Can a postmenopausal woman with severe restless leg syndrome (RLS) and normal serum ferritin levels still have iron deficiency?

Can a Postmenopausal Woman with Severe RLS Have Iron Deficiency Despite Ferritin 89 ng/mL and Transferrin Saturation 24%?

Yes, this postmenopausal woman with severe RLS could still have functionally inadequate iron stores for her neurological needs, despite these seemingly "normal" laboratory values, and should be treated with iron supplementation according to RLS-specific guidelines.

RLS-Specific Iron Thresholds Differ from General Population Standards

The critical distinction here is that RLS requires higher iron thresholds than general iron deficiency screening:

• The American Academy of Sleep Medicine recommends iron supplementation for RLS when ferritin is ≤75 ng/mL or transferrin saturation is <20% 1
• This patient's ferritin of 89 ng/mL is only marginally above the RLS-specific threshold of 75 ng/mL, and her transferrin saturation of 24% is just barely above the 20% cutoff 1
• These RLS-specific cutoffs are substantially higher than the general population cutoff of ≤15 ng/mL used to diagnose absolute iron deficiency 2

The rationale for higher thresholds in RLS is that brain iron deficiency plays a key pathophysiological role in RLS, even when systemic iron stores appear adequate 1. Sleep medicine physicians recognize that optimal neurological function requires ferritin levels ≥50-75 ng/mL, substantially higher than what prevents anemia 1.

Evidence Supporting Iron Deficiency in This Clinical Scenario

Multiple lines of evidence suggest this patient may have inadequate iron stores:

• Hospital-based research found that ferritin <70 ng/mL is the optimal cutoff for identifying iron deficiency in RLS patients with inflammatory conditions 3
• A case report documented iron deficiency on bone marrow examination with iron-responsive RLS in a patient whose ferritin was "well above the conventional cutoff," demonstrating that normal ferritin can mask true iron deficiency in RLS 4
• Functional iron deficiency can exist when transferrin saturation is <20% despite ferritin levels of 100-700 ng/mL, indicating inadequate iron delivery to tissues despite adequate stores 2

Ferritin as an Acute Phase Reactant

A critical pitfall is that ferritin is an acute phase reactant that increases with inflammation, infection, or chronic disease independent of actual iron stores 2:

• This elevation can mask depleted iron stores 2
• In postmenopausal women, chronic low-grade inflammation is common and may artificially elevate ferritin 2
• The patient's ferritin of 89 ng/mL could represent true iron stores that would be much lower (potentially <50 ng/mL) in the absence of inflammation 3

Clinical Features Supporting Iron Deficiency

Research demonstrates that non-anemic iron deficiency (IDNA) is frequent in RLS and presents with specific features 5:

• 42.3% of RLS patients without anemia had iron deficiency in one cohort 5
• Women are at much higher risk for IDNA with a relative risk of 5.51 5
• IDNA RLS patients showed higher risk of severe daytime tiredness or sleepiness 5
• Low serum ferritin is significantly associated with RLS augmentation (worsening despite treatment) 6

Treatment Recommendations for This Patient

The American Academy of Sleep Medicine strongly recommends IV ferric carboxymaltose for RLS patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1:

• Given this patient's severe RLS and borderline iron parameters, IV ferric carboxymaltose 750-1000 mg in one or two infusions is the most appropriate intervention 1
• Alternatively, oral ferrous sulfate is conditionally recommended, though IV formulations may be more effective for rapid correction 1

First-line pharmacological treatment should be alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin), not dopamine agonists 2, 1:

• These agents have strong recommendations with moderate certainty of evidence 2, 1
• They avoid the augmentation risk associated with dopamine agonists 2, 1

Monitoring and Follow-Up

After initiating iron supplementation:

• Recheck ferritin and transferrin saturation in 3 months 1
• Target ferritin should be maintained >75 ng/mL for optimal RLS management 1
• Continue iron supplementation indefinitely with monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline 1
• Monitor for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1

Critical Pitfalls to Avoid

• Do not assume "normal" ferritin excludes iron deficiency in RLS—the thresholds are disease-specific and substantially higher than general population cutoffs 1, 3, 4
• Do not ignore borderline values (ferritin 75-100 ng/mL)—these patients may still benefit from iron supplementation, particularly if symptomatic 1
• Do not start dopamine agonists without first optimizing iron status, as low iron increases augmentation risk 6
• Do not use general population iron deficiency criteria (ferritin <15 ng/mL) for RLS patients—this will miss the majority of cases where iron contributes to symptoms 2, 1