Evaluation of Macrocytosis with Normal B12 and Folate
Your patient has macrocytosis (MCV 103.1) with adequate B12 (733) but low-normal folate (11.6), requiring evaluation for medication effects, alcohol use, thyroid dysfunction, and occult hematologic disorders—while also checking for concurrent iron deficiency that may be masked by the elevated MCV. 1, 2
Immediate Laboratory Assessment
Check the following tests to identify the underlying cause:
Reticulocyte count – This is the single most important next test to distinguish between ineffective erythropoiesis (low/normal reticulocytes suggesting bone marrow disorder or deficiency) versus increased red cell production from hemolysis or hemorrhage (elevated reticulocytes) 2
Complete iron studies including MCH – MCH is more sensitive than MCV for detecting iron deficiency and may reveal concurrent iron deficiency even when macrocytosis masks the expected microcytosis 1, 2. Check ferritin, transferrin saturation, serum iron, and TIBC 2
Peripheral blood smear – Look for hypersegmented neutrophils (suggesting megaloblastic process despite normal B12), schistocytes (hemolysis), or dysplastic features (myelodysplasia) 2, 3
TSH – Hypothyroidism commonly causes macrocytosis without anemia 4
Liver function tests and GGT – Chronic alcohol use causes macrocytosis independent of nutritional deficiencies 4
Critical Diagnostic Considerations
Despite your patient's B12 level of 733, metabolic B12 deficiency can still exist:
Up to 70-83% of B12-deficient patients have normal MCV, and tissue-level deficiency occurs even with "normal" laboratory B12 values 1
Consider measuring homocysteine and methylmalonic acid if clinical suspicion remains high (neurological symptoms, progressive macrocytosis, or other unexplained findings), as metabolic B12 deficiency is defined as B12 below 258 pmol/L with elevated metabolites—but can occur at higher B12 levels 1
Methylmalonic acid is more specific for B12 deficiency than homocysteine, which can be elevated in folate deficiency, pyridoxine deficiency, renal insufficiency, and hypothyroidism 5, 1
The folate level of 11.6 warrants closer attention:
While technically within normal range, this is relatively low-normal and folate deficiency remains a consideration given the macrocytosis 4, 3
Measure erythrocyte (RBC) folate for more accurate assessment of tissue folate stores, as serum folate reflects recent dietary intake rather than body stores 4, 6
Medication and Exposure History
Systematically review for macrocytosis-inducing medications:
Thiopurines (azathioprine, 6-mercaptopurine) – cause macrocytosis through myelosuppressive activity rather than vitamin deficiency 2
Anticonvulsants (phenytoin, valproate) 4
Methotrexate 4
Hydroxyurea 2
Antiretrovirals (zidovudine, stavudine) 2
Quantify alcohol consumption specifically – ask about daily/weekly intake in standard drinks, as chronic alcohol causes macrocytosis independent of folate deficiency 4
Red Flags Requiring Hematology Referral
Refer to hematology if any of the following are present:
Other cytopenias (anemia, thrombocytopenia, or leukopenia) in addition to macrocytosis, which increases likelihood of primary bone marrow disorder 2
Progressive or severe macrocytosis (MCV >110) 2
Dysplastic features on peripheral smear 2
Elevated RDW suggesting mixed nutrient deficiencies (microcytosis from iron deficiency coexisting with macrocytosis) 2
Unexplained macrocytosis after completing initial workup 2
Common Pitfalls to Avoid
Do not assume normal B12 rules out B12-related pathology – concurrent iron deficiency is extremely common in B12-deficient patients and normalizes the MCV through counterbalancing effects (iron deficiency causes microcytosis while B12 deficiency causes macrocytosis) 1, 7, 6
Do not neglect follow-up – even unexplained macrocytosis requires monitoring, as patients may develop primary bone marrow disorders or worsening cytopenias over time 2
In inflammatory conditions, ferritin up to 100 μg/L may still indicate iron deficiency despite being in the "normal" range, making MCH assessment particularly valuable 2