Prog Retin Eye Res. 2014 Jul;41:90-111.

Phenotypes and biomarkers of diabetic retinopathy.

Cunha-Vaz J1, Ribeiro L2, Lobo C3.
  • 1Association for Innovation and Biomedical Research on Light and Image (AIBILI), Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Polo III, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address:
  • 2Association for Innovation and Biomedical Research on Light and Image (AIBILI), Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Polo III, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address:
  • 3Association for Innovation and Biomedical Research on Light and Image (AIBILI), Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Polo III, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address:



Diabetic retinopathy (DR) remains a major cause of blindness as the prevalence of diabetes is expected to approximately double globally between 2000 and 2030. DR progresses over time at different rates in different individuals with only a limited number developing significant vision loss due to the two major vision-threatening complications, clinically significant macular edema and proliferative retinopathy. Good metabolic control is important to prevent and delay progression, but whereas some patients escape vision loss even with poor control, others develop vision loss despite good metabolic control. Our research group has been able to identify three different DR phenotypes characterized by different dominant retinal alterations and different risks of progression to vision-threatening complications. Microaneurysm turnover has been validated as a prognostic biomarker of development of clinically significant macular edema, whereas subclinical macular edema identified by OCT and mfERG appear to be also good candidates as organ-specific biomarkers of DR. Hemoglobin A1c remains the only confirmed systemic prognostic biomarker of DR progression. The availability of biomarkers of DR progression and the identification of different phenotypes of DR with different risks for development of vision-threatening complications offers new perspectives for understanding DR and for its personalized management.

KEYWORDS: Biomarkers; Diabetic retinopathy; Macular edema; Microaneurysm; Optical coherence tomography; Phenotypes

PMID: 24680929



Microaneurysm turnover on fundus photographs, taking into account their exact, specific location in the eye fundus using the RetmarkerDR a software that performs automated analysis of fundus photographs has been shown to be a biomarker of the overall progression of diabetic retinal vascular disease and development of diabetic macular edema (Nunes et al, 2013).


Figure 1. The Retmarker Software automatically calculates microaneurysm formation and disappearance rates. Microaneurysm turnover is the sum of both.


Reduction in macular thickening by measuring the changes in retinal thickness with optical coherence tomography, is another promising biomarker. The measurements are reliable, and changes in retinal thickness are a direct indication of macular edema and breakdown of the blood-retinal barrier (Hee et al, 1998; Bernardes et al, 2011).

Duration of diabetes and level of metabolic control are major risk factors for development of diabetic retinopathy, but, these risk factors do not explain the great variability that characterize the evolution and rate of progression of the retinopathy in different diabetic individuals. There are many diabetic patients who after many years with diabetes never develop sight- threatening retinal changes, maintaining good visual acuity. There are also other patients that even after only a few years of diabetes show a retinopathy that progresses rapidly and may not even respond to available treatment.

We were able to identify three major patterns of diabetic retinopathy progression during a follow-up period of 3 years: Pattern A including eyes presenting slow progressing retinal disease. Pattern B including eyes with persistently high leakage values, indicating an important alteration of the blood-retinal barrier and the presence of retinal edema. This group was identified as a ‘‘wet’’ form of diabetic retinopathy. Pattern C including eyes with active remodelling of the retinal microcirculation with signs of capillary closure identified as an ischemic form (Lobo et al, 2004).

In a recent two-year prospective, observational study of eyes/patients with mild nonproliferative diabetic retinopathy (ETDRS grades 20 and 35) using non-invasive examination procedures, color fundus photography and OCT, and involving 376 eyes/patients we have been able to confirm these three major phenotypes of retinopathy progression. The development of clinically significant macular edema occurred in the period of two years of the study follow-up mainly in phenotypes B and C, with higher incidence on phenotype C.

Looking at DR and the identification of three major phenotypes allows an integrated perspective of DR progression. Chronic hyperglycemia induces generalized cell damage to the retina involving the entire retinal neurovascular unit, but causing different degrees of damage in different cells in different individuals. Some patients develop generalized low-grade vascular, neuronal and glial damage which manifests as a slow progressing neuropathy and slow progressing vascular damage (phenotype A). Other patients develop breakdown of the blood-retinal barrier with resulting retinal edema, apparently associated with an active inflammatory repair process (phenotype B). Finally, another group of patients, possibly due to specific genetic characteristics, shows signs of active microvascular disease, and more rapid progression to vision-threatening complications (phenotype C) (Simões et al, 2014).

Our observations and the identification of different diabetic retinopathy phenotypes in the initial stages of diabetic retinopathy, i.e., mild or moderate nonproliferative diabetic retinopathy, characterized by different rates of progression of the retinopathy suggest that specific approaches should be used when managing these different retinopathy phenotypes (Table 1).


Table 1. Management recommendations for nonproliferative diabetic retinopathy in the absence of clinically significant macular edema.


A patient with mild or moderate nonproliferative diabetic retinopathy, presenting retinopathy phenotype B (wet/leaky), characterized by marked breakdown of the blood-retinal barrier, registered during a period of 1–2 years of follow-up, indicating rapid retinopathy progression, should be watched more closely and examined at least at 6 months intervals.

A patient with mild or moderate nonproliferative diabetic retinopathy presenting retinopathy phenotype C, with ischemic characteristics identified by high microaneurysm formation rates would similarly indicate the need for shorter observation intervals than one year with particular attention for other systemic signs of microthrombosis. Here, however, control of hyperglycemia and blood pressure must be addressed with some degree of caution. Improved metabolic and blood pressure control must be progressive and less aggressive than with phenotype B. It is realized that the ischemia that characterizes phenotype C may become even more apparent in eyes submitted to rapid changes in metabolic control and lowering rapidly the blood pressure may increase the retinal damage associated with ischemia. Finally, a patient with mild or moderate nonproliferative diabetic retinopathy, presenting phenotype A, identified by low levels of alteration of blood-retinal barrier, no signs of capillary closure, low microaneurysm formation rates and with a diabetes duration of more than 10 years, all signs indicating a slowly progression subtype of diabetic retinopathy may be followed at intervals longer than one year.

It is also clear now that only a subset of patients with diabetes who develop some form of retinopathy is expected to loose functional vision during their lifetime. Identification of risk factors to progression to visual loss, precise calculations of risk for progression to visual impairment in individual patients over given time periods appear, finally, to be crucial steps in the decision process of whom to treat, when to initiate treatment and how rigorously.

The continuum of diabetic retinopathy progression may be represented as depicted in figure 1, taking into consideration the three proposed diabetic retinopathy phenotypes: slow progression, “wet”/leaky and ischemic. Different diabetic patients with retinal disease have clearly different rates of progression and these must be identified and taken into account.



Figure 2. Continuum of the progression of diabetic retinopathy.

BRB: Blood-Retinal Barrier; OCT: Optical Coherence Tomography; CSME: Clinically Significant macular Edema


An algorithm that would allow ophthalmologists to take into account a patient’s microaneurysm turnover, retinal thickness progression and HbA1C levels, that is, a so-called “risk calculator”, to estimate the risk of visual impairment for a specific diabetic patient would certainly help in determining appropriate treatment for individual patients.

If the patients with the greatest risk of progression and with the greatest potential to benefit from treatment can be identified by multivariate risk assessment, fewer patients will need to be treated to prevent one case of blindness. This is of extreme importance at a time where scarce resources must be focused and concentrated on the individual cases that need close follow-up and timely treatment.



  1. Nunes, S., Ribeiro, L., Lobo, C., Cunha-Vaz, J., 2013. Three different phenotypes of mild nonproliferative diabetic retinopathy with different risks for development of clinically significant macular edema. Invest. Ophthalmol. Vis. Sci. 54(7), 4595-4604.
  2. Hee MR, Puliafito CA, Wong C, Duker JS,   Reichel E, Rutledge B, Coker JG,   Wilkins JR, Schuman JS,   Swanson EA, Fujimoto JG. (1998) Topography of diabetic macular edema with optical coherence tomography. Ophthalmology 105(2):360-370.
  3. Bernardes R, Santos T, Serranho P, Lobo C, Cunha-Vaz J. (2011) Noninvasive evaluation of retinal leakage using OCT. Ophthalmologica 226:29-36.
  4. Lobo CL, Bernardes RC, Figueira JP, Faria de Abreu JR, Cunha-Vaz JG. (2004) Three-year follow-up of blood–retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative diabetic retinopathy. Arch Ophthalmol 122:211–217.
  5. Simões MJ, Lobo C, Egas C, Nunes S, Carmona S, Costa MA, Duarte T, Ribeiro L, Faro C, Cunha-Vaz J. (2014) Genetic Variantes in ICAM1, PPARGC1A and MTHFR Are Potentially Associated with Different Phenotypes of Diabetic Retinopathy. Ophthalmologica 232:156-162.




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