Management of Isolated Macrocytosis

Initial Diagnostic Workup

The National Comprehensive Cancer Network recommends evaluation for vitamin B12 and folate deficiency with serum B12, folate, and methylmalonic acid levels in patients with isolated macrocytosis 1, 2
Assessment of thyroid function with TSH is recommended as part of the initial diagnostic workup for isolated macrocytosis 1, 2
Liver function tests should be performed to rule out liver disease in patients with isolated macrocytosis 2
A reticulocyte count can help differentiate between decreased production versus increased destruction/loss of red blood cells in patients with isolated macrocytosis 1, 2
A peripheral blood smear examination should be performed to look for megaloblastic changes, such as macro-ovalocytes and hypersegmented neutrophils, in patients with isolated macrocytosis 2
A detailed medication history should be taken to identify drugs that can cause macrocytosis, such as azathioprine, hydroxyurea, methotrexate, and anticonvulsants 2, 3

If a specific cause of macrocytosis is identified, the underlying cause should be treated, such as vitamin supplementation for deficiencies or medication adjustment 1, 2, 3

Methylmalonic acid (MMA) levels can be measured when vitamin B12 deficiency is suspected but serum B12 levels are equivocal, as MMA has greater sensitivity than serum B12 measurement alone, according to the Journal of Crohn's and Colitis 4
Homocysteine levels indicate tissue deficiency of either B12 or folate with greater sensitivity than serum measurements, though MMA is more specific for B12 deficiency, as reported in the Journal of Crohn's and Colitis 4

Bone marrow aspiration and biopsy should be considered when the initial laboratory workup is unrevealing, as suggested by the Journal of Crohn's and Colitis 4
Bone marrow evaluation should also be considered when there are additional cytopenias present, as recommended by the National Comprehensive Cancer Network 5
Myelodysplastic syndrome or primary bone marrow dysplasia should be suspected and evaluated through bone marrow aspiration and biopsy, according to the National Comprehensive Cancer Network and Clinical Cancer Research 5, 6