What are the causes of macrocytic anemia?

Causes of Macrocytic Anemia

Macrocytic anemia is primarily caused by vitamin B12 deficiency, folate deficiency, alcoholism, and myelodysplastic syndrome, with several other important etiologies that require specific diagnostic consideration. 1, 2, 3

Classification of Macrocytic Anemias

Macrocytic anemias (MCV >100 fL) can be divided into two main categories:

1. Megaloblastic Macrocytic Anemias

• Vitamin B12 (cobalamin) deficiency 1, 4, 3

  • Pernicious anemia
  • H. pylori gastritis
  • Prolonged use of antacids
  • Strict vegan diet
  • Malabsorption syndromes

• Folate deficiency 1, 4, 3

  • Increased requirements (pregnancy, hemolysis)
  • Malnutrition
  • Malabsorption
  • Alcoholism

• Medications that interfere with DNA synthesis 1, 3

  • Hydroxyurea
  • Methotrexate
  • Azathioprine
  • Other cytostatic medications

2. Non-Megaloblastic Macrocytic Anemias

• Liver disease/dysfunction 2, 5

• Alcoholism (independent of folate deficiency) 2, 5

• Myelodysplastic syndromes (MDS) 1, 2

• Hypothyroidism 1, 5

• Reticulocytosis (falsely elevated MCV due to larger reticulocytes) 1, 6

  • Hemolytic anemia
  • Recovery from acute blood loss
  • Response to treatment of other anemias

• Rare causes 1

  • Thiamine-responsive megaloblastic anemia syndrome
  • Inherited disorders of DNA synthesis

Diagnostic Approach

When evaluating macrocytic anemia, the reticulocyte count provides crucial initial information:

Elevated Reticulocytes

• Suggests hemolysis or blood loss with compensatory response
• MDS with hemolytic component
• False macrocytosis due to reticulocytosis 1, 6

Normal or Low Reticulocytes

• Vitamin B12 deficiency
• Folate deficiency
• MDS without hemolysis
• Medication effect
• Hypothyroidism
• Liver disease
• Alcoholism 1

Key Laboratory Findings

• Vitamin B12 deficiency: Low serum B12 levels, elevated methylmalonic acid and homocysteine
• Folate deficiency: Low serum folate, elevated homocysteine with normal methylmalonic acid
• MDS: Cytopenia in other cell lines (leukopenia, thrombocytopenia), abnormal bone marrow findings
• Liver disease: Elevated liver enzymes, other signs of hepatic dysfunction
• Alcoholism: History of alcohol use, possible liver function abnormalities
• Hypothyroidism: Elevated TSH, low free T4 1, 5

Clinical Pearls

1. Macrocytic anemia is not synonymous with vitamin deficiency - always consider the full differential diagnosis 6

2. In elderly patients, consider MDS as a potential cause, especially with concurrent cytopenias 2

3. Reticulocyte count is essential to distinguish between production defects and increased RBC turnover 1, 6

4. Peripheral blood smear examination can provide valuable clues:

   • Hypersegmented neutrophils suggest megaloblastic anemia
   • Oval macrocytes suggest liver disease or MDS
   • Round macrocytes suggest alcoholism or other causes 3, 5

5. Medication review is critical, as many drugs can cause macrocytosis with or without anemia 1, 3

By systematically evaluating these causes and using appropriate laboratory testing, the specific etiology of macrocytic anemia can be determined, allowing for targeted treatment of the underlying condition.