Occasionally a patient will be encountered with an elevated erythrocytic MCV (mean cellular volume) yet serum levels for folate and vitamin B12 are within the normal reference range. A careful examination of the blood smear and review of the patient's clinical history can usually identify the cause for the test findings.


Criteria for inclusion:

(1) increased MCV

(2) serum folate within normal reference range

(3) serum vitamin B12 level within normal reference range


Differential diagnosis:

(1) megaloblastic macrocytosis: macrocytic erythrocytes, multi-nucleated neutrophils, giant platelets, often thrombocytopenia, megaloblastic changes in the bone marrow

(2) nonmegaloblastic macrocytosis: macrocytes in the peripheral blood smear without megaloblastic changes

(3) artifactual increase in the MCV: no evidence of anemia and examination of the peripheral blood smear shows no macrocytes


NOTE: Some causes may caused mixed problems, affecting vitamin absorption and metabolism, hemolytic anemia and/or be associated with liver dysfunction.


Causes of megaloblastic macrocytosis:

(1) "normal" (usually low normal) serum folate or vitamin B12 levels despite deficiency in body stores

(2) myelodysplastic syndrome

(3) hereditary defect in enzymes for DNA synthesis or vitamin metabolism (rare, lifelong, often familial)

(4) alcohol at high doses

(5) antineoplastic drugs (doxorubicin, 6-mercaptopurine, 5-fluorouracil, cytosine arabinoside, hydroxyurea)

(6) anticonvulsants (barbiturates, diphenylhydantoin)

(7) antibiotics (trimethroprim, pyrimethamine)

(8) anti-retroviral antinucleosides (AZT)

(9) oral contraceptives

(10) agents used to treat immunologic disorders (methotrexate, sulfasalazine, azathioprine)


Workup of patients with megaloblastic macrocytosis may include:

(1) methylmalonic acid (MMA): elevated in the serum or urine in patients with masked vitamin B12 deficiency

(2) bone marrow examination with cytogenetics

(3) tests for ethanol

(4) liver function tests

(5) metabolic tests for inherited diseases (usually done only after other causes have been excluded – deficiency of transcobalamin II, hereditary orotic aciduria, Lesch-Nyhan syndrome, methylmalonicacidemia, homocystinemia, etc.)


Causes of nonmegaloblastic macrocytosis:

(1) reticulocytosis (polychromasia and elevated reticulocyte count, often associated with a hemolytic anemia)

(2) liver disease

(3) myelodysplastic syndrome

(4) multiple myeloma

(5) hypothyroidism


Causes of artifactual increase in MCV:

(1) high serum glucose (may affect readings in red blood cell analyzers)

(2) high titers of cold agglutinins


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