What are the other causes of low hemoglobin (hypochromic anemia) if iron, vitamin B12 (cobalamin), and folate levels are normal?

Causes of Low Hemoglobin When Iron, B12, and Folate are Normal

When iron, vitamin B12, and folate levels are normal, anemia may be caused by chronic disease, hemoglobinopathies, bone marrow disorders, hemolysis, renal disease, or medication effects. 1

Common Causes of Normocytic Anemia

• Anemia of Chronic Disease (ACD): Associated with chronic inflammatory conditions, infections, or malignancies. Characterized by normal MCV, normal or elevated ferritin, and low transferrin saturation 1

• Chronic Kidney Disease: Decreased erythropoietin production leads to normocytic anemia with normal iron studies 1

• Hemolytic Anemias: Characterized by increased red cell destruction, elevated reticulocyte count, elevated LDH, and decreased haptoglobin 1

• Bone Marrow Disorders: Including myelodysplastic syndromes, leukemia, multiple myeloma, and aplastic anemia 2

Common Causes of Microcytic Anemia (Beyond Iron Deficiency)

• Thalassemia: Hereditary disorder with reduced or absent synthesis of globin chains. Typically presents with microcytosis out of proportion to the degree of anemia 1

• Sideroblastic Anemia: Characterized by ringed sideroblasts in bone marrow, microcytosis, and normal or elevated iron stores 1

• Anemia of Chronic Disease: Can sometimes present with microcytosis 1

• Lead Poisoning: Can cause microcytic anemia with basophilic stippling of red cells 1

Common Causes of Macrocytic Anemia (Beyond B12/Folate Deficiency)

• Medications: Including anticonvulsants, methotrexate, hydroxyurea, azathioprine, and other chemotherapeutic agents 1, 2

• Liver Disease: Causes macrocytosis due to membrane lipid changes 2

• Alcoholism: Direct toxic effect on bone marrow and red cell precursors 2

• Myelodysplastic Syndromes: Characterized by ineffective hematopoiesis 2

• Hypothyroidism: Can cause macrocytic anemia independent of B12/folate status 2

Diagnostic Approach

1. Complete Blood Count with Indices:

   • Evaluate MCV, MCH, RDW, and reticulocyte count 1
   • High reticulocyte count suggests hemolysis or recent hemorrhage 1, 2
   • Low/normal reticulocyte count suggests inadequate bone marrow response 1

2. Peripheral Blood Smear:

   • Look for red cell morphology abnormalities (schistocytes, spherocytes, target cells) 1
   • Evaluate white blood cells and platelets for pancytopenia 1

3. Additional Tests Based on Clinical Suspicion:

   • Hemoglobin electrophoresis for suspected hemoglobinopathies 1
   • LDH, haptoglobin, and bilirubin for suspected hemolysis 1
   • Renal function tests for suspected kidney disease 1
   • Thyroid function tests for suspected hypothyroidism 2
   • Bone marrow examination if myelodysplastic syndrome or other marrow disorder is suspected 2

Special Considerations

• Masked Iron Deficiency: In inflammatory conditions, ferritin may be falsely elevated despite iron deficiency. Consider measuring transferrin saturation, soluble transferrin receptor, or percentage of hypochromic red cells 1

• Combined Deficiencies: Multiple nutritional deficiencies can coexist and mask each other's hematologic effects. For example, iron deficiency can mask the macrocytosis of B12/folate deficiency 3, 4

• Medication Review: Always review current medications as many can cause or contribute to anemia 2

• Response to Therapy: A good response to iron therapy (Hb rise ≥10 g/L within 2 weeks) suggests absolute iron deficiency even if initial iron studies were equivocal 1

• Functional Iron Deficiency: Can occur despite normal ferritin when there is inadequate iron mobilization for erythropoiesis 1

By systematically evaluating these potential causes, the underlying etiology of anemia can be identified even when the common nutritional deficiencies have been excluded.