What blood work should be checked, aside from ferritin levels, in patients with Restless Legs Syndrome (RLS)?

Blood Work for RLS Beyond Ferritin

In all patients with clinically significant RLS, you must check serum ferritin AND transferrin saturation (calculated from iron and total iron binding capacity), ideally in the morning after avoiding iron-containing supplements for at least 24 hours. 1

Essential Laboratory Tests

Beyond ferritin, the following blood work should be obtained:

Iron Studies (Critical)

• Transferrin saturation (calculated from serum iron and total iron binding capacity) 1
  • Iron supplementation thresholds differ from general population: supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1
  • Both parameters are required because ferritin alone can be falsely elevated by inflammation 1
  • Transferrin saturation <20% indicates functional iron deficiency even when ferritin appears adequate 1

Metabolic and Renal Screening

• Electrolytes and renal function tests (BUN, creatinine) 2

  • Chronic kidney disease is a well-established secondary cause of RLS 2
  • End-stage renal disease patients require different treatment algorithms 1

• Hemoglobin A1c 2

  • Diabetes mellitus has been associated with RLS 2
  • Helps identify peripheral neuropathy as an RLS mimic 1

Endocrine Screening

• Thyroid-stimulating hormone (TSH) 2

  • Part of standard endocrine screening for RLS 2
  • Thyroid dysfunction can contribute to RLS symptoms 2

• Serum calcium 2

  • Included in baseline metabolic assessment 2

Additional Tests Based on Clinical Context

• Urine albumin-to-creatinine ratio 2

  • Assesses for renal disease that may be contributing to RLS 2

• Pregnancy test (where applicable) 2

  • Pregnancy is a known secondary cause of RLS 2

Critical Testing Considerations

Timing and Preparation

The American Academy of Sleep Medicine emphasizes that iron studies should be drawn in the morning after avoiding all iron-containing supplements and foods for at least 24 hours prior to blood draw 1. This standardization is crucial because:

• Ferritin has diurnal variation 1
• Recent iron intake can falsely elevate results 1
• Inflammation can raise ferritin independent of true iron stores 1

RLS-Specific Iron Thresholds

These thresholds are different from the general population: 1

• Adults: Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Children: Supplement if ferritin <50 ng/mL 1
• Consider IV iron if ferritin is between 75-100 ng/mL 1

This contrasts with older guidelines that used a ferritin threshold of <50 ng/mL 1, reflecting evolving understanding that brain iron deficiency occurs at higher serum ferritin levels than systemic iron deficiency 3.

Common Pitfalls to Avoid

1. Do not rely on ferritin alone - transferrin saturation must be checked because ferritin can be falsely elevated by inflammation, infection, or liver disease 1

2. Do not use general population iron thresholds - RLS requires higher ferritin targets (≤75 ng/mL vs <30 ng/mL for general anemia) because brain iron metabolism differs from systemic iron metabolism 1

3. Screen for hemochromatosis before iron supplementation - measure transferrin saturation and ferritin to identify patients with iron overload who should not receive iron therapy 4

4. Perform thorough neurologic examination - secondary causes like peripheral neuropathy or radiculopathy require different management than primary RLS 1

5. Recheck iron studies during treatment - monitor serum iron parameters once or twice yearly during iron therapy to avoid iron overload 4

Differential Diagnosis Considerations

The blood work helps distinguish RLS from mimics and identify secondary causes 1:

• Renal function identifies uremia-related RLS 2
• HbA1c identifies diabetic neuropathy 2
• Normal neurologic exam with appropriate iron studies supports primary RLS 1
• Abnormal exam findings suggest peripheral neuropathy, radiculopathy, or vascular disease as alternative diagnoses 1