A retrospective study recently published in Translational Vision Science & Technology assessed whether iron overload is associated with increased risk of ocular hypertension (OHT), primary open-angle glaucoma (POAG), and normal-tension glaucoma (NTG).
Give me some background.
Iron dysregulation plays a critical role in the process of retinal ganglion cell (RGC) degeneration—a hallmark sign of glaucoma—by amplifying oxidative stress (including ferroptosis), and contributing to dysfunction in both trabecular meshwork (TM) cells and RGCs.
- Note: Iron overload is a systemic condition that progressively affects multiple organs due to excessive iron deposition, leading to ferroptosis.
Ferroptosis has gained increasing attention for its pathogenic role in various neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease, and ocular diseases such as choroidal neovascularization and dry age-related macular degeneration (AMD).
Bringing it back to glaucoma…
Studies have suggested that iron reduction mitigates iron-induced neurodegeneration by restoring iron homeostasis and protecting RGCs from oxidative damage.
Consequently: Investigators hypothesized that iron overload may increase the risk of glaucoma, and sought to explore the association between the two using a real-world, multinational cohort.
Let’s move on to the study.
In this retrospective cohort study, researchers utilized the TriNetX multinational database to identify patients ≥40 years old without prior glaucoma, who were then classified into iron overload and non-iron overload subgroups.
Propensity score matching (1:1) was applied to balance demographics, comorbidities, and medication use.
And the findings?
Among 63,577 matched pairs, iron overload was significantly associated with elevated risks of POAG (HR: 1.65, 95% CI: 1.32-2.06) and OHT (hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.06-1.66).
An increased risk was observed for NTG (HR: 1.31, 95% CI: 0.74-2.33) as well, but the wide confidence interval likely reflects the small number of outcome events.
Moreover: Stratified and sensitivity analyses, including those with ferritin > 500 mg/mL, showed consistent associations across age, sex, and comorbidity subgroups.
Expert opinion?
The study authors noted that “prospective longitudinal studies with detailed iron profiling and comprehensive ophthalmologic assessments are necessary to validate the links among iron dysregulation and glaucoma.”
In addition: “Therapeutic strategies aimed at modulating iron homeostasis, such as iron chelators, Nrf2 pathway activators, and antioxidant therapies, may offer neuroprotective potential by reducing ferroptosis-induced RGC damage and preserving visual function,” they added.
Any limitations?
As always, there are a few to note, including:
- Use of the TriNetX platform precluded access to individual medical records, which may have led to diagnostic misclassification for iron overload and glaucoma
- The retrospective study design limited causal interpretations, emphasizing the importance of future prospective studies incorporating direct measurements of iron biomarkers and detailed ophthalmologic evaluations
- Residual confounding from unmeasured factors may have impacted the findings
- The true pre-detection duration of iron overload was unknown—though markedly elevated ferritin often prompts intensive treatment—so the research team could not determine whether exposure duration independently influenced glaucoma risk
- The institutional and regional variations within TriNetX may have impacted the generalizability of the findings
Take home.
These findings indicate that iron overload is associated with a significantly increased risk of POAG and OHT.
And lastly: This study points to systemic iron dysregulation as a modifiable risk factor for glaucomatous disease—suggesting patients with iron overload may benefit from targeted ophthalmologic referral, particularly those with visual symptoms or additional risk factors.