What are the primary causes of macrocytic anemia?

Primary Causes of Macrocytic Anemia

Macrocytic anemia is primarily caused by vitamin B12 deficiency, followed by folate deficiency, with other causes including liver dysfunction, alcoholism, hypothyroidism, myelodysplastic syndrome, and certain medications. 1

Classification of Macrocytic Anemia

Macrocytic anemia is defined by a mean corpuscular volume (MCV) >100 femtoliter (fL) and is classified into two main categories:

1. Megaloblastic Causes

• Vitamin B12 (Cobalamin) Deficiency

  • Most common cause of megaloblastic anemia 1, 2
  • Almost always due to malabsorption rather than inadequate intake 3
  • Causes include:
    • Pernicious anemia
    • Gastrectomy
    • Ileal disease or resection
    • Bacterial overgrowth
    • Pancreatic insufficiency

• Folate (Vitamin B9) Deficiency

  • Second most common cause of megaloblastic anemia 1
  • Often due to inadequate dietary intake 3
  • Other causes include:
    • Increased requirements (pregnancy, hemolytic anemia)
    • Malabsorption
    • Medications (anticonvulsants, methotrexate)

• Impaired DNA Synthesis

  • Medications affecting DNA synthesis (chemotherapeutic agents)
  • Inherited disorders of DNA synthesis (rare)

2. Non-Megaloblastic Causes

• Liver Dysfunction 4, 1
• Alcoholism 4, 1
• Hypothyroidism 4, 1
• Myelodysplastic Syndrome (MDS) 4
• Reticulocytosis (physiologic response to acute blood loss) 1
• Medications (antiretrovirals, immunosuppressants) 4

Laboratory Findings

Typical findings in macrocytic anemia include:

• Elevated MCV (>100 fL)
• Decreased hemoglobin
• Oval macrocytes on peripheral blood smear
• Few reticulocytes
• Moderate leukopenia and thrombocytopenia (especially in megaloblastic anemia) 3
• Elevated RDW (Red cell distribution width) 5

In megaloblastic anemia specifically:

• Decreased serum vitamin B12 (<200 pg/mL) or folate (<4 ng/mL) levels 3, 6
• Hypersegmented neutrophils
• Megaloblasts in bone marrow

Diagnostic Approach

The diagnostic workup for macrocytic anemia should include:

1. Complete blood count with MCV, MCH, and RDW 5
2. Peripheral blood smear examination
3. Vitamin B12 and folate levels 5
4. Thyroid function tests 5
5. Liver function tests 5
6. Reticulocyte count 5
7. Consider bone marrow examination if myelodysplastic syndrome is suspected 4

Common Pitfalls and Caveats

• Coexisting deficiencies: Vitamin B12 and folate deficiencies can coexist. In one study, 71% of folate-deficient patients also had vitamin B12 deficiency 2.
• Masking effect: Folate supplementation can mask the hematologic manifestations of vitamin B12 deficiency while neurological damage progresses.
• Mixed anemias: Patients may have both macrocytic and microcytic features if multiple causes of anemia are present.
• Normal MCV: Early or mild deficiencies may not cause significant macrocytosis.
• Reticulocytosis: Can cause macrocytosis without true megaloblastic anemia 1.
• Myelodysplastic syndrome: Should be considered in elderly patients with unexplained macrocytic anemia, especially with other cytopenias 4.

Management Considerations

Treatment should be directed at the underlying cause:

• For vitamin B12 deficiency: Parenteral or high-dose oral vitamin B12 supplementation
• For folate deficiency: Oral folate supplementation
• For alcohol-related macrocytosis: Alcohol cessation and nutritional support
• For medication-induced macrocytosis: Medication adjustment if possible
• For hypothyroidism: Thyroid hormone replacement
• For suspected MDS: Hematology consultation 4

When laboratory testing is not immediately available, initial treatment of severe megaloblastic anemia should include both vitamin B12 and folate to avoid missing either deficiency 3, 6.