What causes macrocytic anemia?

Causes of Macrocytic Anemia

Macrocytic anemia is primarily caused by vitamin B12 deficiency and folate deficiency, with other common causes including alcohol use disorder, liver disease, medications, hypothyroidism, and myelodysplastic syndrome. 1

Classification of Macrocytic Anemias

Macrocytic anemia (defined as mean corpuscular volume [MCV] >100 fL) can be classified into two main categories:

1. Megaloblastic Macrocytic Anemia

• Vitamin B12 deficiency - most common cause 1

  • Pernicious anemia
  • Malabsorption (gastric bypass, Crohn's disease)
  • Dietary deficiency (strict vegans)
  • H. pylori gastritis
  • Antacid use

• Folate deficiency 2, 3

  • Dietary deficiency
  • Increased requirements (pregnancy, hemolysis)
  • Malabsorption
  • Medications (anticonvulsants, methotrexate, sulfasalazine)

2. Non-megaloblastic Macrocytic Anemia

• Alcohol use disorder 4, 5
• Liver disease 4, 5
• Medications 2
  • Hydroxyurea
  • Azathioprine
  • Methotrexate
  • Anticonvulsants
• Hypothyroidism 2, 5
• Myelodysplastic syndrome (MDS) 2, 6
• Reticulocytosis (hemolysis, acute blood loss) 2, 4

Diagnostic Approach

Initial Evaluation

1. Complete blood count with MCV - confirms macrocytosis (MCV >100 fL)
2. Reticulocyte count 2
   • Low/normal: indicates decreased RBC production (deficiencies, bone marrow dysfunction)
   • High: indicates increased RBC production (hemolysis, blood loss)
3. Peripheral blood smear 4, 5
   • Megaloblastic changes: macro-ovalocytes, hypersegmented neutrophils
   • Non-megaloblastic changes: round macrocytes, target cells

Further Testing Based on Initial Results

1. For suspected megaloblastic anemia:

   • Serum vitamin B12 level
   • Serum folate level
   • Serum methylmalonic acid and homocysteine (more sensitive for B12 deficiency)

2. For suspected non-megaloblastic anemia:

   • Liver function tests
   • Thyroid function tests
   • Alcohol use assessment
   • Medication review
   • Consider bone marrow examination if MDS suspected 6

Important Clinical Pearls

• Vitamin B12 deficiency must be ruled out before treating with folate - Folic acid can mask B12 deficiency while allowing neurological damage to progress 2, 3

• Inflammation affects diagnostic parameters - In inflammatory states, ferritin may be elevated despite iron deficiency 2, 7

• Combined deficiencies can occur - Vitamin B12 and folate deficiencies can coexist, especially in malabsorptive conditions 8

• Medication review is crucial - Many drugs can cause macrocytosis either directly or by interfering with B12/folate metabolism 2

• Consider MDS in elderly patients - Especially with unexplained cytopenias in addition to macrocytic anemia 6

Treatment Considerations

Treatment should be directed at the underlying cause:

• Vitamin B12 deficiency: Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then maintenance with 1 mg every 2-3 months for life 2

• Folate deficiency: Oral folic acid 5 mg daily for a minimum of 4 months 2

• Alcohol-related: Alcohol cessation, nutritional support

• Medication-induced: Consider medication adjustment if possible

• Hypothyroidism: Thyroid hormone replacement

• MDS: Hematology consultation for specialized treatment

By systematically evaluating patients with macrocytic anemia using this approach, the underlying cause can be identified and appropriate treatment initiated to address both the anemia and its root cause.