Aetiology
The cause is unknown, but several aetiological factors have been suggested. Most lesions are probably acquired as a result of a degenerative process associated with ageing, with two-thirds of patients being >70 years of age.[12]
The following factors have been associated with increased risk for, or higher frequency of, angiodysplasia:
Chronic renal failure/end-stage renal disease: in patients with chronic renal failure, angiodysplasia is responsible for 19% to 32% of lower gastrointestinal bleeding episodes, compared with 5% to 6% episodes in the general population.[4] Increased risk of bleeding may be attributed to uraemic platelet dysfunction, use of anticoagulants, or reduced production of erythropoietin.[4] An increased prevalence of angiodysplasia is observed in patients undergoing dialysis and is a common cause of gastrointestinal bleeding in this group.[13][14][15]
Gastrointestinal bleeding: can be severe and multi-focal and is a common cause of hospitalisation.[16][17] Lower gastrointestinal bleeding is defined as bleeding distal to the ileocaecal valve and throughout the colon.[18] Small bowel or midgut gastrointestinal bleeding is defined as bleeding occurring between the ligament of Treitz and the ileocaecal valve and accounts to around 5% to 10% of gastrointestinal bleeding episodes.[8][18]
Aortic stenosis: Heyde's syndrome is characterised by gastrointestinal bleeding from angiodysplasia in the presence of aortic stenosis.[19] One large epidemiological study found a significant association between aortic stenosis and gastrointestinal bleeding presumed due to intestinal angiodysplasia.[20] Prevalence of patients with both aortic stenosis and gastrointestinal bleeding was low, which may have precluded smaller studies finding a significant association.[20] Classically, angiodysplasia is located in the ascending colon, while that associated with Heyde's syndrome is predominantly located in the small intestine.[19] One meta-analysis reported cessation of bleeding after valve replacement.[21]
Scleroderma: gastrointestinal mucosal abnormalities, including gastric and/or small intestinal angiodysplasia and gastric and/or small intestinal telangiectasia, were reported in 52% of patients with systemic sclerosis in one study.[22]
Cardiovascular disease: an important risk factor for the diagnosis of angiodysplasia.[23] In one small cohort study, a significant association was found between hypertension and small bowel angiodysplasia.[24]
Increasing age: one systematic review found that increasing age was a risk factor for the diagnosis of angiodysplasia.[23] Two retrospective studies found that age greater than 80 years was an independent risk factor for symptomatic angiodysplasia of the colon.[25][26]
Advanced age, cardiovascular disease, receiving anticoagulants, multiple lesions, and small lesions have been recognised as significant risk factors for active bleeding.[25]
Pathophysiology
Angiodysplasia can occur throughout the gastrointestinal tract, but it is predominantly located in the proximal colon (77%), followed by the jejunum and ileum (15%) and transverse colon. Angiodysplasia associated with Heyde's syndrome is predominantly located in the small intestine.[19] Histologically, the lesions comprise clusters of dilated vessels, mostly veins, in the mucosa and sub-mucosa of the caecum and ascending colon.[27] The affected vessels are lined with endothelium alone with little or no smooth muscle.[4]
Little is known about the exact mechanism of disease development. One theory is that with ageing comes an associated weakening of the vessel wall. It has been hypothesised that because of increased contractility at the level of muscularis propria, submucosal veins may get obstructed with age. Chronic low-grade obstruction of vessels results in hypoxia. This can induce neovascular growth factors, generating new, abnormal blood vessels.[9] Moreover, capillary congestion and pre-capillary sphincter failure may result in the formation of small arteriovenous collaterals.[4][28] Another theory draws on the predominance of angiodysplasia within the right colon, suggesting that repeated episodes of high intraluminal pressures in this area lead to increased mural tension, obstructing sub-mucosal venous blood flow. The chronic dilation of the sub-mucosal veins eventually leads to dilation of the venules and arteriolar capillary units feeding them, resulting in arteriovenous shunting.[29]
Angiogenesis, the process of new blood vessel formation, has also been implicated.[4][30] In hypoxia or ischaemia, tissue vascularity increases and a higher expression of vascular endothelial growth factor (VEGF) is seen. In angiodysplasia, a similar increase in the expression of angiogenic factors (VEGF and basic fibroblast growth factor) is observed; these angiogenic factors may be involved in the formation of angiodysplasia lesions as well as in modifying the risk of bleeding.[4] Anti-angiogenic drugs such as thalidomide target this pathway.
Heyde's syndrome, a syndrome of aortic valve stenosis and colonic angiodysplasia, has predominantly been attributed to acquired von Willebrand's disease, but the absence of von Willebrand's disease does not rule out the diagnosis of Heyde's syndrome. In Heyde’s syndrome, acquired von Willebrand syndrome type 2A occurs. Eighty percent of patients with aortic stenosis have acquired von Willebrand syndrome. von Willebrand's factor is produced in endothelial cells and undergoes proteolysis in plasma. High molecular weight multimers are haemostatically active. In aortic stenosis, high shear stress around the stenotic valve causes excess proteolysis of von Willebrand's factor and high molecular weight multimers, resulting in bleeding diathesis.[21] Acquired von Willebrand syndrome promotes angiogenesis, resulting in angiodysplasia.[19]
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