What further work‑up should be done for a female patient with unexplained anemia and normal ferritin, reticulocyte count, C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR)?

Further Workup for Unexplained Anemia with Normal Ferritin, Reticulocyte Count, CRP, and ESR

With normal ferritin, reticulocyte count, and inflammatory markers, you should immediately obtain transferrin saturation, vitamin B12, folate, and a peripheral blood smear to identify the underlying cause of this anemia. 1

Immediate Next Steps

Essential Laboratory Tests

• Measure transferrin saturation (TSAT) because ferritin alone can miss iron deficiency, especially when ferritin is between 30-100 μg/L; a TSAT <16-20% indicates functional or absolute iron deficiency even with "normal" ferritin 2, 3

• Check vitamin B12 and folate levels as these are common causes of normocytic or macrocytic anemia that present with normal inflammatory markers 1, 4

• Obtain a peripheral blood smear to evaluate red cell morphology, look for hypersegmented neutrophils (B12/folate deficiency), target cells (thalassemia), or other abnormalities 4, 3

• Measure red cell distribution width (RDW) if not already done, as an elevated RDW suggests mixed deficiencies (iron plus B12/folate) that can neutralize the MCV and mask individual deficiencies 1, 4

Additional Iron Assessment

• Consider soluble transferrin receptor (sTfR) measurement if available, as it is elevated in true iron deficiency but normal or low in anemia of chronic disease, helping differentiate these conditions when ferritin is equivocal 2

• Reticulocyte hemoglobin content (CHr or Ret-He) may provide additional information about functional iron availability, though it is affected by inflammation and should not be used as a sole diagnostic criterion 5, 6

Interpretation Framework

When Ferritin is "Normal" But Iron Deficiency Still Possible

• Ferritin <30 μg/L confirms absolute iron deficiency in the absence of inflammation 3

• Ferritin 30-100 μg/L with TSAT <16% suggests iron deficiency despite the "normal" ferritin range, as ferritin can be falsely elevated by subclinical inflammation not detected by CRP/ESR 2

• Even with normal CRP/ESR, ferritin up to 100 μg/L may still indicate iron deficiency in certain clinical contexts, particularly in patients with chronic conditions 2

Normal Reticulocyte Count Interpretation

• A normal or low reticulocyte count with anemia indicates impaired erythropoiesis rather than hemolysis or acute blood loss, pointing toward nutritional deficiencies (iron, B12, folate), bone marrow disorders, or chronic kidney disease 1, 3

Specific Diagnostic Pathways

If MCV is Low-Normal or Microcytic

• Obtain hemoglobin electrophoresis to exclude thalassemia trait, which presents with microcytosis, normal ferritin, and normal inflammatory markers 1

• Assess for chronic blood loss sources including gastrointestinal evaluation in adult women and men, as occult bleeding can cause iron deficiency before ferritin drops below normal range 3

If MCV is Normal

• Check thyroid-stimulating hormone (TSH) as hypothyroidism commonly causes normocytic anemia with normal inflammatory markers 4

• Measure serum creatinine and calculate GFR to evaluate for chronic kidney disease, which causes normocytic anemia through reduced erythropoietin production 2, 3

If MCV is Elevated

• Vitamin B12 deficiency is the priority diagnosis with macrocytosis and normal inflammatory markers; measure serum B12 and consider methylmalonic acid if B12 is borderline (150-400 pmol/L) 4

• Review medication history for thiopurines (azathioprine, 6-mercaptopurine), methotrexate, hydroxyurea, or anticonvulsants, which cause macrocytosis without inflammation 2, 4

Common Pitfalls to Avoid

• Do not rely solely on ferritin when it falls in the 30-100 μg/L range; always pair it with transferrin saturation to avoid missing functional iron deficiency 2

• Do not assume normal CRP/ESR excludes all inflammation; subclinical inflammation can still elevate ferritin enough to mask iron deficiency 2

• Do not overlook mixed deficiencies; coexisting iron and B12/folate deficiency can produce a normal MCV with elevated RDW, requiring assessment of both iron and vitamin status 1, 4

• Do not forget to check for chronic kidney disease in patients with normocytic anemia and normal inflammatory markers, as this is a common and treatable cause 2, 3

When to Consider Bone Marrow Evaluation

• Refer to hematology for bone marrow examination if initial workup (iron studies, B12, folate, TSH, creatinine, peripheral smear) is unrevealing, or if pancytopenia is present suggesting myelodysplastic syndrome or aplastic anemia 4, 3