What is the appropriate diagnostic approach for iron deficiency anemia?

Diagnostic Approach to Iron Deficiency Anemia

Begin with a complete blood count (CBC) including hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and reticulocyte count, combined with serum ferritin, transferrin saturation (TSAT), and C-reactive protein (CRP) to establish the diagnosis and distinguish iron deficiency anemia from anemia of chronic disease. 1

Initial Laboratory Workup

Minimum Required Tests

The minimum diagnostic workup must include: 1

• Complete blood count with RDW and MCV 1
• Reticulocyte count 1
• Serum ferritin 1
• Transferrin saturation (calculated as serum iron × 100 ÷ total iron-binding capacity) 1
• CRP concentration to assess for inflammation 1

Defining Anemia

Use the WHO hemoglobin thresholds to define anemia: 1

• Men: Hb <13.0 g/dL 1
• Non-pregnant women: Hb <12.0 g/dL 1
• Pregnant women: Hb <11.0 g/dL 1
• Children vary by age (11.0-12.0 g/dL depending on age group) 1

Interpreting Ferritin Based on Inflammatory Status

Without Inflammation (Normal CRP)

Serum ferritin <30 μg/L confirms iron deficiency in patients without clinical, endoscopic, or biochemical evidence of inflammation. 1, 2

Serum ferritin <12-15 μg/L is diagnostic of iron deficiency with 99% specificity, though this threshold misses many cases due to poor sensitivity. 1, 2

Iron deficiency is almost certainly absent when ferritin >100 μg/L in the absence of inflammation. 1

With Inflammation (Elevated CRP/ESR)

Ferritin up to 100 μg/L may still indicate iron deficiency when inflammation is present, because ferritin is an acute-phase reactant that rises with inflammation. 1, 2

Ferritin 30-100 μg/L with elevated CRP indicates a mixed picture of true iron deficiency combined with anemia of chronic disease. 1, 2

Ferritin >100 μg/L with TSAT <20% and elevated CRP defines anemia of chronic disease with functional iron deficiency. 1, 2

Ferritin >150 μg/L rarely represents true iron deficiency even in inflammatory states. 2

Role of Transferrin Saturation

Calculate TSAT and use <20% as the threshold to confirm iron deficiency, particularly when ferritin is between 30-100 μg/L. 1, 2

TSAT <16% combined with low MCV, raised RDW, and microcytic hypochromic red cells on blood film strongly supports iron deficiency anemia. 1

In the presence of inflammation, the diagnostic criteria for anemia of chronic disease are ferritin >100 μg/L AND TSAT <20%. 1, 2

Red Blood Cell Indices

Mean Corpuscular Volume (MCV)

Microcytosis (MCV below normal range) is characteristic of iron deficiency anemia but may be absent in combined deficiencies. 1

Macrocytosis suggests vitamin B12 or folate deficiency, but also occurs with thiopurine medications, alcohol abuse, hypothyroidism, or reticulocytosis. 1

Normocytosis with normal or elevated ferritin suggests anemia of chronic disease. 1

Red Cell Distribution Width (RDW)

Elevated RDW indicates iron deficiency and can reveal coexisting microcytosis and macrocytosis that neutralize each other to produce a falsely normal MCV. 1, 2

Reticulocyte Count Interpretation

Low or normal reticulocytes indicate inability to respond appropriately to anemia due to deficiencies (iron, B12, folate) or primary bone marrow disease. 1, 2

Elevated reticulocytes indicate increased red cell formation, which excludes deficiency states and points toward hemolysis. 1, 2

When reticulocytes are elevated, measure haptoglobin, lactate dehydrogenase, and bilirubin to assess for hemolysis. 1

Extended Workup When Diagnosis Remains Unclear

Proceed to extended testing when the minimum workup does not establish a clear diagnosis: 1

• Vitamin B12 and folic acid concentrations 1
• Soluble transferrin receptor (sTfR), which is elevated in true iron deficiency and not affected by inflammation 1, 2
• Percentage of hypochromic red cells and reticulocyte hemoglobin 1
• Haptoglobin, lactate dehydrogenase, and bilirubin if hemolysis is suspected 1
• Creatinine and urea to assess renal function 1

Consult hematology if the cause of anemia remains unclear after extended workup. 1

Common Pitfalls and Caveats

Do not assume dietary insufficiency is the sole cause of iron deficiency anemia; gastrointestinal blood loss from occult malignancy (colon or gastric cancer) is the most common cause in adult men and post-menopausal women and requires investigation. 1

Do not rely on ferritin alone when inflammation is present; always calculate TSAT because functional iron deficiency can exist with high ferritin when TSAT <20%. 1, 2

Do not dismiss mild anemia as less significant than severe anemia; there is no evidence that mild anemia is less indicative of important underlying disease. 1

Recognize that serum ferritin may be falsely elevated above 12-15 μg/L in patients with concurrent chronic inflammation, malignancy, or hepatic disease despite true iron deficiency. 1

In patients with extensive small bowel resection, extensive ileal Crohn's disease, or ileal-anal pouch, assess vitamin B12 and folate more frequently than annually. 1

Special Population Considerations

Inflammatory Bowel Disease

In IBD patients during remission, ferritin <30 μg/L reliably indicates iron deficiency. 1, 2

During active IBD inflammation, use ferritin <100 μg/L as the screening threshold and confirm with TSAT <20%. 1, 2

Monitor IBD patients every 6-12 months in remission or mild disease, and at least every 3 months with active disease. 2

Pregnancy

Screen all pregnant women with a complete blood count in the first trimester and again at 24-28 weeks of gestation. 3

In pregnancy, define anemia as hemoglobin <11.0 g/dL in the first trimester and <10.5-11.0 g/dL in the second or third trimester. 3

Mild anemia with hemoglobin ≥10.0 g/dL and mildly low or normal MCV is likely iron deficiency anemia; a trial of oral iron serves as both diagnostic and therapeutic. 3