Isolated Macrocytosis in a 76-Year-Old Woman with Normal Hemoglobin
In this 76-year-old woman with an MCV of 101 fL and normal hemoglobin (15.3 g/dL), the most likely causes are alcohol use, medications, or early vitamin B12 deficiency, and the initial workup should include a detailed medication and alcohol history, vitamin B12 level, thyroid function tests, liver function tests, and a peripheral blood smear. 1, 2
Understanding the Clinical Context
This patient has isolated macrocytosis without anemia, which is a distinct clinical scenario that still requires evaluation because macrocytosis may be the first indicator of underlying pathology even when hemoglobin is normal. 2, 3 The MCV of 101 fL represents mild macrocytosis (just above the 100 fL threshold), which narrows the differential compared to more severe elevations. 4
Differential Diagnosis by MCV Severity
The degree of MCV elevation helps categorize likely causes:
MCV 100-114 fL (this patient): Most commonly caused by alcohol use, medications (especially chemotherapy agents like thiopurines), early vitamin B12 deficiency, hypothyroidism, or liver disease. 1, 4, 5
MCV 114-130 fL: Suggests bone marrow failure syndromes, myelodysplastic syndrome, hemolytic anemia, or more advanced megaloblastic anemia. 4
MCV >130 fL: Almost always indicates severe vitamin B12 or folate deficiency, or medication effects. 4, 5
Recommended Initial Workup
Essential First-Line Tests
Order these tests immediately:
Vitamin B12 level: B12 deficiency can present with isolated macrocytosis before anemia develops, and 20.9% of B12-deficient patients have macrocytosis without anemia. 1, 2 Delays beyond 3 months can cause irreversible neurologic damage. 1
Red blood cell folate level: Although less common after grain fortification (prevalence <1%), folate deficiency should still be checked as part of the megaloblastic workup. 6, 1
Thyroid function tests (TSH): Hypothyroidism is a recognized cause of macrocytosis without anemia. 1, 2
Liver function tests: Chronic liver disease accounts for a significant proportion of macrocytosis cases. 2, 5
Peripheral blood smear: Look specifically for hypersegmented neutrophils (present in 86% of megaloblastic cases), macro-ovalocytes (72% of megaloblastic cases), or other morphologic abnormalities. 2
Reticulocyte count: A normal or low count indicates production failure, while elevation suggests hemolysis or hemorrhage. 1, 7
Critical History Elements to Elicit
Obtain specific details about:
Alcohol consumption: Quantify daily/weekly intake precisely, as alcohol abuse is the single most common cause of macrocytosis, accounting for 36.5-80.2% of cases depending on the population studied. 2, 3, 8 The highest MCV in alcoholics without vitamin deficiency is typically 120 fL. 8
Medication exposures: Specifically ask about chemotherapy agents (thiopurines), anticonvulsants, methotrexate, hydroxyurea, and antiretroviral medications. 1, 2 Drug-related macrocytosis accounts for 12.9% of cases. 2
Neurologic symptoms: Paresthesias, ataxia, cognitive changes, or gait disturbances mandate immediate B12 testing regardless of MCV level. 1
Gastrointestinal history: Prior small-bowel resection or inflammatory bowel disease increases risk for B12 deficiency. 6
Tests That Are NOT Indicated Initially
Do not order these tests in isolated macrocytosis with normal hemoglobin:
Hemolysis markers (LDH, haptoglobin): These should only be ordered when the reticulocyte count is elevated, indicating increased red cell destruction. 6 In isolated macrocytosis with normal hemoglobin and normal reticulocyte count, hemolysis is extremely unlikely. 6
Bone marrow biopsy: Not indicated at this stage unless other cytopenias develop or myelodysplastic syndrome is suspected based on additional findings. 1
When to Escalate the Workup
Order additional testing if:
RDW is elevated (>14%): This suggests a mixed deficiency state (e.g., concurrent iron and B12 deficiency) where microcytic and macrocytic processes coexist, potentially masking each other. 1, 7
Pancytopenia or other cytopenias develop: This raises concern for bone marrow failure syndromes or myelodysplastic syndrome and warrants hematology consultation. 1
Initial workup is unrevealing: If vitamin levels, thyroid function, and liver function are normal, and no medication or alcohol cause is identified, consider haptoglobin, LDH, bilirubin, and transferrin saturation to evaluate for hemolysis or combined deficiencies. 1
Common Pitfalls to Avoid
Ignoring isolated macrocytosis because hemoglobin is normal: Macrocytosis without anemia still requires evaluation, as it may be the first clue to vitamin B12 deficiency, preleukemia, or alcoholism. 2, 3
Ordering reflexive "anemia panels" with hemolysis markers: In the absence of elevated reticulocytes, hemolysis workup wastes resources and delays appropriate evaluation. 6
Missing combined deficiencies: If RDW is markedly elevated, consider that iron deficiency may coexist with B12 or folate deficiency, normalizing the MCV. 1, 7
Failing to quantify alcohol intake: Vague questioning about alcohol use misses the most common cause; ask specific quantities consumed per day/week. 8
Monitoring Strategy
If the initial workup identifies a treatable cause (e.g., B12 deficiency, hypothyroidism), treat appropriately and recheck hemoglobin and MCV at 3-month intervals. 6 If no cause is identified after comprehensive evaluation, refer to hematology for consideration of bone marrow examination or observation with serial monitoring. 7