Retinal vascular manifestations of metabolic disorders

doi:10.1016/j.tem.2006.07.006

Trends in Endocrinology & Metabolism

Volume 17, Issue 7, September 2006, Pages 262-268

https://doi.org/10.1016/j.tem.2006.07.006 Get rights and content

Metabolic diseases have profound effects on the structure and function of the retinal circulation. The recent development of retinal photography and digital imaging has enabled more precise documentation of diabetic retinopathy, as well as other retinal microvascular changes, such as retinal arteriolar narrowing, venular dilation and isolated retinopathy signs in nondiabetic individuals. These retinal microvascular signs have been shown to be associated with long-term risks of type 2 diabetes and hypertension, components of the metabolic syndrome (e.g. obesity, dyslipidemia), and a range of macro- and micro-vascular conditions (e.g. stroke, cardiovascular mortality). There is evidence that endothelial dysfunction and inflammation might be possible mechanisms involved in the development of various retinal microvascular changes in patients with diabetes, hypertension and other metabolic disorders. Further understanding of how these processes influence the retinal vasculature might help to elucidate the diverse vascular manifestations of metabolic diseases.

Introduction

The retinal vasculature is unique, in that it is the only part of the human circulation that can be directly visualized noninvasively, thus offering an opportunity to examine the effects of various systemic and metabolic diseases on the microcirculation. In the past decade, the development of retinal photographic techniques, including high-resolution digital imaging, has enabled accurate and reproducible assessment of subtle retinal vascular changes (e.g. changes in retinal vascular caliber, isolated retinopathy lesions). Recent population-based studies using these photographic methods have provided new understanding of the associations and clinical significance of retinal vascular changes in metabolic diseases, including diabetes, hypertension and the metabolic syndrome. It has now become evident that these retinal vascular changes might be markers of the early preclinical stages of these metabolic disorders and might predict the onset of clinical disease. The purpose of this review is to summarize recent studies on the retinal vascular manifestations seen in diabetes, obesity, hypertension, the metabolic syndrome and dyslipidemia (Table 1); to explore possible underlying mechanisms; and to examine the research and clinical implications of these new associations.

Section snippets

Retinal vascular manifestations in diabetes

In individuals with diabetes, the primary retinal vascular complication, diabetic retinopathy, is well known and extensively described. Diabetic retinopathy is the leading cause of blindness among persons aged 20–64 years in the USA [1]. Additionally, diabetes has been linked to the development of several retinal vascular conditions, including retinal vein occlusion, retinal arteriolar emboli, retinal artery occlusion and the ocular ischemic syndrome [2] (Table 1).

Diabetic retinopathy, broadly

Retinal vascular manifestations in obesity

In contrast to diabetes, the retinal vascular manifestations of obesity are less well appreciated. There is evidence that obesity is a risk factor for the development of retinopathy signs in people with and without clinical diabetes. There are reports of a positive correlation between obesity and retinopathy in type 1 diabetes from the DCCT [28], the EURODIAB Prospective Complications studies [29], the Diabetes Incidence Study in Sweden [30] and the World Health Organization (WHO) Multinational

Retinal vascular manifestations in dyslipidemia

There is good evidence from epidemiological studies that elevated serum lipid levels are associated with the development of hard exudates and macular edema in diabetic patients 29, 38, 39, and in clinical trials lipid-lowering therapy has been found to reduce the requirement for laser treatment in patients with retinopathy [9].

There are fewer data regarding the retinal vascular effects of dyslipidemia in people without diabetes. Data from studies in the general population have shown that

Retinal vascular manifestations in impaired glucose metabolism

There is increasing recognition that typical lesions of diabetic retinopathy (microaneurysms and hemorrhages) are commonly seen in individuals without clinically diagnosed diabetes. Studies have shown that signs of retinopathy can be detected from photographs in up to 14% of the general adult population aged 40 years and older [41]. Prospective data from the Beaver Dam Eye Study and Blue Mountains Eye Study further show that 6–10% of nondiabetic persons over the age of 40 years develop some

Retinal vascular manifestations in metabolic syndrome

The diagnosis of metabolic syndrome has been outlined by the WHO, the American Association of Clinical Endocrinologists (AACE) and the Adult Treatment Panel III report of the National Cholesterol Education Program (ATP III) [48]. According to ATP III, a diagnosis of metabolic syndrome can be made when three of five characteristics are present: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol, high blood pressure and IFG. Demonstration of insulin resistance

Retinal vascular manifestations in hypertension

The primary retinal manifestation of hypertension is a spectrum of clinical signs known as hypertensive retinopathy. These signs include generalized and focal arteriolar narrowing, arteriovenous nicking, flame- and blot-shaped retinal hemorrhages, cotton-wool spots and optic disc swelling [49]. These signs were categorized into four grades of increasing severity by Keith et al. [50] in 1939. There are several limitations with this traditional classification, including the difficulty in

Endothelial dysfunction and inflammation as mechanisms of retinal vascular changes

Endothelial dysfunction and inflammation have been hypothesized as key mechanisms that contribute to the development of diabetes and its vascular complications. Studies have demonstrated abnormal microvascular reactivity and flow in the skin, and increased markers of endothelial dysfunction (e.g. E-selectin and intercellular adhesion molecules) and inflammation (CRP) in persons with diabetes [69] and in those at risk of diabetes, such as persons with insulin resistance [70], obese individuals 34

Future research and conclusions

There are several potential areas for future research. First, objective quantitative measurement of the retinal vasculature using new photographic imaging technology has improved the understanding of the associations of various metabolic diseases with cardiovascular factors and microvascular processes. There is increasing evidence that generalized arteriolar narrowing seen in the retina might be a preclinical marker of hypertension. However, larger venular diameters appear to predict IFG, and

Acknowledgements

Funding was provided by the National Health and Medical Research Council, Australia (Grant No 350448), the Science Technology Innovation Grant, Victoria and the Sylvia and Charles Viertel Clinical Investigator Award (TYW).

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Cited by (144)

A Datasheet for the INSIGHT Birmingham, Solihull, and Black Country Diabetic Retinopathy Screening Dataset
2023, Ophthalmology Science
Diabetic retinopathy (DR) is the most common microvascular complication associated with diabetes mellitus (DM), affecting approximately 40% of this patient population. Early detection of DR is vital to ensure monitoring of disease progression and prompt sight saving treatments as required. This article describes the data contained within the INSIGHT Birmingham, Solihull, and Black Country Diabetic Retinopathy Dataset.
Dataset descriptor for routinely collected eye screening data.
All diabetic patients aged 12 years and older, attending annual digital retinal photography-based screening within the Birmingham, Solihull, and Black Country Eye Screening Programme.
The INSIGHT Health Data Research Hub for Eye Health is a National Health Service (NHS)–led ophthalmic bioresource that provides researchers with safe access to anonymized, routinely collected data from contributing NHS hospitals to advance research for patient benefit. This report describes the INSIGHT Birmingham, Solihull, and Black Country DR Screening Dataset, a dataset of anonymized images and linked screening data derived from the United Kingdom’s largest regional DR screening program.
This dataset consists of routinely collected data from the eye screening program. The data primarily include retinal photographs with the associated DR grading data. Additional data such as corresponding demographic details, information regarding patients’ diabetic status, and visual acuity data are also available. Further details regarding available data points are available in the supplementary information, in addition to the INSIGHT webpage included below.
At the time point of this analysis (December 31, 2019), the dataset comprised 6 202 161 images from 246 180 patients, with a dataset inception date of January 1, 2007. The dataset includes 1 360 547 grading episodes between R0M0 and R3M1.
This dataset descriptor article summarizes the content of the dataset, how it has been curated, and what its potential uses are. Data are available through a structured application process for research studies that support discovery, clinical evidence analyses, and innovation in artificial intelligence technologies for patient benefit. Further information regarding the data repository and contact details can be found at https://www.insight.hdrhub.org/.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Associations between body mass index and choroidal thickness, superficial and deep retinal vascular indices, and foveal avascular zone measured by OCTA
2023, Photodiagnosis and Photodynamic Therapy
The present study explores the effects of Body Mass Index (BMI) on choroidal thickness, the deep and superficial retinal capillary plexuses, and the foveal avascular zone (FAZ).
The subjects in this prospective study were divided into five groups based on their calculated BMI. Choroidal thickness, superficial and deep retinal capillary plexuses, and FAZ were measured using enhance depth imaging (EDI) and optical coherence tomography angiography (OCTA). The groups were then compared and correlations with BMI were evaluated.
The study included 210 eyes of 105 subjects. The comparison of the BMI groups revealed a significant decrease in the mean choroidal thicknesses in the obese groups (p = 0.001), and a significant negative correlation between BMI and mean choroidal thickness (p = 0.02). The results of the analysis of the mean superficial and deep retinal capillary plexuses did not differ between the groups (p = 0.089, p = 0.808 respectively), while the deep FAZ measurements revealed a significant decrease in the obese groups (p = 0.003).
Choroidal thickness and deep FAZ are significantly negatively correlated with BMI, suggesting potential choroidal and retinal microvascular effects of obesity.
Severity of Diabetic Retinopathy and the Risk of Future Cerebrovascular Disease, Cardiovascular Disease, and All-Cause Mortality
2021, Ophthalmology
To determine the relationship between the severity of diabetic retinopathy and the future risk of cerebrovascular accident (CVA), myocardial infarction (MI), congestive heart failure (CHF), and all-cause mortality in patients with type 2 diabetes mellitus.
Retrospective cohort study.
Patients with type 2 diabetes who underwent diabetic retinopathy screening via fundus photography.
The relationship between retinopathy status and the 5-year risk of first-time CVA, MI, CHF, and all-cause mortality was investigated using multivariate Cox proportional hazards regressions that controlled for age, gender, race or ethnicity, hemoglobin A1c, duration of diabetes, high-density lipoprotein level, low-density lipoprotein level, history of hypertension, systolic blood pressure, diastolic blood pressure, tobacco use, statin use, body mass index, urine microalbumin-to-creatinine ratio, and estimated glomerular filtration rate.
Five-year risk of first-time CVA, MI, CHF, and all-cause mortality.
Seventy-seven thousand three hundred seventy-six patients were included in this study. The average age was 59.8 years with 53.6% male, 31.2% non-Hispanic White, and 41.4% Hispanic patients. Diabetic retinopathy was significantly associated with all outcomes on multivariate analysis. Compared with patients with no retinopathy, those with minimal nonproliferative diabetic retinopathy (NPDR) had a higher risk of CVA (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.18–1.46), MI (HR, 1.30; 95% CI, 1.15–1.46), CHF (HR, 1.29; 95% CI, 1.19–1.40), and death (HR, 1.15; 95% CI, 1.05–1.25). Similarly, patients with moderate to severe NPDR had a higher risk of each outcome (CVA: HR, 1.56; 95% CI, 1.29–1.89; MI: HR, 1.92; 95% CI, 1.57–2.34; CHF: HR, 1.90; 95% CI, 1.66–2.18, and death: HR, 1.55; 95% CI, 1.32–1.82), as did patients with proliferative diabetic retinopathy (CVA: HR, 2.53; 95% CI, 1.84–3.48; MI: HR, 1.89; 95% CI, 1.26–2.83; CHF: HR, 1.96; 95% CI, 1.47–2.59; and death: HR, 1.87; 95% CI, 1.36–2.56).
Diabetic retinopathy is significantly associated with future risk of CVA, MI, CHF, and death, with higher degrees of retinopathy appearing to carry a heightened risk for each outcome. Retinal information may provide valuable insights into patients’ risk of future vascular disease and death.
Retinal capillary and arteriolar changes in patients with chronic kidney disease
2018, Microvascular Research
Citation Excerpt :
This is in line with the results of Nagaoka et al and underlines that impaired renal function is associated with decreased retinal blood flow, probably via constriction of retinal arterioles. Endothelial dysfunction, inflammation and altered coagulation are known to lead to arteriolar hypertrophic remodeling (Nguyen and Wong, 2006; Camera et al., 2007; Nguyen et al., 2007). Hypertrophic remodeling is characterized by proliferation of the extracellular matrix and thickening of basal membranes resulting in an increased cross-sectional wall area and media to lumen ratio (Rizzoni and Agabiti Rosei, 2006; Pelikanova, 2007).
Premature cardiovascular disease is a leading cause of death in patients with chronic kidney disease (CKD). In animal models CKD has been shown to cause renal and extrarenal vascular remodeling and capillary rarefaction, but data in humans with CKD are sparse. Retinal arteriolar wall-to-lumen ratio (WLR) is an established marker of early end-organ damage and there is evidence that arteriolar and capillary changes in the retinal circulation mirror those in the general and in particular the cerebrovascular microcirculation.
The aim of this study was to compare retinal capillary density and arteriolar structure between patients with CKD and healthy individuals.
We compared 76 patients with CKD stage 3+ or proteinuria >500 mg/g creatinine in the presence of a normal GFR from the German Chronic Kidney Disease cohort to 53 healthy control subjects, who participated in clinical trials during 2007 and 2015 in our Clinical Research Center. Retinal vascular parameters were measured non-invasively in vivo by scanning laser Doppler Flowmetry (SLDF, Heidelberg Engineering, Germany). Capillary rarefaction was assessed by intercapillary distance.
Patients with CKD showed greater WLR (0.403 ± 0.11 vs 0.351 ± 0.11, p = 0.010) and greater wall thickness (WT) (15.1 ± 4.1 vs 13.5 ± 3.8, p = 0.026) compared to healthy individuals. Intercapillary distance (ICD) (22.4 ± 5.7 vs 20.2 ± 4.1, p = 0.008) was greater in the CKD group compared to the healthy control group. After adjustment for differences in clinical characteristics of the groups (age, gender, BMI, serum cholesterol) WLR (p = 0.046), WT (p = 0.025) and ICD (p = 0.003) remained significantly different between the two groups. There was a correlation between serum phosphate level and WLR in the CKD group (r = 0.288, p = 0.013).
Patients with moderately severe CKD show retinal signs of end-organ damage indicated by an increased wall-to-lumen ratio and capillary rarefaction.
Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
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Endothelial dysfunction and cardiovascular diseases: The role of human induced pluripotent stem cells and tissue engineering
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Trends in Endocrinology & Metabolism

ReviewRetinal vascular manifestations of metabolic disorders

Introduction

Section snippets

Retinal vascular manifestations in diabetes

Retinal vascular manifestations in obesity

Retinal vascular manifestations in dyslipidemia

Retinal vascular manifestations in impaired glucose metabolism

Retinal vascular manifestations in metabolic syndrome

Retinal vascular manifestations in hypertension

Endothelial dysfunction and inflammation as mechanisms of retinal vascular changes

Future research and conclusions

Acknowledgements

Ophthalmology

Am. J. Kidney Dis.

Arch. Med. Res.

Am. J. Cardiol.

Ophthalmology

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Am. J. Ophthalmol.

Lancet

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Ophthalmology

Exp. Eye Res.

Ophthalmology

Important causes of visual impairment in the world today

JAMA.

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Arch. Ophthalmol.

Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy

JAMA.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38

BMJ

Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial

Lancet

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J. Am. Soc. Nephrol.

The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy

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Retinal vessel diameters and the incidence of gross proteinuria and renal insufficiency in people with type 1 diabetes

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Obesity (Silver Spring)

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Diabetes

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Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes

Diabetes Care

The incidence of retinopathy 10 years after diagnosis in young adult people with diabetes: results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS)

Diabetes Care

Review
Retinal vascular manifestations of metabolic disorders