Ferritin Goal for Restless Legs Syndrome
The target ferritin level for restless legs syndrome is ≤75 ng/mL (or transferrin saturation <20%), which is substantially higher than general population iron deficiency thresholds and reflects the unique brain iron requirements in RLS pathophysiology. 1
RLS-Specific Iron Thresholds
The American Academy of Sleep Medicine establishes distinct ferritin cutoffs for RLS that differ markedly from general population guidelines:
- Iron supplementation is recommended when serum ferritin ≤75 ng/mL OR transferrin saturation <20% in adults with clinically significant RLS 2, 1
- For pediatric RLS patients, supplementation is recommended when ferritin <50 ng/mL 1
- These thresholds are higher than general population cutoffs (<15-30 ng/mL) because brain iron deficiency plays a central role in RLS pathophysiology, even when systemic iron stores appear adequate 1
Treatment Algorithm Based on Iron Status
For ferritin ≤75 ng/mL or transferrin saturation <20%:
- Start with oral ferrous sulfate (65 mg elemental iron) as first-line, though absorption is poor when ferritin >50-75 ng/mL 3
- IV ferric carboxymaltose (1000 mg) receives a strong recommendation with moderate certainty of evidence and may be preferred for faster response 2, 1
For ferritin 75-100 ng/mL:
- Use IV iron formulations only, as oral iron is poorly absorbed in this range 3
- IV ferric carboxymaltose, ferumoxytol, or low molecular weight iron dextran enable the H-ferritin binding and macrophage uptake necessary for CNS penetration 2
For ferritin >100 ng/mL:
- Iron supplementation is generally not indicated based on current evidence 3
Critical Testing Requirements
- Check serum ferritin and transferrin saturation in ALL patients with clinically significant RLS as an essential component of care 2, 1
- Testing must be performed in the morning after avoiding iron-containing supplements and foods for at least 24 hours 1, 4
- This timing is crucial because ferritin levels fluctuate and supplementation can falsely elevate results 3
Important Assay Considerations
A critical pitfall: Ferritin measurements vary significantly between different laboratory assays. The Roche method yields approximately 60% higher values than the Beckman method at the 75 ng/mL threshold (121 ng/mL Roche equivalent) 5. Clinicians should:
- Verify which assay their laboratory uses
- Adjust cutoffs accordingly if using Roche or similar methods to avoid withholding beneficial treatment 5
- Use transferrin saturation <20% as an additional criterion when ferritin values are uncertain 1, 5
Clinical Significance of Iron Repletion
- Low serum ferritin is independently associated with dopaminergic augmentation, a major cause of RLS treatment failure 6
- Iron supplementation not only relieves fundamental RLS symptoms but also lowers the risk of augmentation when dopaminergic agents are used 6
- Response to IV ferric carboxymaltose can occur as early as day 8, with clinically relevant improvement by week 4 and continued benefit through week 12 7, 8
Integration with Pharmacological Treatment
- Iron status assessment and correction should occur BEFORE or concurrent with initiating alpha-2-delta ligands (gabapentin, pregabalin), which are now first-line pharmacological therapy 1
- For patients with persistent low ferritin despite supplementation or moderate to severe RLS, non-dopaminergic agents should be prioritized to prevent augmentation 6