In a patient with restless‑legs syndrome who has normal ferritin but low transferrin saturation, is intravenous iron therapy indicated and what dosing regimen is recommended?

IV Iron for Low Transferrin Saturation with Normal Ferritin in Restless Legs Syndrome

Yes, intravenous iron therapy is indicated for RLS patients with low transferrin saturation (<20%) even when ferritin is normal, as low TSAT indicates functional iron deficiency that impairs brain iron availability—the core pathophysiologic mechanism in RLS. 1

Rationale for Treatment

The 2025 American Academy of Sleep Medicine guidelines emphasize that brain iron deficiency is a leading pathophysiologic concept in RLS, and routine screening of iron indices is essential, with supplementation thresholds different from the general population 1. The key principle is that TSAT <20% has high sensitivity for diagnosing absolute or functional iron deficiency, even when ferritin appears normal 1.

Understanding the Discordant Iron Parameters

• Low TSAT with normal ferritin represents functional iron deficiency, where total body iron stores may be adequate but iron is not readily available for erythropoiesis or, critically for RLS, for brain iron metabolism 1
• CSF studies demonstrate that RLS patients have reduced CSF ferritin (1.11 vs 3.50 ng/mL) and elevated CSF transferrin (26.4 vs 6.71 mg/L) compared to controls, indicating low brain iron despite normal serum parameters 2
• Ferritin can be falsely elevated due to inflammation (as an acute phase reactant), masking true iron deficiency when TSAT is low 1

Recommended IV Iron Formulation and Dosing

Ferric carboxymaltose 1000 mg as a single IV infusion is the preferred regimen, based on the highest quality RLS-specific evidence 1, 3:

• The AASM guidelines give ferric carboxymaltose a STANDARD recommendation (the strongest level) for RLS treatment 1
• A randomized controlled trial in RLS patients with ferritin <75 μg/L or ferritin 75-300 μg/L with TSAT <20% showed significant improvement in International RLS Severity Scale scores by week 12 (difference -4.66, P=0.021) 3
• Slow-release, high-dose formulations like ferric carboxymaltose enable H-ferritin binding and macrophage iron uptake, allowing CNS penetration necessary for RLS benefit 1

Alternative IV Iron Formulations

If ferric carboxymaltose is unavailable:

• Low molecular weight iron dextran or ferumoxytol receive conditional recommendations, with similar pharmacologic properties to carboxymaltose 1
• Ferric derisomaltose (FDI) can be given as 1000 mg infusion or up to 20 mg/kg (max 1500 mg) diluted in 100 mL normal saline 1
• Iron sucrose is NOT recommended for RLS with normal ferritin, as fast-release, low-dose formulations failed to show clinically significant benefit over placebo in high-quality studies 1

Administration Guidelines

Dilute ferric carboxymaltose in 100 mL normal saline and infuse over 15 minutes 1:

• Do not evaluate iron parameters within 4 weeks of infusion, as circulating iron interferes with assays 1
• Reassess iron indices and RLS symptoms at 4-8 weeks post-infusion, with primary assessment at 12 weeks when maximal benefit is expected 1, 3
• Hemoglobin should increase 1-2 g/dL within 4-8 weeks if anemia was present 1

Safety Considerations

• Test doses are required for iron dextran and strongly recommended for patients with drug allergies receiving ferric gluconate or iron sucrose 1
• Infusion reactions are rare (<1:250,000 with modern formulations) but can be life-threatening 1
• Avoid iron supplementation during active infection due to concerns about promoting bacterial growth 1
• Monitor for hypophosphatemia post-infusion, particularly with ferric carboxymaltose 1

Monitoring and Repeat Dosing

Target TSAT >20% and maintain ferritin 50-75 ng/mL for RLS patients 1:

• If TSAT remains <20% at 8-12 weeks, consider repeat infusion 1
• Frequency of repeat dosing depends on underlying etiology: if no ongoing blood loss or malabsorption, a single total dose infusion may suffice 1
• For patients with persistent low iron indices, repeat iron studies every 3-6 months 1

Upper Safety Limits

• Withhold IV iron if TSAT >50% or ferritin >800 ng/mL to avoid iron overload 1
• In RLS specifically, avoid pushing ferritin above 300 ng/mL unless TSAT remains low 1

Oral Iron: Not Recommended in This Scenario

Oral iron (ferrous sulfate) receives only conditional recommendation for RLS and is poorly absorbed when ferritin >50-75 ng/mL 1:

• Oral iron relies on gastrointestinal absorption, which is limited when ferritin is normal 1
• Side effects (constipation, nausea) frequently limit compliance 1
• IV iron does not rely on GI absorption, making it superior for functional iron deficiency 1

Critical Pitfall to Avoid

Never assume normal ferritin excludes iron deficiency in RLS—the combination of low TSAT with normal ferritin specifically indicates functional iron deficiency requiring IV supplementation 1. This discordant pattern is common in inflammatory states and represents inadequate iron availability for tissue needs despite adequate storage iron 1.