My Clinical Notes

Pathogenesis

 

Macrovascular disease

• Involves large and medium sized muscular arteries
• Causes accelerated atherosclerosis resulting in increased risk of;
  • MI
  • Stroke
  • Lower extremity gangrene

 

Microvascular disease

• Capillary dysfunction
• Causes nephropathy, neuropathy and retinopathy
• Diabetes is the most common causes of blindness and end stage renal failure in the west

 

At least 3 metabolic pathways appear to be involved in the pathogenesis of long term diabetic complications;

 

1) Formation of Advanced Glycation end products (AGEs)

• Formed as a result of nonenymatic reactions between intracellular glucose derived dicarbonyl precursors with the amino group of proteins – intracellular and extracellular
• Properties of AGEs
• Cross linking of extracellular matrix proteins
• Cross linking of collagen type I in large vessels decreases their elasticity
• Cross linking of collagen type IV in the basement membrane decreases endothelial adhesion and increases fluid filtration
• AGE cross linked proteins are resistant to proteolysis
• AGE modified matric components trap nonglycosylated or interstitial proteins e.g. trapping of LDL causing atherosclerotic acceleration and binding of albumin to the glomerular basement membrane

 

• Circulating plasma proteins are modified by addition of AGE residues and in turn bind to AGE receptors on endothelial cells, mesangial cells and macrophages.
• This results in NF-κB transcription of cytokines, growth factors and other proinflammatory molecules
• This results in;
  • Release of cytokines and growth factors from macrophages and mesangial cells, IGF-1, TGF-β, PDGF, VEGF
  • Increased endothelial permeability
  • Increased procoagulant activity on endothelial cells and macrophages
  • Enhanced proliferation of and synthesis of extracellular matris by fibroblasts and smooth muscle cells

 

• AGEs are believed to be central to both macrovascular pathogenesis and microvascular pathology of diabetes

 

 

2) Activation of PKC

• Intracellular hyperglycaemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and cause activation of PKC
• The downstream affects of PKC are;
• Production of VEGF, implicated in the neovascularisation characterising diabetic retinopathy
• Increased activity of the vasoconstrictor endothelin-1 and decreased activity of the vasodilator Nitric oxide synthase
• Production of profibrinogenic molecule such as TGF-β leading to increased ECM deposition and basement membrane
• Production of the procoagulant plasminogen activator inhibitor-1 (PAI-1) leading to reduced fibrinolysis and possible vascular occlusive episodes
• Production of pro-inflammatory cytokines by the endothelium

 

3) Intracellular hyperglycaemia with disturbances in polyol pathways

• In some tissues that don’t require insulin for glucose transport, hyperglycaemia leads to an increase in intracellular glucose that is metabolised by the enzyme aldoreductase to sorbitol, a polyl and eventually to fructose
• NADPH is a cofactor in this reaction
• NADPH is also required as a cofactor for the enzyme glutathionine reductase that is required to make glutathione an antioxidant
• The cell is therefore more susceptible to oxidative stress

 

Morphology of diabetes and its late complications

 

Diabetic macrovascular disease

• Hallmark is accelerated atherosclerosis, involving the aorta, large and medium sized arteries
• The most common cause of death in diabetes is MI caused by atherosclerosis of the coronary arteries
• Gangrene of the lower extremities is 100 times more common than in the general population
• The large renal vessels are also subject to atherosclerosis
• Hyaline arteriolosclerosis, the vascular lesion associated with hypertension, is more prevalent and more severe in diabetics
• It causes a amorphous hyaline thickening of the walls of the arterioles resulting in lumen narrowing

 

Diabetic microvascular disease

• Diffuse thickening of the basement membrane by hyaline material composed predominantly of type IV collagen
• Seen in the capillaries of the skin, skeletal muscle, retina, renal glomeruli and renal medulla
• It is also seen in nonvascular structures such as the renal tubules, Bowmans capsule, peripheral nerves and placenta
• Despite the increased thickness of the basement membrane the capillaries are leakier
• The microangiopathy underlies diabetic nephropathy, retinopathy and some forms of neuropathy

 

Diabetic nephropathy

• Three lesions are encountered;
  • Glomerular lesions
    • Glomerular basement membrane thickening throughout the entire length
    • Diffuse mesangial sclerosis – diffuse increase in mesangial matrix
    • Nodular glomerulosclerosis – glomerular lesions with ball like deposits of laminated matrix situated in the periphery of the glomerulus. This change is called the Kimmelstiel-Wilson lesion
  • Renal vascular lesions principally arteriolosclerosis
    • Hyaline arteriolosclerosis affects not only the afferent but also the efferent arteriole
  • Pyelonephritis
    • An acute or chronic inflammation that usually begins in the interstitium and then spreads to affect the tubules. Occurs in nondiabetics but less commonly
    • One pattern of acute pyelonephritis more common in diabetics is papillary necrosis

 

Diabetic retinopathy

• The retinal vasculopathy of diabetes can be classified into;
  • Background diabetic retinopathy
  • Proliferative diabetic retinopathy
• Background diabetic retinopathy includes a spectrum of changes ranging from structural and functional abnormalities of angiogenesis within the retina
  • The basement membrane of retinal blood vessels becomes thickened and the number of pericytes relative to endothelial cells diminishes
  • Microaneurysms may develop
  • The vessels may become leaky resulting in macular oedema and are subject to micro-occlusion
  • Non perfusion of the retina due to microcirculatory change is associated with upregulation of VEGF and retinal angiogenesis
• Proliferative diabetic retinopathy is defined by the appearance of new vessels that sprout from existing vessels on the surface of either the optic nerve head or on the surface of the retina
  • This may result in haemorrhage, wrinkling of the retina causing visual distortion, or may exert traction on the retina causing detachment
  • Retinal neovascularisation may be accompanied by neovascularisation of the iris. Contraction of the iris may lead to adhesions between between the iris and trabecular meshwork, thus occluding aqueous outflow and increasing intraocular pressure – neovascular glaucoma

 

Diabetic neuropathy

• 50% of diabetics have clinical peripheral neuropathy after 25 years of disease and 100% have electrophysiological abnormalities
• Several clinicopathological patterns of diabetes-related peripheral nerve abnormalities have been categorised;
  • Distal symmetrical sensory or sensorimotor neuropathy
  • Autonomic neuropathy
  • Focal or multifocal asymmetric neuropathy
• These may occur in any combination and sensory and autonomic are more likely to occur together
• Pathogenesis is thought to involve vascular insufficiency creating ischaemic injury of the peripheral nerve

 

Morphology

• Predominant pathological finding is axonal neuropathy
• There is often some segmental demyelination
• There is a relative loss of small myelinated fibres and unmyelinated fibres but larger fibres are also affected
• Endoneural arterioles show thickening, hyalinisation and thickening of the basement membrane
• Whether the lesions are due to ischaemia or metabolic derangement is unclear

 

This entry was posted on Sunday, February 10th, 2008 at 12:47 pm and is filed under Cardiovascular. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.