Glaucoma News: Texas Study Alarmingly Finds That Glucocorticoids And Steroids Can Cause Glaucoma And Also Accelerate Glaucoma Progression!
: Glaucoma is a complex group of optic neuropathies that lead to irreversible vision loss and blindness, and its prevalence has been on the rise, posing a significant burden to global healthcare systems. In 2020, nearly 118 million people worldwide had glaucoma, and this number is expected to skyrocket to over 600 million by 2040! The disease is characterized by progressive retinal ganglion cell loss and optic nerve degeneration, primarily linked to elevated intraocular pressure (IOP). In this Glaucoma News
report, we delve into a groundbreaking discovery made by the North Texas Eye Research Institute-USA and the University of North Texas Health Science Center. Their study has revealed a previously unsuspected connection between glucocorticoids (GCs) and the development of glaucoma, particularly primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG).
Thailand Medical News would like to add that all forms of corticosteroids be it oral, topical, inhaled or injectable forms, can contribute to onset of Glaucoma or increase its progression especially with frequent use!
Understanding Glaucoma and Its Risk Factors
Before delving into the new research findings, it's crucial to understand the complexities of glaucoma. There are several risk factors associated with its development, including age (typically over 40 years), elevated IOP, ethnicity, family history, myopia, and sensitivity to glucocorticoids (steroid responders). Moreover, individuals with diabetes, connective tissue disorders like rheumatoid arthritis, and those undergoing long-term steroid treatment are at higher risk of developing glaucoma. The risk also appears to increase in urban areas, likely due to the environmental factors such as air pollution. African Americans, South Asians, East Asians are 6 to 8 times more likely and Hispanics 2-3 more likely to develop glaucoma compared to Caucasians. First degree relatives of individuals with glaucoma are at higher risk of also developing glaucoma. Myopia associated with elongation of the eye globe is a glaucoma risk factor, perhaps due to the altered geometry of the optic nerve head (ONH).
Categories of Glaucoma
Glaucoma is classified into various subsets, each with unique characteristics. The two primary forms are primary open-angle glaucoma (POAG) and primary closed-angle glaucoma (PACG), both of which result from mechanical obstructions in the trabecular meshwork (TM), a crucial component of the aqueous humor outflow system. Other categories include secondary open-angle glaucoma, congenital glaucoma, and juvenile glaucoma, which stem from developmental anomalies, medications like GCs, exfoliation syndrome, pigment dispersion, and eye injuries. Glaucoma is insidious in nature, typically beginning as a painless and asymptomatic condition but leading to the gradual loss of peripheral vision, which can ultimately result in central vision loss and blindness.
Glaucoma's Impact on Optic Nerve and Retinal Ganglion Cells
The devastating vision loss in glaucoma is primarily attributed to the degeneration of retinal ganglion cells (RGCs) and the optic nerve axons. These cells are vital for processing visual information and
transmitting it to the brain. Glaucoma leads to the damage of RGC axons at the optic nerve head (ONH), causing the loss of RGCs and compromising the optic nerve's structural integrity. This damage often presents as an increased optic cup-to-disk ratio, reduced retinal nerve fiber layer thickness, notches at the neural rim, hemorrhages at the optic disc margin, and distinctive visual field defects.
Role of Glucocorticoids
Glucocorticoids, a class of steroid hormones, are known for their anti-inflammatory and immunosuppressive properties. These hormones, particularly cortisol in humans, play a crucial role in regulating various metabolic processes, such as carbohydrate, lipid, protein, and electrolyte metabolism. They are also used therapeutically to treat a wide range of inflammatory and immune-related diseases. However, their long-term use can lead to the development of ocular hypertension in some individuals, who are known as steroid responders.
Glucocorticoid-Induced Ocular Hypertension and Glaucoma
Prolonged glucocorticoid therapy can lead to a condition known as glucocorticoid-induced ocular hypertension (GC-OHT), which is a precursor to glucocorticoid-induced glaucoma (GIG). Interestingly, GIG closely mimics primary open-angle glaucoma (POAG) both clinically and molecularly, to the extent that past or present glucocorticoid therapy is often considered during the diagnostic process. GC-OHT can progress to GIG if left unaddressed, and the elevation in intraocular pressure in both conditions is primarily due to pathogenic damage to the trabecular meshwork (TM).
Mechanisms of GC-Induced Ocular Hypertension
Understanding the mechanisms behind GC-induced ocular hypertension is crucial for the development of effective treatments. The trabecular meshwork (TM), responsible for regulating the aqueous humor outflow and intraocular pressure, is significantly affected by GCs. GCs cause pathological changes in TM cells, leading to an increase in resistance to aqueous humor outflow. These changes include increased deposition of extracellular matrix (ECM) components, such as fibronectin, glycosaminoglycans (GAGs), elastin, collagen, and laminin, resulting in a reduction in aqueous humor drainage. Additionally, GCs lead to the reorganization of the actin cytoskeleton, causing further resistance to outflow. In severe cases, GC treatment can result in the formation of cross-linked actin networks (CLANs) within TM cells, further exacerbating the pathology.
Models of Glucocorticoid-Induced Ocular Hypertension
To better understand GC-OHT, researchers have turned to various animal models, including non-human primates and rodents. These models have been instrumental in uncovering the mechanisms responsible for GC-OHT and have been used to develop potential disease-modifying therapies. For instance, a mouse model of weekly periocular dexamethasone (DEX) acetate administration has allowed researchers to study the effects of glucocorticoid receptor isoforms (GRa and GRb) in regulating GC-OHT.
The Role of GRb in Regulating DEX-OHT
One of the intriguing discoveries in this research is the role of GRb, an alternative spliced isoform of the glucocorticoid receptor. TM cells isolated from glaucoma donors express significantly lower levels of GRb compared to normal TM cells, rendering them highly sensitive to GCs. Transduction of the TM with an adenovirus carrying the GRb gene resulted in a remarkable reversal of GC-OHT in mice. This suggests that gene therapy involving selective delivery of GRb to the TM could be a promising therapeutic approach for patients undergoing long-term GC therapy.
Future Directions in Glaucoma Research
The discovery of the link between glucocorticoids and the development of glaucoma, particularly GC-OHT and GIG, is a significant step forward in our understanding of this sight-threatening condition. GCs are vital in the treatment of many diseases and conditions, but their potential side effects, such as ocular hypertension, have long been a concern. This research offers insights into the molecular mechanisms responsible for GC-OHT, potentially paving the way for new treatments and preventive strategies for glaucoma patients.
The findings discussed thus far shed light on the intricate relationship between glucocorticoids, their receptors, and glaucoma. They also underscore the pressing need for further research to fully comprehend the molecular mechanisms involved. This understanding is crucial for developing more targeted and effective therapies for glaucoma patients.
: Investigating how glucocorticoid receptors and their isoforms influence trabecular meshwork cells and their responses to glucocorticoids can lead to the development of specific therapeutics. Strategies aimed at regulating the expression or activity of these receptors, such as gene therapy or small molecules that influence receptor isoform balance, could help manage ocular hypertension in glucocorticoid-induced glaucoma.
Early Detection and Monitoring
: The discovery that almost all primary open-angle glaucoma patients develop glucocorticoid-induced ocular hypertension during glucocorticoid therapy suggests a potential avenue for early detection and monitoring. Identifying genetic markers or molecular signatures related to glucocorticoid receptor isoform expression could enable ophthalmologists to identify patients at higher risk of developing glaucoma upon glucocorticoid treatment.
: The variability in individual responses to glucocorticoids, both in terms of increased intraocular pressure and glaucoma development, calls for personalized medicine approaches. Tailoring treatment strategies to a patient's genetic makeup and glucocorticoid receptor expression profiles could improve outcomes and reduce side effects.
: If further research confirms the role of glucocorticoids in the pathogenesis of glaucoma, there may be an opportunity to develop preventive strategies. This could include alternative medications or therapies for individuals at high risk of glucocorticoid-induced glaucoma due to their genetic predisposition.
Education and Awareness
: Raising awareness among healthcare providers, particularly those prescribing glucocorticoids, is essential. Many cases of glucocorticoid-induced glaucoma go undetected until patients experience visual impairment. Educating healthcare professionals about the risks and the need for regular eye examinations in patients on long-term glucocorticoid therapy can lead to earlier intervention and better outcomes.
: Glaucoma is a global public health concern. In addition to exploring the role of glucocorticoids in glaucoma, further research into the epidemiological factors contributing to glaucoma prevalence worldwide is needed. Identifying why certain populations are more susceptible to glaucoma can lead to targeted interventions to reduce the global burden of this disease.
: Interdisciplinary collaboration is key to advancing glaucoma research. Ophthalmologists, geneticists, pharmacologists, and other specialists must work together to unravel the complexities of this condition and develop innovative treatments.
: Patients with glaucoma, especially those at risk of glucocorticoid-induced glaucoma, should be encouraged to advocate for their eye health. Regular eye check-ups, open communication with healthcare providers, and awareness of glaucoma risk factors can help ensure early diagnosis and intervention.
: Investigating the potential impact of lifestyle factors, such as diet, exercise, and environmental influences, on glaucoma risk is another avenue for research. Understanding how these factors interact with glucocorticoid exposure and genetic predisposition can provide valuable insights.
Glaucoma remains a major global health challenge, causing irreversible vision loss in millions of people. The recent discovery of the role of glucocorticoids and glucocorticoid receptors in glaucoma pathogenesis represents a significant advancement in our understanding of this complex disease.
The intricate interplay between glucocorticoids and the eye's trabecular meshwork, where aqueous humor outflow is regulated, sheds light on the mechanisms leading to ocular hypertension and glaucoma. The identification of specific glucocorticoid receptor isoforms, their expression levels, and their influence on trabecular meshwork cells provides valuable insights into the variability in individual responses to glucocorticoid therapy.
As research in this field progresses, the potential for more targeted treatments, personalized medicine approaches, and even preventive strategies grows. These advancements hold the promise of better therapies and early interventions that could significantly impact the treatment and prevention of glaucoma.
The study findings were published on a preprint server and are currently being peer reviewed.
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Steroid-induced Glaucoma: An Avoidable Irreversible Blindness
Association of trabecular meshwork height with steroid-induced ocular hypertension
Steroid-Induced Glaucoma In Youngsters: A Major Public Health Issue Of Near Future
Long-term corticosteroid-induced chronic glaucoma model produced by intracameral injection of dexamethasone-loaded PLGA microspheres
Incidence, Risk Factors, Treatment, and Outcome of Ocular Hypertension following Intravitreal Steroid Injections: A Comparative Study
(Please note that there are over 115 published studies on corticosteroids being able to cause glaucoma and also cause the progression of existing glaucoma!)