What is the etiology of microcytosis?

Etiology of Microcytosis

The primary causes of microcytosis (MCV <80 fL) are iron deficiency anemia, thalassemia trait, anemia of chronic disease, lead toxicity, and sideroblastic anemia, with iron deficiency being the most common etiology. 1, 2

Major Causes of Microcytosis

1. Iron Deficiency Anemia

• Most common cause of microcytosis worldwide 2
• Laboratory findings:
  • Low serum ferritin (<30 μg/L without inflammation, <100 μg/L with inflammation) 3
  • Low transferrin saturation
  • Low serum iron
  • Elevated total iron-binding capacity
  • Elevated red cell distribution width (RDW)
• Etiology includes:
  • Gastrointestinal blood loss (most common cause in adults)
  • Menstrual blood loss
  • Malabsorption
  • Increased iron requirements (pregnancy)
  • Inadequate dietary intake

2. Thalassemia Trait

• Second most common cause of microcytosis 1, 4
• Laboratory findings:
  • Very low MCV (often out of proportion to the degree of anemia)
  • Normal or elevated RBC count
  • Normal serum ferritin
  • Normal transferrin saturation
  • Elevated HbA2 >3.5% (in beta-thalassemia trait) 5
  • Normal or slightly elevated RDW

3. Anemia of Chronic Disease/Inflammation

• Can present with microcytosis, though often normocytic 3, 1
• Laboratory findings:
  • Normal or elevated serum ferritin (>100 μg/L)
  • Low transferrin saturation
  • Low serum iron
  • Low total iron-binding capacity
  • Normal or slightly elevated RDW
  • Elevated inflammatory markers (CRP)

4. Lead Toxicity

• Less common cause of microcytosis
• Laboratory findings:
  • Elevated blood lead levels
  • Basophilic stippling of red cells
  • Elevated free erythrocyte protoporphyrin

5. Sideroblastic Anemia

• Rare cause of microcytosis 5
• Laboratory findings:
  • Presence of ringed sideroblasts in bone marrow
  • Elevated serum iron
  • Increased transferrin saturation
  • Normal or elevated ferritin

Diagnostic Approach to Microcytosis

1. Initial evaluation: Complete blood count with red cell indices, serum ferritin, transferrin saturation, and CRP 3, 1

2. Laboratory parameters for differential diagnosis:

Parameter	Iron Deficiency	Anemia of Chronic Disease	Thalassemia
MCV	Low (<80 fL)	Low or normal	Very low
MCH	Low	Low or normal	Very low
Serum Ferritin	Low (<15 μg/L)	Normal or high (>100 μg/L)	Normal
TSAT	Low	Low	Normal
RDW	Elevated	Normal or slightly elevated	Normal
RBC Count	Low or normal	Low or normal	Normal or elevated

1. Further testing if initial evaluation is inconclusive:
   • Hemoglobin electrophoresis (for thalassemia)
   • Serum transferrin receptor (elevated in iron deficiency)
   • Bone marrow examination (gold standard for iron deficiency) 6
   • Lead levels (if lead toxicity suspected)

Clinical Pearls and Pitfalls

• Coexisting conditions: Iron deficiency and thalassemia can coexist in approximately 8% of cases with microcytosis 7
• Inflammatory states: Serum ferritin is an acute phase reactant; levels up to 100 μg/L may still be consistent with iron deficiency in the presence of inflammation 3
• Diagnostic indices: The Mentzer index (MCV/RBC count) and RBC count are useful in differentiating iron deficiency from thalassemia trait 7
• Mixed anemias: Microcytosis and macrocytosis can coexist, resulting in a normal MCV; a high RDW suggests this possibility 3
• Non-anemic iron deficiency: Iron deficiency can cause microcytosis before anemia develops 3

Remember that once iron deficiency anemia is diagnosed, the underlying cause must be identified, particularly in adults where gastrointestinal blood loss (potentially from malignancy) must be excluded 2.