Elevated MCV with Otherwise Normal CBC
The most common causes of isolated macrocytosis (elevated MCV with normal hemoglobin, WBC, and platelets) are chronic alcohol use, medication effects, and vitamin B12 or folate deficiency—even when overt anemia is absent. 1, 2
Initial Diagnostic Approach
Order vitamin B12 and folate levels immediately, as these deficiencies can present with isolated macrocytosis before anemia develops. 1 In fact, 20.9% of vitamin B12 deficiency cases present with isolated macrocytosis without anemia. 3
Essential First-Line Laboratory Tests
- Vitamin B12 and folate levels are mandatory to identify macrocytic deficiency states 1
- Reticulocyte count distinguishes between deficiency states versus compensatory responses (hemolysis or recent bleeding) 1, 2
- Peripheral blood smear to look for macro-ovalocytes and hypersegmented neutrophils, which indicate megaloblastic changes even without anemia 2, 3
- Thyroid-stimulating hormone (TSH) to exclude hypothyroidism 2, 4
- Liver function tests to assess for chronic liver disease 2, 5
Critical History Elements to Elicit
- Alcohol consumption history, as alcoholism accounts for 18-36.5% of macrocytosis cases and causes macrocytosis independent of nutritional deficiencies 1, 5, 3
- Complete medication review focusing on:
- Symptoms of B12 deficiency, including paresthesias, gait disturbance, or cognitive changes—these indicate neurological involvement requiring urgent treatment 1
Degree of MCV Elevation Guides Differential
- MCV 100-110 fL: Most commonly medication effect, alcohol use, or early vitamin deficiency 2, 5
- MCV 110-120 fL: Strongly suggests vitamin B12 or folate deficiency, liver disease, or myelodysplastic syndrome 2
- MCV >120 fL: Usually caused by vitamin B12 deficiency and warrants immediate evaluation 5
When to Pursue Advanced Testing
If initial workup (B12, folate, TSH, liver function, alcohol history, medication review) is unrevealing, obtain:
- Methylmalonic acid (MMA) and homocysteine levels to detect tissue-level B12 or folate deficiency with greater sensitivity than serum B12 alone 1
- Haptoglobin and LDH if reticulocyte count is elevated, to assess for hemolysis 1
Mandatory Hematology Referral Criteria
Refer immediately to hematology if: 1
- Cause remains unclear after complete workup
- Any cytopenias develop (even mild)
- Peripheral smear shows dysplastic features
- MCV continues rising despite appropriate vitamin replacement
- Patient has risk factors for myelodysplastic syndrome (age >60, prior chemotherapy)
Critical Treatment Considerations
Never treat folate deficiency before excluding B12 deficiency, as folate supplementation can mask severe B12 depletion while allowing irreversible neurological damage to progress. 1
- For B12 deficiency with neurological symptoms: Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then 1 mg IM every 2 months for life 1
- For B12 deficiency without neurological symptoms: Hydroxocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg IM every 2-3 months for life 1
- For folate deficiency: Oral folic acid 5 mg daily for minimum 4 months 1
Common Pitfalls to Avoid
- Do not dismiss isolated macrocytosis as "normal variant"—it may be the first clue to vitamin deficiency, preleukemia, or alcoholism before anemia develops 4, 3
- Do not rely on peripheral smear alone—only 30% of vitamin deficiency cases show obvious megaloblastic changes on routine blood smear 4
- Do not assume medication-induced macrocytosis is benign without checking B12/folate—these can coexist 7
- Do not overlook inflammatory bowel disease patients, who require annual B12 and folate monitoring, especially with small bowel disease or resection 1, 7