How do I rule out iron deficiency?

How to Rule Out Iron Deficiency

Measure serum ferritin as your primary test—a level <30 μg/L rules in iron deficiency in the absence of inflammation, while a level >100 μg/L effectively rules it out. 1

Initial Laboratory Approach

Start with a complete blood count (CBC) to assess hemoglobin, hematocrit, mean corpuscular volume (MCV), and red cell distribution width (RDW). 2 However, recognize that hemoglobin and hematocrit are late indicators of iron deficiency—they only become abnormal after iron stores are completely depleted and erythropoiesis is impaired. 1, 2 You cannot rule out iron deficiency based on normal hemoglobin alone. 2

Key CBC Findings:

• Microcytosis (low MCV) is characteristic of iron deficiency but may be absent in early deficiency or when combined with folate/B12 deficiency 1
• Elevated RDW (>14%) with microcytosis strongly suggests iron deficiency 2
• Normal MCV does not exclude iron deficiency—this is a critical pitfall, as microcytosis is a late finding 2

Serum Ferritin: The Most Powerful Test

Serum ferritin is the most sensitive and specific test for iron stores and should be your primary diagnostic tool. 1, 2

Interpretation Without Inflammation:

• <12-15 μg/L: Diagnostic of iron deficiency with 99-100% specificity 1, 2
• <30 μg/L: Generally indicates low body iron stores 2, 3
• <45 μg/L: Provides 92% specificity for iron deficiency 2
• >100 μg/L: Iron deficiency is almost certainly not present 1

Critical Caveat—Inflammation:

Ferritin is an acute-phase reactant that becomes falsely elevated in chronic infection, inflammation, malignancy, hepatitis, cirrhosis, neoplasia, or arthritis. 1 This elevation can mask depleted iron stores. 1

When inflammation is present (elevated CRP, ESR, or clinical signs), use ferritin <100 μg/L as your diagnostic threshold for iron deficiency. 1, 2 A ferritin between 30-100 μg/L in the setting of inflammation suggests combined iron deficiency and anemia of chronic disease. 1

Transferrin Saturation: The Confirmatory Test

Transferrin saturation (TSAT) is calculated as: (serum iron ÷ total iron-binding capacity) × 100. 1

• TSAT <16-20% confirms iron deficiency, particularly when combined with low ferritin 1, 2, 3
• TSAT is less affected by inflammation than ferritin, making it valuable in inflammatory states 1, 2
• TSAT reflects iron immediately available for hemoglobin synthesis 2

**Among nonpregnant women, TSAT <16% has 93% specificity for iron deficiency.** 2 For women with anemia, a ferritin >15 μg/L combined with TSAT >16% suggests the anemia is not due to iron deficiency. 1

Diagnostic Algorithm

1. Order CBC with ferritin and TSAT as your initial panel 2
2. Check inflammatory markers (CRP, ESR) to guide ferritin interpretation 1, 2
3. If ferritin <15-30 μg/L: Iron deficiency is confirmed 2
4. If ferritin 15-45 μg/L: Add TSAT; if <20%, iron deficiency is confirmed 2
5. If ferritin >100 μg/L and TSAT >20%: Iron deficiency is effectively ruled out 1
6. If inflammation is present and ferritin 30-100 μg/L with TSAT <16%: Likely combined iron deficiency and anemia of chronic disease 1

Advanced Tests When Diagnosis Remains Unclear

If doubt persists after ferritin and TSAT:

• Therapeutic trial of oral iron for 3 weeks with reassessment—a positive response confirms iron deficiency 1
• Soluble transferrin receptor (sTfR): Elevated in iron deficiency, normal/low in anemia of chronic disease; less affected by inflammation 1, 2
• Reticulocyte hemoglobin content: Provides direct assessment of functional iron availability 1, 2
• Bone marrow aspiration: The gold standard showing absent stainable iron, but rarely needed 1, 2

Common Pitfalls to Avoid

• Do not rely solely on hemoglobin/hematocrit—these are late indicators and will miss early iron deficiency 1, 2
• Do not ignore inflammatory markers when interpreting ferritin—chronic disease can mask true deficiency by elevating ferritin 1, 2
• Do not assume normal MCV excludes iron deficiency—microcytosis is a late finding 2
• Do not test iron parameters within 4 weeks of IV iron administration—circulating iron interferes with assays and gives falsely elevated results 2
• In men and postmenopausal women with confirmed iron deficiency, do not assume dietary insufficiency—approximately 62% have gastrointestinal bleeding requiring investigation 2

Timing of Reassessment

After initiating iron supplementation, recheck iron parameters and hemoglobin at 4-8 weeks. 2 Hemoglobin should increase by 1-2 g/dL within this timeframe if treatment is effective. 2