Initial Evaluation of Suspected Anemia
Begin with a complete blood count (CBC) including hemoglobin, red cell indices (MCV, MCH, MCHC), white blood cell count with differential, platelet count, and absolute reticulocyte count, followed immediately by iron studies (serum ferritin and transferrin saturation) and vitamin B12 and folate levels. 1
Essential Laboratory Tests for Initial Workup
Core Anemia Panel
- Hemoglobin is preferred over hematocrit because it has better reproducibility across laboratories and is not affected by sample storage time or patient glucose levels 2, 1
- Complete blood count assesses bone marrow function across all cell lines; abnormalities in two or more cell lines warrant hematology consultation 2, 1
- Absolute reticulocyte count is essential to assess bone marrow response—a low count indicates impaired erythropoiesis (common in iron deficiency), while an elevated count suggests hemolysis or acute blood loss 2, 3, 1
Iron Studies
Serum ferritin is the single most useful marker for iron stores 2, 3, 1
- Ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 3, 1
- Ferritin <45 ng/mL defines iron deficiency anemia when combined with low hemoglobin 2
- Critical pitfall: Ferritin is an acute phase reactant and can be falsely elevated in inflammation, chronic disease, malignancy, or liver disease 2, 1
- In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency 3
Transferrin saturation (TSAT) helps identify iron availability for erythropoiesis 3, 1
Additional Essential Tests
- Vitamin B12 and folate levels must be obtained to rule out deficiencies that may contribute to or cause anemia 2, 1
- Serum creatinine and GFR to evaluate for chronic kidney disease as a cause of anemia 2
Interpretation Based on Red Cell Indices
Microcytic Anemia (MCV <80 fL)
- Most commonly indicates iron deficiency anemia, the most prevalent cause of anemia globally 1
- Low MCH and MCHC suggest hypochromic anemia, strongly associated with iron deficiency 3
Normocytic Anemia (MCV 80-100 fL)
- May indicate hemorrhage, hemolysis, or anemia of chronic inflammation 1
- The anemia of chronic kidney disease is typically normochromic and normocytic 2
Macrocytic Anemia (MCV >100 fL)
- Suggests vitamin B12 or folate deficiency 1
Specific Diagnostic Thresholds
Defining Anemia
- Men: Hemoglobin <13 g/dL 2
- Non-pregnant women: Hemoglobin <12 g/dL 2
- Use the lower limit of normal for the relevant population and laboratory performing the test 2
Confirming Iron Deficiency Anemia
Iron deficiency anemia is present when BOTH criteria are met 2:
- Hemoglobin below threshold (as above) AND
- Ferritin <45 ng/mL (or <30 μg/L without inflammation)
Additional Workup Based on Initial Results
If Iron Deficiency is Confirmed
For men and postmenopausal women 2:
- Perform non-invasive testing for H. pylori and celiac disease 2
- Strong recommendation: Proceed with bidirectional endoscopy (gastroscopy and colonoscopy) to evaluate for gastrointestinal malignancy and bleeding sources 2
- Celiac disease is found in 3-5% of iron deficiency anemia cases and should be routinely screened serologically 2
For premenopausal women 2:
- Conditional recommendation for endoscopy given lower prevalence of neoplasia
- Those who place high value on avoiding endoscopy risks may reasonably select initial empiric iron supplementation alone 2
- However, if symptoms are present or iron supplementation fails, endoscopic evaluation is indicated 2
If Bidirectional Endoscopy is Unrevealing
- Consider video capsule endoscopy to evaluate the small bowel, particularly in patients requiring antiplatelet or anticoagulant therapy 2
- Capsule endoscopy is the preferred test for examining the small bowel because it is highly sensitive for mucosal lesions 2
If Iron Studies Show Elevated Ferritin with Low TSAT
- Consider anemia of chronic inflammation/disease 1
- Measure C-reactive protein to assess the contribution of inflammation to elevated ferritin 1
- Treat the underlying condition; erythropoietin therapy may be considered in specific situations such as chronic kidney disease 1
Treatment Initiation
Iron Replacement Therapy
- Oral iron in divided doses is first-line for most patients 2
- Intravenous iron should be used if 2:
- Intolerance to oral iron
- Gastrointestinal uptake problems (e.g., hepcidin elevation)
- Short timeline before surgery
- Malabsorption of oral iron
Response Assessment
- A good response to iron therapy (hemoglobin rise ≥10 g/L within 2 weeks) is highly suggestive of absolute iron deficiency, even if iron studies are equivocal 2
- Check hemoglobin at one month; if there is not a 1-2 g/dL increase, consider malabsorption, continued bleeding, or an unknown lesion 4
- Continue hemoglobin monitoring and ensure iron stores are restored (ferritin >100 ng/mL) 2
If No Response to Iron Therapy
- Investigate for ongoing blood loss 2
- Consider small bowel evaluation with capsule endoscopy 2
- Evaluate renal tract for other causes 2
- Consider bone marrow aspiration and biopsy when initial workup is unrevealing 1
Critical Pitfalls to Avoid
- Do not miss inflammation-masked iron deficiency: Ferritin can be falsely normal or elevated despite true iron deficiency in inflammatory states, chronic disease, malignancy, or liver disease 2, 3, 1
- Do not delay gastrointestinal evaluation in high-risk patients: 9% of patients older than 65 years with iron deficiency anemia have gastrointestinal cancer 4
- Do not assume menstruation explains iron deficiency in premenopausal women without further evaluation if symptoms are present or treatment fails 2
- Do not overlook celiac disease: Screen all patients with iron deficiency anemia for celiac disease 2