Non-Ocular Biomarkers in Diabetic Retinopathy: A Game Changer for Screening?

Abstract

Diabetic retinopathy (DR) is the most common cause of visual impairment in diabetic patients, and early and precise detection is required to prevent the advancement of the disease. Conventional imaging techniques like fundus photography and optical coherence tomography (OCT) need specialized machines and trained personnel, which restricts their availability in remote and underprivileged regions. Emerging progress in biomarker studies has identified potential non-ocular and non-invasive biomarkers with the potential to aid early detection of DR by non-ophthalmologists in the course of community screenings. In this review, new non-ocular biomarkers obtained from nail fold capillaries, skin autofluorescence, and systemic circulation are discussed as regards their prospective usefulness in screening for DR as well as stratifying risk. By incorporating these biomarkers into clinical practice, it may be possible to create a less expensive, more accessible, and more efficient method of DR detection, and thus decrease the worldwide burden of diabetes-related visual impairment.

Introduction

Diabetic retinopathy (DR) continues to be an important public health issue, affecting millions of patients with diabetes mellitus globally. As a non-progressive microvascular complication, DR may result in permanent visual impairment if it is not detected and managed at the initial stage. Conventional diagnostic methods, including fundus photography, fluorescein angiography, and OCT, are based on retinal imaging and specialized ophthalmic expertise and present high hurdles in low-resource environments. The demand for less expensive screening tools has fueled the interest to identify other biomarkers that are predictive of DR risk regardless of direct ocular examination. Non-ocular biomarkers offer a new potential for the detection of early disease alterations, especially in primary health care and community health environments. This review assesses new non-ocular biomarkers and whether they are feasible for mass DR screening.

Current Challenges in DR Detection

Despite advancements in ophthalmic imaging technology, several challenges persist in the early detection of DR:

1. Limited Access to Specialized Care: Many rural and underserved communities lack the necessary infrastructure and trained professionals for DR screening.

2. Late Diagnosis: Many individuals with diabetes do not undergo routine ophthalmic examinations, leading to delayed diagnosis and treatment.

3. Cost and Resource Constraints: The high cost of retinal imaging equipment and maintenance presents a barrier to large-scale DR screening programs.

4. Need for Non-Invasive, Scalable Screening Methods: A more practical and widely deployable screening strategy could significantly reduce the burden of undiagnosed DR.

Given these challenges, non-ocular biomarkers have emerged as a promising alternative for DR risk assessment.

Non-Ocular Biomarkers in DR Detection

Several non-ocular biomarkers have been proposed for early DR detection. These biomarkers originate from systemic changes associated with diabetes-related microvascular dysfunction and oxidative stress. The key categories of non-ocular biomarkers include:

1. Nailfold Capillaroscopy (NFC) Findings

   • Nailfold capillaroscopy is a non-invasive technique used to assess microvascular abnormalities.

   • Studies have reported that individuals with DR exhibit distinct capillary alterations, including increased tortuosity, capillary dropout, and reduced capillary density.

   • These changes correlate with systemic microangiopathy, suggesting their potential role as an early indicator of DR progression.

2. Skin Autofluorescence (SAF) and Advanced Glycation End Products (AGEs)

   • Skin autofluorescence (SAF) provides a measure of tissue accumulation of advanced glycation end products (AGEs), which play a role in diabetes-related vascular damage.

   • Elevated SAF levels have been linked to an increased risk of DR, with studies demonstrating a strong correlation between skin AGE accumulation and retinal microvascular dysfunction.

   • Since SAF measurement is non-invasive and does not require specialized training, it presents a viable option for community-based DR screening.

3. Circulating Biomarkers in Blood and Saliva

   • Inflammatory Markers: Systemic inflammation contributes to DR pathogenesis. Biomarkers such as C-reactive protein (CRP), interleukins (IL-6, IL-1β), and tumor necrosis factor-alpha (TNF-α) have been associated with DR severity.

   • Metabolic Markers: Altered levels of serum lipids, homocysteine, and oxidative stress markers (e.g., malondialdehyde) have been linked to DR risk.

   • Salivary Biomarkers: Non-invasive salivary diagnostics have shown promise in detecting changes in oxidative stress markers, making them a potential tool for DR screening.

4. Glycemic Variability and Hemodynamic Markers

   • Glycemic fluctuations contribute to DR development beyond HbA1c levels. Continuous glucose monitoring (CGM) metrics, such as time in range (TIR) and glycemic excursions, have been explored as predictors of DR progression.

   • Vascular stiffness and arterial wave reflections, assessed through non-invasive pulse wave analysis, provide insights into systemic vascular dysfunction and may serve as early DR indicators.

Clinical Applications of Non-Ocular Biomarkers in DR Screening

The integration of non-ocular biomarkers into clinical practice has several potential applications:

1. Community-Based DR Screening

   • Portable devices measuring SAF or NFC could enable primary care physicians and non-specialists to conduct DR risk assessments without requiring retinal imaging.

   • Incorporating systemic biomarkers into routine diabetes management may facilitate earlier DR detection.

2. Risk Stratification and Personalized Medicine

   • Combining multiple biomarkers (e.g., SAF, nailfold capillary density, and inflammatory markers) could enhance DR risk prediction models.

   • Personalized screening strategies may allow for more targeted ophthalmologic referrals, reducing the burden on specialized care centers.

3. Telemedicine and Remote Monitoring

   • Non-invasive biomarker assessments could be integrated into telemedicine platforms, enabling remote risk assessment and follow-up.

   • AI-driven predictive models incorporating biomarker data may further enhance DR detection accuracy.

Future Directions and Research Needs

While non-ocular biomarkers hold significant promise, further research is required to:

1. Standardize Biomarker Measurement Protocols

   • Establish reference ranges and diagnostic thresholds for each biomarker.

   • Ensure reproducibility across different populations and healthcare settings.

2. Validate Biomarkers in Large-Scale Clinical Trials

   • Conduct multicenter studies to evaluate the sensitivity and specificity of non-ocular biomarkers compared to conventional DR screening methods.

3. Develop Cost-Effective Screening Tools

   • Enhance the affordability and accessibility of biomarker-based screening devices for widespread implementation.

Conclusion

Non-ocular biomarkers are a novel and promising strategy for the early diagnosis of diabetic retinopathy, especially in environments where traditional ophthalmic screening is not possible. Through the use of systemic biomarkers like nail fold capillaroscopy results, skin autofluorescence, and circulating inflammatory markers, clinicians can enhance DR risk stratification and facilitate timely interventions. Subsequent research would be directed toward confirming these biomarkers in non-Caucasian populations and implementing them within scalable community-level screening initiatives. With the potential for further technologies and biomarker identification, the detection of DR using non-invasive means can potentially become a central aspect of managing diabetes and reducing the burden of diabetes blindness on a global level.

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