What are the common etiologies of an elevated mean corpuscular volume on a complete blood count?

Etiology of Elevated MCV on CBC

The most common causes of elevated MCV are vitamin B12 or folate deficiency, chronic alcohol use, and medications—with the specific etiology determined by the degree of MCV elevation and peripheral smear findings. 1, 2

Classification by MCV Severity

The degree of MCV elevation provides critical diagnostic clues:

• MCV >130 fL: Almost exclusively caused by vitamin B12 or folate deficiency (megaloblastic anemia) or certain medications 3
• MCV 114-130 fL: Consider alcoholism/liver disease, bone marrow failure syndromes, myelodysplastic syndrome, myeloid malignancies, or hemolytic anemia 3
• MCV 100-114 fL: Broadest differential including lymphoid malignancies, chronic renal failure, hypothyroidism, solid tumors, or early stages of conditions in the higher MCV categories 3

Primary Etiologies

Nutritional Deficiencies (Megaloblastic)

• Vitamin B12 deficiency is a leading cause of macrocytosis with megaloblastic changes, presenting with macro-ovalocytes and hypersegmented neutrophils on peripheral smear 1, 2
• Folate deficiency causes similar megaloblastic changes but is less common than B12 deficiency 1, 4
• Megaloblastic anemia accounts for less than 10% of macrocytosis cases in hospitalized patients but remains clinically critical due to potential for irreversible neurological damage if untreated 5

Alcohol and Liver Disease

• Chronic alcohol use is the single most common cause of macrocytosis in hospitalized patients, causing macrocytosis independent of nutritional deficiencies 1, 5, 4
• Liver disease frequently causes macrocytosis through multiple mechanisms 2, 5
• These conditions typically produce MCV values between 100-120 fL 3

Medications

• Drug-induced macrocytosis is the most common cause in some series, particularly in hospitalized patients 5, 4
• Key offending agents include:
  • Hydroxyurea (causes self-limiting macrocytosis that resembles pernicious anemia morphologically but is unrelated to B12/folate deficiency) 6
  • Anticonvulsants (particularly phenytoin) 1
  • Methotrexate and other chemotherapeutic agents 7, 1
  • Sulfasalazine 1

Bone Marrow Disorders

• Myelodysplastic syndrome (MDS) is the leading cause of macrocytosis among hematologic malignancies, accounting for 19.3% of cases in specialized hematology clinics 3
• Bone marrow failure syndromes collectively represent 11.8% of macrocytosis cases 3
• Aplastic anemia accounts for 8.1% of cases 3
• These conditions become increasingly important in elderly patients and warrant hematology referral 8

Hemolysis and Reticulocytosis

• Hemolytic anemia causes macrocytosis due to increased reticulocyte production (young RBCs are larger) 2, 5
• Acute hemorrhage with reticulocytosis produces similar findings 2
• Reticulocyte count distinguishes this category from other causes 1

Other Causes

• Hypothyroidism produces mild macrocytosis (typically MCV 100-110 fL) 2, 8, 3
• Chronic renal failure can cause macrocytosis 1, 3
• Plasma cell dyscrasias account for 7.2% of cases 3

Diagnostic Algorithm

Initial Laboratory Evaluation

1. Peripheral blood smear examination is mandatory to distinguish megaloblastic from non-megaloblastic causes 1, 2

   • Macro-ovalocytes and hypersegmented neutrophils (≥6 lobes) indicate megaloblastic anemia 1, 4
   • Non-megaloblastic smear requires different diagnostic pathway 2

2. Vitamin B12 and folate levels are mandatory first-line tests 1

   • For equivocal B12 levels, methylmalonic acid (specific for B12 deficiency) and homocysteine (elevated in both B12 and folate deficiency) provide greater sensitivity 1, 5

3. Reticulocyte count differentiates between:

   • Low/normal: deficiency states, bone marrow disorders, medications 1, 2
   • Elevated: hemolysis or hemorrhage 1, 2

4. Additional targeted tests:

   • Serum ferritin and transferrin saturation (coexisting iron deficiency can mask full macrocytosis) 1
   • Liver function tests 2, 5
   • Thyroid function tests 2, 5
   • Haptoglobin and LDH if hemolysis suspected 1

Critical Diagnostic Pitfalls

• Always exclude B12 deficiency before treating folate deficiency—folate supplementation can mask B12 depletion while allowing irreversible neurological damage to progress 1
• Coexisting iron deficiency can normalize MCV despite ongoing B12/folate deficiency, masking the diagnosis 1
• Hydroxyurea-induced macrocytosis morphologically resembles pernicious anemia but is unrelated to vitamin deficiency; prophylactic folic acid is recommended for patients on hydroxyurea 6
• Macrocytosis without anemia (20.9% of B12 deficiency cases) still requires full evaluation as it may be the first clue to underlying pathology 4

When to Refer to Hematology

Immediate hematology consultation is required for: 1

• Unexplained macrocytosis after complete workup
• Suspicion for myelodysplastic syndrome (especially with concurrent cytopenias)
• Confirmed hemolytic anemia
• Pancytopenia
• No response to appropriate vitamin or iron replacement after 2-3 weeks