How to diagnose iron deficiency anemia in a Complete Blood Count (CBC)?

Diagnosing Iron Deficiency Anemia on Complete Blood Count

A CBC alone cannot definitively diagnose iron deficiency anemia—you must obtain additional iron studies (serum ferritin, transferrin saturation) to confirm the diagnosis, as hemoglobin and red cell indices are late markers that only become abnormal with severe iron depletion. 1, 2

Initial CBC Findings Suggestive of Iron Deficiency Anemia

Hemoglobin and Hematocrit

• Hemoglobin is the preferred measure over hematocrit for detecting anemia, with better reproducibility and lower coefficients of variation 1
• Use age- and sex-specific cutoffs to define anemia (see reference values below) 1
• Critical limitation: Hemoglobin and hematocrit decrease only in late-stage iron deficiency and are unreliable as sole indicators 1, 2

Red Blood Cell Indices

• Microcytosis (low MCV) is characteristic of iron deficiency but may be absent in combined deficiencies 1
• Low mean corpuscular hemoglobin (MCH) and low mean corpuscular hemoglobin concentration (MCHC) support iron deficiency 3, 4
• Elevated red cell distribution width (RDW) suggests iron deficiency, with moderate discriminating power (AUC 0.73) 3, 4

Why CBC Parameters Are Insufficient Alone

The fundamental problem: Normal CBC values do not exclude iron deficiency, and individuals can have normal hemoglobin, hematocrit, MCV, and MCHC while having depleted iron stores on ferritin testing 2. Studies show that less than 50% of anemic patients (by hemoglobin criteria) are actually iron deficient, meaning CBC screening has poor positive predictive value 1.

Required Confirmatory Tests Beyond CBC

Essential Iron Studies

• Serum ferritin <12 µg/dL is diagnostic of absolute iron deficiency in the general population 1
• Transferrin saturation (TSAT) <16% indicates iron deficiency in the general population 1
• Important caveat: Ferritin is an acute phase reactant and may be falsely elevated (>100 µg/dL) in inflammation, malignancy, or hepatic disease despite true iron deficiency 1

Diagnostic Algorithm

1. Obtain CBC with indices (hemoglobin, hematocrit, MCV, MCH, MCHC, RDW) 1
2. If anemia is present, immediately order serum ferritin and transferrin saturation 1
3. If ferritin <12 µg/dL or TSAT <16%, diagnose iron deficiency anemia 1
4. If ferritin 12-100 µg/dL with clinical suspicion, consider additional testing or therapeutic trial of iron supplementation 1
5. Confirm diagnosis by hemoglobin increase >1.0 g/dL after 3 weeks of oral iron therapy 1

CBC Performance Characteristics for Iron Deficiency Anemia

When iron deficiency anemia is already established (not just iron deficiency), CBC parameters show improved but still suboptimal diagnostic accuracy 3, 4:

• Hematocrit: AUC 0.96 at cutoff 35.5% 3
• MCH: AUC 0.81 at cutoff 29.15 pg 3
• MCHC: AUC 0.80 at cutoff 337.5 g/L 3
• MCV: AUC 0.77 at cutoff 84.10 fL 3
• RBC count: AUC 0.73 at cutoff 4.04 × 10¹²/L 3

Common Pitfalls to Avoid

• Do not assume microcytosis equals iron deficiency—thalassemia, hemoglobinopathies, and chronic disease can cause identical findings 1
• Do not rely on normal hemoglobin to exclude iron deficiency—iron stores may be depleted before anemia develops 2
• Do not interpret ferritin in isolation—values between 12-100 µg/dL are indeterminate in the presence of inflammation 1
• Avoid improper capillary sampling technique (excessive finger squeezing), which causes falsely low hemoglobin readings 1
• Consider racial differences—Black individuals have hemoglobin distributions 0.8 g/dL lower than White individuals, potentially increasing false-positive anemia diagnoses 1

Additional Workup When Iron Deficiency Confirmed

• Complete blood count with differential to assess white blood cells and platelets—abnormalities suggest bone marrow dysfunction from malignancy or vasculitis 1
• Reticulocyte count to evaluate bone marrow response—elevated count suggests hemolysis rather than iron deficiency 1
• Stool guaiac testing to identify gastrointestinal bleeding as the source 1
• Consider vitamin B12, folate, and thyroid function if macrocytosis or inadequate response to iron therapy 1