www.diabeticretinopathy.org.uk

Mechanism of diabetic retinopathy

David Kinshuck

The retina

light entering the eye

Enlarge   Light enters the eye from the left in this diagram...shown by the yellow arrow. It passes through the clear jelly of the eye (the vitreous) to reach the retina (pink)

 

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).

fovea...the yellow dot in the centre of the retina  

 

Second, 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).

The yellow dot is the fovea, where light is focused. The red & blue lines are the larger retinal blood vessels spreading out from the optic nerve.

See Animation.  enlarge 

 

How does the retina work?

rods, sones, bloodvessels, and light

Light ...in yellow... falls onto the retina. The retinal cells are rods (the long straight cells) and cones (the cells with the pointed end).
There are tiny blood vessels (capillaries) on the surface of the retina ...the red ovals
enlarge

 

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.

Retina in diabetes

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 Iceland.  Diabetes with the high glucose levels and high blood pessure damages the retinal capillaries, the tiny blood vessels in the retina:

background diabetic retinopathy...dot and blots

 

 

 

The small red dots are 'microaneurysms', tiny damaged capillaries.

The bigger red blobs are small haemorrhages, little flecks of blood. The white dots are exudates (leakage). Your sight is not affected at this stage. This is the term given to early damage of the retina in diabetes. Your sight should be perfectly good at this stage. A doctor examining your eye will notice tiny abnormalities.

enlarge 

Mechanism of damage

First,  four biochemical pathways lead to tissue damage. Cell tight junctions fail, permeability increases, cells swell (muller, neuronal, prricytye, endothelial cells), there is leukocyte infiltration, and then tissues become short of oxygen (hypoxia, see). The angiotensin 2, vegf, and prostaglandin pathways all lead to tissue damage and leakage.

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 JAMA 2012. 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.

capillary changes in diabetic retinopathy Enlarge

 

  1. 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.
  2. 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'.
  3. These 'new vessels' are very delicate and very easily bleed, and this blood can damage your eye badly. This is 'proliferative' retinopathy. The proliferation is followed by fibrosis, that is scar formation.
  4. The vitreous gel starts to shrink and pull the retina off. Whilst VEGF and IGF and other growth factors control the neovascularisation,the growth factors that control the fibrosis/scarring are different (BJO 2012).
  5. Laser prevents blood vessel growth and prevents the bleeding.
  6. Avastin injections are used to treat diabetic retinopathy. Avastin is an anti-VEGF drug. By blocking the effect of VEGF, Avastin stops the new vessels growing and reduces retinal leakage for a while.
  7. 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. Anti-scarring agents are needed BJO 2012.

The capillary network under the microscope

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

healthy and diabetic retinal capillary network

the mechanism of diabetic retinal capillary damage

Enlarge

 

Some technical details

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     Dickhkopf-1

Microaneurysms

graphs of microaneurysm progression

The graphs show that μaneurysm measurement is a good way to determine how active the retinopathy is. Also, image analysis software can detect them accurately from retinal photographs, and grade the retinopathy.

The number of retinal haemorrhages is also related to retinaopthy activity. The can be monitored the same way as micoraneurysms: by the doctor or optometrist looking into the eye, or better still by comparing photographs, or by using the image software analysis.

 

The biochemical processes

After Dodson & Forrester, these are described here and review.

 

Inflammation

There is an inflammatory component to diabetic retinopathy, involving CRP, IL6, and TNF systems (example high CRP). Suppressing inflammation can reduce macular oedema.

 

Genetics

There are many genetic influences on retinopathy. Here is one example and another and anotherIGF1 . Endothelin .   Gly482Ser polymorphism    MTHFR gene  Chromosome 6   UCP     GSTM1 and GSTT1 null genotype  

 

Optic nerve

This too may be affected, see diabetic papillopathy. These processes occur in the different types of diabetic retinopathy as discussed on adjacent pages.

 

Renal Disease

This too is affected. A deterioration in renal disease can aggravate retinopathy, perhaps by putting blood pressure up.

 

Laser...how does it work

as retinal oxgen levels decrease, blood flow increases Enlarge Retinal blood vessels become damaged from the retinopathy. Oxygen cannot pass through the damaged retina, and so oxygen levels decrease. The retina responds by 'autoregulating' its blood flow...blood flow then increases. This causes more leakage and oedema 
(after Stefansson)

 

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.

 

 

Enlarge   after laser blood flow decreases, resulting in less leakage and oedema (after Stefansson)

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)

damaged photoreceptors

damaged photoreceptors

VEGF leaks out

VEGF leaks out..leakage..
photoreceptor damage

more leakage

reduced with anti-VEGF injection or laser

more photoreceptor damage

(laser... more oxygen available..less hypoxia)

more VEGF

less leakage, less photoreceptor damage

more leakage

less VEGF

and so on

surrounding retina healthier

 

Laser with poor diabetic control

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 with good diabetic control

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 with poor then good diabetic control

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 stabilize.

However, the initial increase in retinopathy may need a lot of laser for 1-3 years. Good control is really important in the long term. Hypoxia causes this deterioration.

 

Laser with poor then good diabetic control...many years later...'legacy' effect

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. Nevertheless, good control significantly reduces the risk of problems. There are no legacy effects of blood pressure control..risks reduce immediately. The graphs are very diagrammatic.

 

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