vascular endothelial growth factor (VEGF; secreted in response to hypoxia), fibroblast growth factor(FGF), and TGF-β. Formation of new vessels may not be restricted to the retina. They may grow into the preretinal space and vitreous and eventually cause retinal detachment. New vessel formation may also occur in the iris, where it causes rubeosis iridis and possibly neovascular glaucoma.
Classification
For the purposes of therapy and prognosis, diabetic retinopathy may be classified according to the Early Treatment Diabetic Retinopathy Study Research Group [165] as follows:
1. Background retinopathy, characterized by microaneurysms, hard exudates, generalized venous dilatation, intraretinal hemorrhages, and occasional cotton wool spots (retinal infarcts). Background diabetic retinopathy does not necessarily progress to more advanced stages.
2. Preproliferative retinopathy, characterized by localized irregularities of venous caliber (beading), which are strong predictors of neovascularization; venous looping and reduplication: multiple (≥ 5) cotton wool spots; and intraretinal microvascular abnormalities (IRMAs—abnormally branched vessels within the retina).
3. Proliferative retinopathy, characterized by abnormal new vessels growing into the preretinal space, vitreous, or, occasionally, on the iris. Bleeding from these vessels, retinal detachment due to contraction of fibrotic structures that develop in the hemorrhages, and neovascular glaucoma may cause impairment of vision.
Another cause of impaired vision is maculopathy due to capillary leakage (edematous, wet maculopathy) or to ischemia (dry maculopathy).
Management
The different classes of diabetic retinopathy require different action depending on the risk of loss of vision. In general, the best primary prevention is near-normal metabolic control, normal blood pressure, and giving up smoking [127,130,158,159,166,167]. In secondary prevention, abrupt normalization of poor metabolic control of long duration should be avoided because of the so-called normoglycemic re-entry phenomenon [168,169]. Dyslipoproteinemia increases the risk of hard exudates, maculopathy [170], and vascular proliferations [171] and should be effectively treated. Guidelines for ophthalmological intervention have been developed (for references see [172–174]). The most important technical methods of treating diabetic retinopathy are photocoagulation and vitreous surgery, which may save useful vision in up to 70% of cases of severe proliferative diabetic retinopathy. A difficult problem is dry (ischemic) maculopathy. Treatments based on improving the microcirculation are still experimental [175].
Any diabetic person requires an ophthalmological checkup at diagnosis and annually thereafter. Background retinopathy should be monitored every 6 months. Referral to the ophthalmologist is indicated soon in the case of preproliferative diabetic retinopathy or maculopathy. Referral is urgent if new vessels develop, particularly if they originate from the optic disk. Immediate referral is indicated if retinal detachment, vitreous hemorrhage, or neovascular glaucoma is suspected.
Nephropathy
Diabetic nephropathy is a microvascular
