What causes normocytic anemia?

Causes of Normocytic Anemia

Normocytic anemia is most commonly caused by hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, or renal insufficiency. 1 These conditions result in anemia with normal red blood cell size (mean corpuscular volume 80-100 fL).

Classification by Mechanism

Normocytic anemia can be effectively categorized using the reticulocyte index (RI) to determine whether the problem is due to decreased production or increased loss/destruction of red blood cells:

Low Reticulocyte Index (Decreased Production)

• Anemia of chronic inflammation/disease

  • Associated with various inflammatory conditions, cancer, and infections
  • Characterized by normal/elevated ferritin, low transferrin saturation
  • Mediated by inflammatory cytokines that reduce iron availability

• Chronic kidney disease

  • Primary cause is insufficient erythropoietin production by diseased kidneys 1
  • Usually develops when GFR drops below 20-30 ml/min 2
  • Additional contributing factors may include shortened RBC survival and blood loss

• Bone marrow disorders

  • Aplastic anemia (failure of bone marrow to produce blood cells)
  • Myelodysplastic syndromes
  • Bone marrow infiltration by cancer or fibrosis
  • Myelosuppression from chemotherapy or radiation

• Endocrine disorders

  • Hypothyroidism
  • Hypopituitarism
  • Adrenal insufficiency

• Nutritional deficiencies in early stages

  • Early iron deficiency (before becoming microcytic)
  • Early B12 or folate deficiency (before becoming macrocytic)

High Reticulocyte Index (Increased Loss/Destruction)

• Acute blood loss

  • Trauma
  • Gastrointestinal bleeding
  • Genitourinary bleeding
  • Obstetric/gynecologic bleeding

• Hemolytic anemia

  • Diagnosed by signs of hemolysis: jaundice, hepatosplenomegaly, unconjugated hyperbilirubinemia, increased reticulocyte count, decreased haptoglobin 3
  • Immune-mediated (autoimmune, drug-induced)
  • Microangiopathic (DIC, TTP, HUS)
  • Inherited disorders (sickle cell disease, hereditary spherocytosis)
  • Mechanical (heart valves, ECMO)

Diagnostic Approach

The diagnostic approach to normocytic anemia should include:

1. Reticulocyte count/index - Key to differentiating between production problems and destruction/loss 1

2. Iron studies - Serum ferritin, transferrin saturation, serum iron, and TIBC 4

   • Low ferritin (<15 μg/L) suggests iron deficiency
   • Normal/high ferritin with low transferrin saturation suggests anemia of chronic disease

3. Inflammatory markers - CRP, ESR to assess for underlying inflammatory conditions

4. Hemolysis evaluation when suspected:

   • Direct Coombs test
   • Haptoglobin levels
   • LDH and indirect bilirubin
   • Peripheral blood smear

5. Kidney function tests - BUN, creatinine, GFR to assess for renal disease

6. Additional testing based on clinical suspicion:

   • Vitamin B12 and folate levels
   • Thyroid function tests
   • Bone marrow examination in selected cases

Common Pitfalls and Caveats

• Normocytic anemia is often multifactorial in elderly patients and those with chronic diseases
• Anemia of chronic disease is frequently mistaken for iron deficiency anemia and inappropriately treated with iron supplements 5
• Mixed deficiencies can present as normocytic anemia before developing classic microcytic or macrocytic features
• "Idiopathic" normocytic anemia is more common in older adults and often has a benign course 6
• Bone marrow examination is rarely contributive in normocytic anemia without other concerning features 6
• Always investigate for underlying causes, particularly occult blood loss, before labeling anemia as "idiopathic"

By systematically evaluating the reticulocyte index and following a structured diagnostic approach, the specific cause of normocytic anemia can usually be identified and appropriately managed.