E WHY DO THE FEATURES OF DIABETIC RETINOPATHY OCCUR?
1 The Effect of High Blood Sugars on the Eye
In 1993 it was conclusively proved that there was a direct link between blood sugar levels in people with diabetes mellitus and development of microvascular complications. This had long been thought to be the case in Europe following several small studies but doctors in America were not so convinced. The publication of the “Diabetes Control and Complications Trial” results in 1993 and the “United Kingdom Prospective Diabetes Study” in 1998 settled the debate.
Although the exact cause of diabetic retinopathy is controversial, it is widely accepted that the main problem is capillary occlusion. Capillaries are the small blood vessels connecting arteries, which pump blood into the eye, to the veins, that drain blood away. It is the capillaries that supply oxygen and other vital nutrients to all the cells of the eye. If they become occluded (blocked) the affected cells become starved of oxygen and nutrients (ischaemia). As a consequence the retina tries to grow in new blood vessels to supply the ischaemic areas. Unfortunately these new blood vessels do not grow safely within the layers of the retina but grow on its surface where they form attachments with the overlying vitreous. It is these attachments to the vitreous that cause the devastating complications of bleeding into the jelly in the middle of the eye (vitreous haemorrhage) and of the retina separating from the back of the eye (traction retinal detachment).
CAPILLARY OCCLUSION
High blood sugars damage the wall of a capillary as well as the blood within its lumen. Glucose in the blood is transported into the cells by special proteins called glucose transporters (GLUT). Some transporters respond to the amount of glucose present within the blood and others require the presence of insulin to work. These transporters also move glucose out of the cells into the blood.
Basement Membrane Thickening
Basement membrane thickening occurs and may be a direct consequence of glucose sticking to protein within the membrane itself. This “glycation” of protein results in a basement membrane that is thickened and this impairs the flow of oxygen and nutrients into the retina. High blood sugar levels in the endothelial cells also encourage them to produce more basement membrane thus thickening it further.
Endothelial Cell Damage
The retinal endothelial cells regulate uptake of glucose through glucose-dependent glucose transporters. Persistently high levels of glucose also make the individual cells of the endothelium less adherent leading to “gaps” in the capillary wall and leakage into the tissues. This thickening of the retina by fluid is termed oedema.
Altered Properties of The Blood
High glucose levels also alter the contents and physical properties of blood. Blood consists of three main components- red blood cells that carry oxygen, white blood cells that fight infection and platelets that help form clots. Glycation of platelets and red blood cells makes them stiffer and more likely to become trapped within the capillaries. High sugar levels increase this tendency to clot as the endothelial cells start to release chemicals (prostaglandins) that cause the blood vessels to narrow. High blood sugar levels make the problem worse by impairing fibrinolysis, the body’s “clot-busting system”. This is partly as a result of damage to fibrin by glycation and partly as a result of reduced levels of plasminogen activator. White blood cells (leucocytes) are also involved. High blood sugar levels make leucocytes more “active” and more likely to stick (adhere) to the sides of blood vessels. These too become trapped leading to obstruction of capillaries.
Clinical Appearance of Occluded Capillaries
Individual occluded capillaries cannot be seen on photographs or by looking clinically. Fluorescein angiography will, however, easily demonstrate their absence.
If large areas of capillaries are occluded then the retina will become pale and featureless. This is a subtle finding that is often only appreciated when comparing digital photographs with the corresponding image from a fluorescein angiogram.
MICROANEURYSM FORMATION
Microaneurysms are balloon-like structures on the sides of capillaries. They occur on capillaries that are adjacent to capillaries that have become occluded. There are two theories as to why they occur.
One theory is that microaneurysms are the result of the loss of pericytes on the sides of capillaries. Pericytes are cells that sit on the basement membrane of the capillary.
They have glucose transporters that take up glucose according to the prevailing glucose levels in the blood. This means that if the blood glucose level is high the level of glucose in the pericyte will also be high. High glucose levels upset the workings of the pericyte and they die off. As a consequence the capillary wall “balloons out” causing a little pouch termed a microaneurysm. The other theory is that microaneurysms represent an attempt by the capillary to grow a new branch into the area of ischaemia. However, for whatever reason this attempt is unsuccessful and rather than a new vessel (neovascularisation) being formed one just sees a balloon-like dilatation on the side of the capillary- a “microaneurysm”.
Clinical Appearance of Microaneurysms
Microaneurysms are the first sign of diabetic retinopathy that can be detected clinically on photographs or by ophthalmoscopy. They are deemed a cardinal feature. Absence should make one suspicious that any abnormal features seen on a photograph or by ophthalmoscopy are not caused by diabetic retinopathy. As noted previously the capillaries that microaneurysms originate from are not clinically visible. This means that microaneurysms appear like isolated red dots unattached to any blood vessel. They tend to first appear temporal to the macula where the super-temporal and infero-temporal arcades come together.
Microaneurysms are not static and “disappear” as the capillaries to which they are attached thrombose and become occluded.
