Pathophysiology of Diabetic retinopathy

Pathophysiology of Diabetic retinopathy simplified

1. PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY Dr. NIKHIL GOTMARE @ eyea mnikhil

2. Pathophysiology of diabetic retinopathy

3. ANATOMICAL CONSIDERATIONS

4. ● BRB compartmentalises the neurosensory retina from the vascular component of the eye. ● Inner BRB is formed by tight junctions between the retinal vascular endothelial cells and glial cells . ● Outer BRB by tight junctions between RPE ( zonula occludens

5. The pericytes are wrapped around the capillaries and are thought to be responsible for the structural integrity of the vessel wall.

6. ANATOMICAL LESIONS

7. Diabetic retinopathy is a microangiopathy affecting the retinal precapillary arterioles, capillaries and venules . Retinopathy has features of both: - microvascular leakage . (mild- mod NPDR) - microvascular occlusion .(sever NPDR-PDR)

8. Microvascular leakage Hard exudate ( Circinate pattern) Degeneration and loss of pericytes Plasma leakage Capillary wall weakening microaneurysm Retinal edema outpouching of capillaries at structurally weak points

9. M icroaneurysms - Earliest & most specific sign. ● 10 to 100 microns in diameter, and appear as red dots. microaneurysm Intraretinal hemmorhage Dot blot h’age Flame shaped h’age rupture (outer plexiform and inner nuclear) (nerve fiber layer)

10. Pericyte loss Endothelial loss Changes in tight junctions AGE Leukostasis Breakdown of blood retinal barrier Inflow of fluid > outflow EDEMA - Development of retinal edema requires accumulation of fluid which occurs if : Leakage : Absorption : - Microanurerysms . - Incompetent capillaries - Uptake from adjusent capillaries - Healthy RPE cells

11. Microvascular occlusion Increased plasma viscosity Deformation of RBC Increased platelets stickiness Decreased capillary blood flow and perfusion Endothelial cell damage and proliferation Capillary basement membrane thickening Retinal hypoxia VEGF Proliferative retinopathy Neovascularization and fibrovascular proliferation Rubeosis iridis A-V shunt IRMA* * intraretinal microvascular abnormalities

12. New vessel proliferation Fibrous glial tissue proliferaion Tractional RD RD IRMA

13. Basement membrane thickening ● Repeated endothelial cell death with regeneration and replacement , with each new generation contributing their own basement lamina along with entrapment of cellular debris from the dead cells lead to basement membrane thickening. ● Glycation of basement membrane proteins → alteration in the structure, chemical composition → increase in type IV collagen and laminin .

14. Loss of endothelial cells Due to chronic leucocyte mediated injury.

15. BIOCHEMICAL CHANGES

16. 1. Polyol pathway Glucose Sorbitol Fructose NADPH NADP NAD NADH Damaging effects on pericytes & endothelial cells Aldose reductase Sorbitol dehydrogenase

17. 2. Advanced Glycation End-products [AGEs] Alters structure & function of various intra &extracellular proteins Reducing sugars Amino groups of proteins, lipids & NA Schiff base Amadori product [ eg : HbA1c] AGEs ↑ VEGF ↑ Endothelins ↑ Leukostasis

18. 3. VEGF and other growth factors ● VEGF is produced by RPE cells, ganglion cells, Muller cells , pericytes , endothelial cells, glial cells and neurons . ● 6 major isoforms, with isoform 165 being most important. ● Hyperglycemia and hypoxia accentuate the production of VEGF.

19. VEGF Phosphorylation of tight junction & cytoskeletal proteins Fenestraion in endothelial cell membranes Breakdown of BRB + bFGF , Angiotensin II, IGF New vessel formation Neovascularisation

20. VEGF Leakage Hemorrhages , exudates, Vascular leakage NPDR with ME Angiogenesis PDR

21. 4. Oxidative stress ● Imbalance between the level of free radicals and the antioxidant defences in a biological system. ● Glycolysis and TCA cycle → synthesis of ATP via oxidative phosphorylation → production of free radicals. ● Chronic hyperglycemia - ↑ production of such free radicals.

22. Cross linking, Fragmentation, oxidation of proteins, lipids, nucleic acids Cellular dysfunction, Leukostasis , ↑ vascular permeability Enzymatic reactions Electron transport Oxidases Auto-oxidation ↓ in hyperglycemia

23. 5. DAG & PKC Hyperglycemia increases de novo synthesis of diacylglycerol, which is an activating factor for the isoforms of protein kinase C. [ PKC β 2 ] Disruption of nitric oxide regulation ↑ VEGF PKC ↑ vascular permeability Leukostasis Vasoconstriction ↓ blood flow

24. 6. Leucostasis Leucocyte adhesion to the vessel wall, mediated by intercellular adhesion molecule-1(ICAM-1) [ ↑ in diabetes ], leads to ↑ vascular permeability Pericyte apoptosis Endothelial cell apoptosis

25. 7. Hemodynamic changes and RAAS ● The mechanical stretch and sheer stress imparted on endothelial cells by high blood pressure → endothelial dysfunction. ● RAAS - angiotensin II is involved in PKC activation as well as VEGF signalling.

26. HYPERGLYCEMIA PKC ROS AGEs SORBITOL ↑VEGF LEUKOSTASIS PERICYTE & ENDOTHELIAL CELL LOSS Breakdown of BRB RAAS Microaneurysms & BM thickening Neovascularisation

27. Overall, all the above processes and changes result in a generalised disorder of the small blood vessels of the retina, giving rise to the typical clinical picture of diabetic retinopathy .