What is the next step in managing a patient with low hemoglobin (Hb) and hematocrit (Hct) levels, but normal ferritin and iron levels?

Management of Low Hemoglobin/Hematocrit with Normal Ferritin and Iron

When hemoglobin and hematocrit are low but ferritin and serum iron appear normal, you must first consider functional iron deficiency or false-normal ferritin due to inflammation, then systematically evaluate for non-iron causes of anemia. 1

Initial Assessment: Rule Out Masked Iron Deficiency

Check for Inflammatory States

• Ferritin is an acute phase reactant and can be falsely elevated in the presence of inflammation, infection, or chronic disease, masking true iron deficiency. 1
• A ferritin level <45 μg/L provides optimal sensitivity and specificity for iron deficiency in clinical practice, but levels up to 150 μg/L may still represent iron deficiency when inflammation is present. 1
• If chronic inflammatory conditions exist (arthritis, chronic infection, malignancy, liver disease), ferritin levels between 30-150 μg/L should not be considered reassuring. 1

Evaluate Additional Iron Parameters

• Check transferrin saturation (TSAT) immediately—a TSAT <20% indicates functional iron deficiency even when ferritin appears normal. 1
• Measure mean cell hemoglobin (MCH) and mean cell volume (MCV), as MCH is more reliable than MCV and decreases in both absolute and functional iron deficiency. 1
• Consider checking soluble transferrin receptor (sTfR) if available, particularly when chronic disease is present, as the sTfR/log ferritin ratio provides superior discrimination. 1
• Percentage of hypochromic red cells >10% is highly sensitive for functional iron deficiency. 1

Therapeutic Trial of Iron

• A rise in hemoglobin ≥10 g/L (≥1 g/dL) within 2 weeks of iron supplementation is highly suggestive of iron deficiency, even when initial iron studies appear equivocal. 1, 2
• This therapeutic trial is both diagnostic and therapeutic, making it a practical first step. 1

Evaluate for Non-Iron Causes of Anemia

If iron studies are truly normal (ferritin >45 μg/L, TSAT >20%, normal MCV/MCH) and there's no response to iron therapy, investigate alternative causes:

Hemoglobinopathies

• Order hemoglobin electrophoresis, particularly in patients with microcytosis disproportionate to anemia or appropriate ethnic background (Mediterranean, African, Southeast Asian descent). 1
• Thalassemia characteristically shows MCV reduced out of proportion to the degree of anemia. 1

Vitamin Deficiencies

• Check vitamin B12 and folate levels, as deficiency can cause anemia with normal iron parameters. 1
• These deficiencies can coexist with or mask iron deficiency. 1

Chronic Kidney Disease

• Assess renal function, as anemia of chronic kidney disease presents with normal or elevated ferritin but functional iron deficiency. 1
• In CKD patients, target TSAT >20% and ferritin 100-500 ng/mL for optimal erythropoiesis. 1

Anemia of Chronic Disease/Inflammation

• This presents with low-normal to elevated ferritin, low TSAT, and low serum iron despite adequate stores. 1
• The iron is "locked" in storage sites and unavailable for erythropoiesis. 3

Race-Specific Considerations

• Black patients have hemoglobin distributions 0.8 g/dL lower than white patients independent of iron status, leading to higher false-positive rates for anemia screening. 1
• Consider using additional iron status tests (ferritin, TSAT) rather than relying solely on hemoglobin cutoffs in Black patients. 1

Common Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency—inflammation can mask depleted stores. 1
• Do not rely on hemoglobin/hematocrit alone without checking iron parameters, as many iron-deficient individuals maintain normal CBC initially. 4
• Avoid checking only serum iron, as it has significant diurnal variation and is less reliable than ferritin and TSAT. 1
• Do not overlook functional iron deficiency in patients on erythropoiesis-stimulating agents or with high erythropoietic demand. 1, 3

Practical Algorithm

1. Recheck ferritin with inflammatory markers (CRP, ESR) 1
2. Measure TSAT, MCV, and MCH 1
3. If TSAT <20% or MCH low: Trial oral iron 3-6 mg/kg elemental iron daily with vitamin C 2
4. Recheck hemoglobin in 2 weeks—if rise ≥1 g/dL, continue iron for 3 months 1, 2
5. If no response to iron: Order hemoglobin electrophoresis, B12, folate, renal function 1
6. If ferritin 100-500 ng/mL with low TSAT: Consider functional iron deficiency or anemia of chronic disease 1