Understanding Iron Parameters in Restless Legs Syndrome
You are correct to be confused—the RLS-specific ferritin threshold of ≤75 ng/mL represents a LOWER cutoff for iron deficiency in the brain, not higher levels indicating poor mobilization. In RLS, brain iron deficiency occurs even when serum ferritin appears "normal" by general population standards, which is why sleep medicine uses a much higher threshold than the typical <15-30 ng/mL cutoff used for systemic iron deficiency 1.
Why RLS Uses Different Iron Thresholds
Brain iron deficiency is the core pathophysiology of RLS, and central nervous system iron stores can be depleted even when serum ferritin is 50-75 ng/mL—levels considered adequate for erythropoiesis 1, 2.
The American Academy of Sleep Medicine recommends iron supplementation when ferritin is ≤75 ng/mL OR transferrin saturation is <20% because these parameters serve complementary diagnostic purposes 1, 2.
Ferritin can be falsely elevated by inflammation, making it an unreliable sole indicator—this is why transferrin saturation <20% identifies functional iron deficiency even when ferritin appears adequate 2.
The Logic Behind the Dual Criteria
Transferrin saturation <20% identifies patients with inadequate iron delivery to tissues despite seemingly normal ferritin, revealing functional iron deficiency where iron stores exist but cannot be mobilized effectively 2.
Ferritin ≤75 ng/mL identifies absolute iron deficiency in the context of RLS, where brain iron requirements are higher than systemic requirements 1, 3.
The "OR" in the guideline means you treat if either parameter is abnormal—you don't need both to be abnormal 1, 2.
Treatment Algorithm Based on Iron Status
Ferritin ≤75 ng/mL OR transferrin saturation <20%: Start oral ferrous sulfate (65 mg elemental iron) or consider IV ferric carboxymaltose as first-line treatment 3.
Ferritin 75-100 ng/mL: Use IV iron only (oral iron is poorly absorbed in this range and unlikely to be effective) 3.
Ferritin >100 ng/mL with adequate transferrin saturation: Iron supplementation is generally not indicated based on current evidence 3.
Critical Testing Requirements
Blood must be drawn in the morning after fasting, with the patient avoiding all iron-containing supplements and foods for at least 24 hours prior 2.
Both serum ferritin AND transferrin saturation must be checked—checking only one parameter misses patients who would benefit from iron therapy 2.
Ferritin measurements vary significantly between different laboratory assays (Beckman vs. Roche methods can differ by 50-60% for the same sample), so clinicians should be flexible with cutoff values and rely on transferrin saturation when ferritin results are borderline 4.
Common Pitfall to Avoid
Do not use general population ferritin cutoffs (<15-30 ng/mL) for RLS—this is the single most common error and results in undertreating brain iron deficiency 3. The higher threshold of ≤75 ng/mL reflects the increased iron requirements of the central nervous system in RLS patients 1.
Before initiating iron therapy, screen for hemochromatosis in patients with elevated transferrin saturation (>45%) or ferritin (>300 ng/mL), as iron supplementation can unmask hereditary iron overload 5.
Re-measure iron parameters once or twice yearly during ongoing iron therapy to monitor response and avoid iron overload 5.