What are the causes of macrocytic anemia?

Macrocytic Anemia Causes

Macrocytic anemia (MCV >100 fL) is primarily divided into megaloblastic causes—most commonly vitamin B12 or folate deficiency—and non-megaloblastic causes including alcoholism, myelodysplastic syndrome (MDS), certain medications (hydroxyurea, diphenytoin, azathioprine), liver disease, and hypothyroidism 1.

Megaloblastic Causes (Most Common)

The majority of macrocytic anemia is megaloblastic, resulting from impaired DNA synthesis that produces large nucleated red blood cell precursors 1.

Vitamin B12 Deficiency

• Most common cause overall 2, 3
• Occurs in 10-20% of older adults 4
• Key risk groups: elderly (>60 years), vegetarians/vegans, malabsorption syndromes, pernicious anemia (lack of intrinsic factor), atrophic gastritis with achlorhydria, post-bariatric surgery (RYGB, BPD-DS), metformin use (7-11% absolute risk) 4
• Can present with neurologic and psychiatric symptoms even with low-normal B12 levels; confirm with elevated methylmalonic acid 4

Folate Deficiency

• Less common than B12 deficiency 1
• Causes: inadequate intake, malabsorption, increased requirements (pregnancy, hemolysis, chronic myeloid leukemia), certain medications 5

Combined B12 and Folate Deficiency

• Occurs in 21.7% of megaloblastic cases 3
• Particularly in malabsorption syndromes 5

Non-Megaloblastic Causes

Myelodysplastic Syndrome (MDS)

• Increasingly important cause, especially in elderly 1, 6, 7
• Presents with macrocytic anemia (usually), often with other cytopenias 6
• Requires bone marrow examination showing dysplasia with or without excess blasts 6
• Critical pitfall: Elderly patients with macrocytic anemia and MDS may be misdiagnosed as megaloblastic anemia; if no response to vitamin replacement occurs, suspect MDS 3

Alcoholism

• Common non-megaloblastic cause 1
• Can cause isolated macrocytosis without anemia 5

Medications

• Hydroxyurea 1
• Diphenytoin 1
• Azathioprine/6-mercaptopurine (thiopurines) 5
• Methotrexate 5

Liver Disease

• Chronic liver dysfunction causes non-megaloblastic macrocytosis 2, 7, 3
• Accounts for 15% of non-megaloblastic cases 3

Hypothyroidism

• Recognized cause of non-megaloblastic macrocytosis 5, 2, 7

Reticulocytosis

• Important consideration: Elevated reticulocyte count in response to hemolysis or acute blood loss can cause "false" macrocytosis since reticulocytes are larger than mature RBCs 8, 5, 2
• High reticulocyte index (>2.0) indicates increased RBC production, suggesting hemolysis or hemorrhage rather than production defect 1

Primary Bone Marrow Disorders

• Account for 35% of non-megaloblastic cases 3
• Include aplastic anemia, pure red cell aplasia, inherited bone marrow failure syndromes 9

Diagnostic Algorithm

When MCV >100 fL:

1. Check reticulocyte count first 1, 5:

   • If elevated (RI >2.0): Consider hemolysis or acute blood loss, not true production defect
   • If low/normal: Proceed with deficiency workup

2. For low/normal reticulocytes, obtain:

   • Serum B12 and folate levels 1
   • If B12 low-normal with symptoms: Check methylmalonic acid 4
   • Peripheral blood smear for megaloblastic changes, hypersegmented neutrophils 1

3. If B12/folate normal, evaluate:

   • Liver function tests 6, 3
   • Thyroid function tests 5, 6
   • Medication history (especially hydroxyurea, azathioprine, metformin) 4, 1, 5
   • Alcohol use 1, 5

4. If above negative and especially if other cytopenias present:

   • Strongly consider MDS 6, 7
   • Obtain bone marrow examination 6, 3
   • Hematology referral appropriate 7

Critical Clinical Pearls

• MCV >110 fL strongly suggests megaloblastic anemia (p=0.0007) 3
• Macrocytosis with normal or elevated ferritin may mask coexisting iron deficiency; check RDW (elevated suggests iron deficiency) 5
• In elderly patients not responding to vitamin replacement within 4 weeks, suspect MDS 3
• Folate fortification does not mask macrocytic anemia in B12 deficiency, though high-dose folate supplements might 4