Microaneurysms are, as the name suggests, small saccular outpouchings
that involve capillaries of many vascular districts such as the heart, kidney
and eye. Ophthalmologists know that although they occur in several pathologic
conditions such as hypertension, venous occlusion and hemorheologic diseases,
including methemoglobinemia and sickle-cell disease, they are the hallmark of
Their existence has been documented since 1879, but the firm
relationship with diabetes was first described by Ballantyne and Loewenstein in
Their importance is underscored by the fact that they are the first
clinically evident sign of diabetic nonproliferative eye disease, so the
recognition of microaneurysms can be the first step in secondary prevention of
diabetic retinopathy progression to the proliferative stage and consequent
severe visual loss.
Mechanism of formation
Ophthalmological clinical examination reveals that microaneurysms are
small circular deep-red dots in the fundus. They must be differentiated from
punctate hemorrhages also seen in diabetic retinopathy. Fluorescein angiography
can aid differential diagnosis. It reveals microaneurysms as hyperfluorescent
dots, which may be accompanied by focal leakage of the dye. Spectral-domain
optical coherence tomography also shows microaneurysms as round or oval
well-demarcated intraretinal hyperreflective lesions.
The mechanism for the formation of microaneurysms is not completely
understood. It is known that diabetes is characterized by vessel basement
membrane thickening and selective degeneration with pericyte loss, which leads
to local structural weakness in the vessel wall with subsequent dilatation and,
as secondary effect, focal vascular endothelial cell proliferation.
However, histological findings show that aneurysms can be hypercellular,
thin-walled or hypocellular, which suggests that either or both mechanisms
described may be involved. Moreover, a small number of microaneurysms arise as
a result of capillaries forming U-shaped loops with resultant disappearance of
the adjacent walls.
Diabetic retinopathy development
Based on several studies that investigated the pathogenesis of the
initial phases of diabetic retinopathy, loss of pericytes is the most important
factor, along with change of hydrostatic pressure and impaired tissue
oxygenation. A molecular view of this process reveals that chronic
hyperglycemia leads to glycation of retinal capillary basement membrane and
formation of toxic products such as sorbitol or advanced glycation end
products. This results in decreased adhesion and proliferation inhibition of
It is also important to stress that researchers now better understand
the role of some molecules in early stages of diabetes. For example, we know
that endothelial cell mitogens such as VEGF may promote endothelial cell
proliferation, and intravitreal administration of VEGF to primates results in
the development of retinal microaneurysms, as suggested by Tolentino and
Tumor necrosis factor alpha (TNF-á), one of the major
pro-inflammatory cytokines in diabetic retinopathy, plays a large role in
endothelial cell injury and apoptosis during diabetes. Studies have shown that
TNF-á antagonists inhibit diabetic apoptosis.
Finally, the overexpression of Bcl-2, an anti-apoptotic protein, in
vascular endothelium inhibits both early-stage capillary degeneration and
Microaneurysm size, type
Thanks to histological studies, today we know that microaneurysms are
often found in close association with focal areas of capillary nonperfusion,
the majority of which originate in the inner layers of the retina and are
characterized by pericyte loss.
Most commonly, a mean of two vessels are associated with microaneurysms.
However, as many as five associated vessels can be seen in small
microaneurysms; the larger the microaneurysm, the fewer associated vessels.
Microaneurysm size ranges from 14 ìm to 136 ìm.
Ultrastructural examination enabled Stitt and colleagues to differentiate four
arbitrary stages of microaneurysm formation. Type 1 is the only type with
intact endothelium and is characterized by a slightly thickened basement
membrane and leucocytes and monocytes that occlude the lumen. Type 2 shows
dense aggregates of intact red blood cells and some macrophages in the lumen
with a thickened and laminated basement membrane. Type 3 is similar to type 2
but with red blood cell breakdown products visible in the lumen. In type 4
microaneurysms, dense walls of thickened basement membrane with lumen expansion
and macrophages can be found.
Moore and colleagues classified three categories of microaneurysm
according to morphology: saccular, fusiform and focal bulges.
Since the first studies on diabetic lesions, microaneurysm behavior has
been found to be singular and erratic. Microaneurysms appear and disappear in
the same area over time, known as turnover. Hypotheses have been made to
understand the underlying mechanisms; it seems likely that the occlusion of the
feeding capillary or complete obliteration of the lumen could be responsible
for ultimate microaneurysm disappearance. On the other hand, the recanalization
of a microaneurysm can result in its reappearance. This behavior reflects the
trend of systemic factors such as the hyperglycemia, hemorheologic and
fibrinolytic properties of blood.
Some authors have studied the appearance and disappearance rates of
microaneurysms with fundus photography, fluorescein angiography and automated
measurements. It was found that the overall number of microaneurysms remains
approximately constant, with a disappearance rate of 40% to 80% per year, and
that the formation rate is inversely correlated with duration of diabetes and
directly correlated with HbA1c values.
Chen and colleagues found that every 10% increase in HbA1c (eg, from
8.1% to 9%) is associated with an increase of 0.7 microaneurysms. Either
turnover or absolute count of microaneurysms is strictly related to later
diabetes complications (eg, macular edema and proliferative retinopathy). The
turnover value provides information about a dynamic process, while absolute
count has a static meaning, so together they can be a predictive factor for
disease progression and reflect the severity of diabetic retinopathy.
An additional clinically significant risk factor for microaneurysm
formation is increased waist circumference, even more so than body mass index.
The excess abdominal adipose tissue could cause hypercoagulability, endothelial
cell dysfunction and atherosclerosis, influencing microaneurysm development
Worldly wisdom teaches that prevention is better than cure.
No phrase could be more appropriate in diabetes treatment. The importance of
patient education, together with early detection and specific research, could
reduce the burden of blindness and low vision affecting so many working-age
people in developed countries. Strategies to find, quantify and treat the
earliest retinopathy lesions such as microaneurysms should be further
- Aguilar E, Friedlander M, Gariano RF. Endothelial proliferation in
diabetic retinal microaneurysms. Arch Ophthalmol.
- Beltramo E, Pomero F, Allione A, DAlù F, Ponte E,
Porta M. Pericyte adhesion is impaired on extracellular matrix produced by
endothelial cells in high hexose concentrations. Diabetologia.
- Chen SJ, Chou P, Lee AF, et al. Microaneurysm number and
distribution in the macula of Chinese type 2 diabetics with early diabetic
retinopathy: a population-based study in Kinmen, Taiwan. Acta
- Frank RN. Etiologic mechanisms in diabetic retinopathy. In: Ryan
SJ, ed. Retina. St. Louis: Mosby; 2001:1259-1284.
- Fryczkowski AW, Chambers RB, Craig EJ, Walker J, Davidorf FH.
Scanning electron microscopic study of microaneurysms in the diabetic retina.
Ann Ophthalmol. 1991;23(4):130-136.
- Goatman KA, Cree MJ, Olson JA, Forrester JV, Sharp PF. Automated
measurement of microaneurysm turnover. Invest Ophthalmol Vis Sci.
- Hellstedt T, Immonen I. Disappearance and formation rates of
microaneurysms in early diabetic retinopathy. Br J Ophthalmol.
- Joussen AM, Doehmen S, Le ML, et al. TNF-alpha mediated apoptosis
plays an important role in the development of early diabetic retinopathy and
long-term histopathological alterations. Mol Vis.
- Kern TS, Du Y, Miller CM, Hatala DA, Levin LA. Overexpression of
Bcl-2 in vascular endothelium inhibits the microvascular lesions of diabetic
retinopathy. Am J Pathol. 2010;176(5):2550-2558.
- Kohner EM, Dollery CT. The rate of formation and disappearance of
microaneurysms in diabetic retinopathy. Trans Ophthalmol Soc UK.
- Kohner EM, Sleightholm M. Does microaneurysm count reflect severity
of early diabetic retinopathy? Ophthalmology.
- Kohner EM, Stratton IM, Aldington SJ, et al. Microaneurysms in the
development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study
Group. Diabetologia. 1999;42(9):1107-1112.
- Microaneurysms in diabetic retinopathy. Br Med J.
- Moore J, Bagley S, Ireland G, McLeod D, Boulton ME. Three
dimensional analysis of microaneurysms in the human diabetic retina. J
Anat. 1999;194(Pt 1):89-100.
- Sjølie AK, Klein R, Porta M, et al. Retinal microaneurysm
count predicts progression and regression of diabetic retinopathy. Post-hoc
results from the DIRECT Programme. Diabet Med.
- Stitt AW, Gardiner TA, Archer DB. Histological and ultrastructural
investigation of retinal microaneurysm development in diabetic patients.
Br J Ophthalmol. 1995;79(4):362-367.
- Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous
injections of vascular endothelial growth factor produce retinal ischemia and
microangiopathy in an adult primate. Ophthalmology.
- Daniele Veritti, MD, can be reached at the Department of
Ophthalmology, University of Udine, p.le S. Maria della Misericordia, 33100
Udine, Italy 33100; +39-0432-559907; email:
- Disclosures: Drs. Veritti and Macor have no relevant financial