# Retinal Capillary Density Reduction Contributes to Dysthyroid Optic Neuropathy via an L‐Arginine‐NO Pathway: A Metabonomics and Clinical Trial Study

## TL;DR

Reduced retinal capillary density in dysthyroid optic neuropathy is linked to L-arginine and nitric oxide pathway dysfunction, with potential treatment using oral L-arginine.

## Contribution

Identifies L-arginine-NO pathway as a novel mechanism in dysthyroid optic neuropathy and suggests oral L-arginine as a potential treatment.

## Key findings

- DON patients show reduced retinal capillary density and elevated pulse pressure.
- Metabolomic profiling reveals dysregulation in the L-arginine metabolic pathway in DON.
- Oral L-arginine treatment improves retinal capillary density and visual function in early-stage DON.

## Abstract

Dysthyroid optic neuropathy (DON) is the most severe complication of thyroid‐associated ophthalmopathy (TAO). Although recent evidence indicates that reduced retinal capillary density (RCD) may increase DON risk independently of orbital apex crowding, the underlying mechanisms and associated metabolic reprogramming remain unclear. In a retrospective analysis of TAO patients with and without DON, those with DON demonstrated elevated pulse pressure (PP), decreased RCD, and higher incidences of dyslipidemia, hyperglycemia, and internal carotid artery calcification. To explore the metabolic basis of these findings, untargeted and targeted metabolomic profiling of plasma from TAO patients and healthy controls was conducted, identifying DON‐associated abnormalities in the L‐arginine metabolic pathway (registration number: ChiCTR2000035598). Integrating these results with existing literature suggests that oxidative stress drives dysregulated L‐arginine–nitric oxide (NO) metabolism, contributing to progressive RCD loss. In early‐stage DON patients treated with oral L‐arginine, improvements in RCD, PP, and visual function were observed (registration number: ChiCTR2300076962). Further analyses implicated reduced NO bioavailability, due to L‐arginine depletion and endothelial NO synthase (eNOS) uncoupling, as a key contributor to declining RCD. Given that oral L‐arginine can improve PP via NO‐mediated pathways in cardiovascular disease, our findings offer a promising new therapeutic direction for DON management.

Oxidative stress induces endothelial nitric oxide synthase (eNOS) uncoupling and L‐arginine depletion, reducing nitric oxide (NO) bioavailability in vascular endothelium and contributing to decreased retinal capillary density (RCD) in dysthyroid optic neuropathy (DON). This mechanism also explains the elevated pulse pressure (PP), increased incidence of arteriosclerosis, and systemic risk factors such as advanced age, hyperlipidemia, and smoking in DON.