Microaneurysms key in detecting diabetic retinopathy

Close examination of microaneurysms can reveal important information about retinal disease.
Daniele Veritti, MD
Daniele Veritti

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 diabetic retinopathy.

Their existence has been documented since 1879, but the firm relationship with diabetes was first described by Ballantyne and Loewenstein in 1943.

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 pericyte.

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 colleagues.

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 oxidative stress.

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.

Turnover

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 rate.

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 investigated.

References:

  • Aguilar E, Friedlander M, Gariano RF. Endothelial proliferation in diabetic retinal microaneurysms. Arch Ophthalmol. 2003;121(5):740-741.
  • Beltramo E, Pomero F, Allione A, D’Alù F, Ponte E, Porta M. Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations. Diabetologia. 2002;45(3):416-419.
  • 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 Diabetol. 2010;47(1):35-41.
  • 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. 2003;44(12):5335-5341.
  • Hellstedt T, Immonen I. Disappearance and formation rates of microaneurysms in early diabetic retinopathy. Br J Ophthalmol. 1996;80(2):135-139.
  • 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. 2009;15:1418-1428.
  • 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. 1970;90:369-374.
  • Kohner EM, Sleightholm M. Does microaneurysm count reflect severity of early diabetic retinopathy? Ophthalmology. 1986;93(5):586-589.
  • 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. 1971;3(5774):548-549.
  • 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. 2011;28(3):345-351.
  • 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. 1996;103(11):1820-1828.

  • 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: verittidaniele@gmail.com.
  • Disclosures: Drs. Veritti and Macor have no relevant financial disclosures.
Daniele Veritti, MD
Daniele Veritti

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 diabetic retinopathy.

Their existence has been documented since 1879, but the firm relationship with diabetes was first described by Ballantyne and Loewenstein in 1943.

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 pericyte.

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 colleagues.

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 oxidative stress.

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.

Turnover

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 rate.

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 investigated.

References:

  • Aguilar E, Friedlander M, Gariano RF. Endothelial proliferation in diabetic retinal microaneurysms. Arch Ophthalmol. 2003;121(5):740-741.
  • Beltramo E, Pomero F, Allione A, D’Alù F, Ponte E, Porta M. Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations. Diabetologia. 2002;45(3):416-419.
  • 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 Diabetol. 2010;47(1):35-41.
  • 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. 2003;44(12):5335-5341.
  • Hellstedt T, Immonen I. Disappearance and formation rates of microaneurysms in early diabetic retinopathy. Br J Ophthalmol. 1996;80(2):135-139.
  • 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. 2009;15:1418-1428.
  • 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. 1970;90:369-374.
  • Kohner EM, Sleightholm M. Does microaneurysm count reflect severity of early diabetic retinopathy? Ophthalmology. 1986;93(5):586-589.
  • 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. 1971;3(5774):548-549.
  • 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. 2011;28(3):345-351.
  • 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. 1996;103(11):1820-1828.

  • 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: verittidaniele@gmail.com.
  • Disclosures: Drs. Veritti and Macor have no relevant financial disclosures.