Retinopathy is a disease of the retina, occurring in about a
quarter of people with diabetes.
How does the eye 'work'? Light enters the eye from the front, and passes
through the eye to hit the retina, just like in a camera.
The retina contains cells that convert the light into the electric signals, and these signals are then sent on to the brain so we can see.
Two types of diagram are used in the descriptions in this section about retinopathy.
First, a side or 'cut through' view of the eye, like a cut through drawing of a camera as opposite (upper picture).
Secondly, the view the doctor sees when he looks into your eye, like a map, with the blood vessels spreading out from the centre (the optic nerve). This is shown immediately opposite.
See Animation.
The retinal cells stand next to each other, a bit like houses in a street. The main cells are the rods and cones: these are the cells that take up light and convert it into electrical messages, which are then sent onto the brain.
These cells receive their oxygen and other nutrients from tiny blood vessels nearby. These blood vessels are like pipes which pass nearby the cells; imagine a largish pipe passing past your house, containing blood. The walls of these pipes/blood vessels are very thin, and so nutrients can pass through them. These nutrients are the ‘food’ for the cells.
If you are diabetic you are likely to have a slightly high blood sugar. Over
the years the high sugar level can damage the tiny blood vessels.
The longer you are diabetic, especially if you have been diabetic for 14 years
or more, the more likely this is to happen. This damage can be slowed down by
controlling your sugar and blood pressure etc, and this is discussed in Preventing
Problems.
There are three basic components of this damaging process.
Previously nearly all type 1 patients had retinopathy at 20 years (see), and 95% eventually needed laser. These days figures are probably much better, and they certainly are in Icleand.
First, tissues become short of oxygen (hypoxia, see). Retinal function becomes reduced at his point; this is background or mild non-proliferative retinopathy. At around this time, white blood cells (leucocytes) stick to the capillary blood vessel walls, and the capillaries block. This causes more shortage of oxygen in the tissues (hypoxia and ischaemia).
The retina responds to this by increasing blood flow through the larger blood vessels. This is pre-proliferative or moderate non-proliferative retinopathy. At around this time, the cells in the capillary walls develop a thicker basement membrane (ie a thicker cell wall). Pericytes are cells supporting the blood vessel wall, and these start to die at this stage. The endothelial cells release the growth chemical VEGF, and start to leak fluid (macula oedema). Later, the endothelial cells die as the capillaries block, and too little oxygen reaches the retinal cells.
The VEGF causes even more leakage of neighbouring capillaries; and it also stimulates the capillaries to grow ('new blood vessels').
The leakage causes the retina to swell up a little and become waterlogged, a bit like a sponge. This swelling then damages the retinal cells themselves. This is the main mechanism in ‘maculopathy’ and 'macula oedema). This process is like a very leaky sieve or a raincoat that lets water in, instead of keeping it out animation.
At the same time control of the blood flow to the retina is faulty, and blood flow to the retina increases. This naturally increases the retinal leakage further.
Secondly, the endothelial cells produce VEGF, and this stimulates other tiny blood vessels to grow. These are called ‘new’ blood vessels, and ophthalmologists call these ‘new vessels’.
These 'new vessels' are very delicate and very easily bleed, and this blood can damage your eye badly . This is ‘proliferative' retinopathy. Laser prevents blood vessel growth and prevents the bleeding.
Avastin injections are used to treat diabetic retinopathy. Avastin is an anti-VEGF drug. By blocking the effect of VEGF, Avstin stops the new vessels growing and reduces retinal leakage for a while.
The tiny blood vessels may eventually close and block. If the retina is badly damaged by leakage or very severe diabetes, the blood vessels may close up, and nutrients will not reach the retinal cells. This happens in ‘ischaemic’ macular disease.
This capillary damage can be seen when the retina is examined under the microscope. It is likely that some of this damage is reversible with good diabetic control. see animation
Some people are genetically more prone to develop retinopathy, and this may be due to the genes involving VEGF see or renal function.
Nitric oxide here , here, is also involved. VEGF is believed to mediate macular oedema, see Aiello. Similarly endothelin-1 may be involved. There are also inflammatory factors, which may be medicated by VEGF: this explains why triamcinolone and high dose aspirin help retinopathy.
Other hormones are involved, such as IGF1 , Atrial natriuretic peptide, growth hormone , SDF1, MIF, and other enzymes. Angiopoietin, prorenin. Hepatocyte growth factor Summary
There is a genetic component, and the age of onset is important. Genes appear to play a crtically important role in type 2 diabetes, involving neuropeptide Y, a growth factor released by the hypoxic endothelium, as here.
Smoking may have a variable impact (many papers argue smoking has no impact, but I have seen good quality evidence at meetings suggesting it has a major impact). Retinopathy occurs at the same time as renal problems develop, and blood pressure rises see and prorenin. Aldose reductase genes are involved.
Cataract surgery may cause progression, but this is variable also
(search).
Macula oedema may be aggravated by vitreo-retinal traction, and resolve as the
vitrous detaches. Vitrectomies may
help if there is substantial traction.
Pregnancy also influences hormones and growth factors, see
So microaneurysms are one of the best way to detect progression of retinopathy, also having the advantage that image analysis software can detect them accurately from retinal photographs.
After Dodson & Forrester, these are described here and review. There is an inflammatory component to diabetic retinoopathy, involving CRP, IL6, and TNF systems (example).
There are many genetic influences on retinopathy. Here is one example and another and another. IGF1 . Endothelin . Gly482Ser polymorphism MTHFR gene
This too may be affected, see diabetic papillopathy. These processes occur in the different types of diabetic retinopathy as discussed on adjacent pages.
This too is affected. A deterioration in renal disease can aggravate retinopathy, perhaps by putting blood pressure up.
Laser works by killing RPE cells (retinal pigment epithelium). This then kills photoreceptors, which then results in less hypoxia (hypoxia= low oxygen levels) . (after Stefansson)
With fewer photoreceptors, there is less oxygen consumption, so inner retina hypoxia reduces. With less inner retinal hypoxia, there is then reduced blood flow. This results in lower permeability and less leakage, and less VEGF and other growth factors produced.
In the adjacent retina, with less VEGF from the nearby damaged retina, (autoregulation improves) there is reduced retinal blood flow. This lowers hydrostatic pressure, and this reduces oedema & leakage.
diabetic
retinopathy (no laser) |
diabetic
retinopathy (laser) |
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 |
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damaged photoreceptors |
damaged photoreceptors |
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VEGF leaks out |
VEGF leaks out..leakage.. photoreceptor damage |
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more leakage |
laser |
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more photoreceptor
damage |
more oxygen available..less
hypoxia |
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more VEGF |
less leakage, less
photoreceptor damage |
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more leakage |
less VEGF |
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|
and so on |
surrounding retina
healthier |
Laser reduces leakage. But if the diabetic control (HbA1c and blood pressure) is poor the process continues.
The sight gets worse, but at a much slower rate than without the laser. The laser reduces the leakage and slows the process down tremendously.
Laser reduces leakage. The retinopathy may deteriorate a little, but if diabetic control is very good it stops getting worse in most patients. All haemorrhages and all oedema disappear.
Rarely the retinopathy still gets worse. This may be due to blood pressure (below 115 mmHg systolic ideal), kidney damage, or some other factors (not all of which are understood).
Laser will reduce leakage.
But for some reason, improving the diabetic control from poor to good can increase the retinopathy for 1-3 years. Extra laser may be needed.
After 1-3 years, the oedema will start to reduce, and haemorrhages start to disappear, and the retinopathy completely stablise.
However, the initial increase in retnopathy may need a lot of laser for 1-3 years. Good control is really important in the long term. Hypoxia causes this deterioration.
In the DCCT study, half the patients had their diabetes intensively controlled. This improved their retinopathy, and they had a slower progression rate of their retinopathy. But even many years later their diabetic retinopathy progressed quicker than the patients whose diabetes was already very well controlled.
This 'legacy effect' is one of the many problems patients face.
Neverthe less, good control significantly reduces the risk of problems. There
are no legacy effects of blood pressure control..risks reduce immediately.
(This graph is
very diagramatic.)
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