Differential diagnosis of macrocytosis

	Mechanism of macrocytosis	Relevant history and examination	Diagnostic testing
Heritable causes
RBC enzyme deficiencies (G6PD, PK, others)	Acute or chronic hemolysis with reticulocytosis	Ingestion of oxidant foods or medications Positive family history	Hemolysis testing^* Blood smear review for RBC morphology RBC enzyme assays
RBC membrane disorders (HE, HSt)	Chronic hemolysis with reticulocytosis	Positive family history	Blood smear review for RBC morphology Osmotic fragility, osmotic gradient ektacytometry, or EMA binding Disease-specific genetic or other testing
Inherited bone marrow failure syndromes (FA, others)	Bone marrow dysfunction	Positive family history Syndromic features in some cases	CBC for cytopenias and immature forms Blood smear review Bone marrow examination Disease-specific genetic or other testing
Congenital dyserythropoietic anemia	Bone marrow dysfunction	Syndromic features in some cases	CBC for cytopenias Bone marrow examination Hemolysis testing^* Genetic testing
Some sideroblastic anemias (XLSA, MLASA, TRMA, others)	Bone marrow dysfunction Decreased rate of nuclear maturation due to impaired DNA synthesis (megaloblastic changes)	Positive family history Syndromic features in some cases	CBC for cytopenias Bone marrow examination Disease-specific genetic or other testing
Acquired causes
Vitamin B12 or folate deficiency	Decreased rate of nuclear maturation due to impaired DNA synthesis (megaloblastic changes)	Certain dietary practices History of gastric bypass surgery Neuropsychiatric symptoms or findings	Serum vitamin B12 or folate level Blood smear review for megaloblastic changes (multi-lobed neutrophils) For diagnostic uncertainty, serum metabolite testing (methylmalonic acid, homocysteine)
Medications:^¶ 6-mercaptopurine Antibiotics (various) Azathioprine Capecitabine Cladribine Cytosine arabinoside Hydroxyurea Imatinib Methotrexate Sunitinib Zidovudine	Depends on medication; may include: Decreased rate of nuclear maturation due to impaired DNA synthesis (megaloblastic changes) Hemolysis Tetracyclines reduce folate absorption Metformin and nitrous oxide cause vitamin B12 deficiency	History of relevant condition under treatment Medication history	Reticulocyte count If reticulocyte count is increased, hemolysis testing^* Blood smear for megaloblastic changes (multi-lobed neutrophils) If unsure, testing for other causes of macrocytosis If/when appropriate, response to drug discontinuation
Reticulocytosis	Reticulocytes are larger than mature RBCs	Hemolytic anemia (acute or chronic) Treatment of iron deficiency or vitamin B12 or folate deficiency Recovery from blood loss Treatment with erythropoietin	Reticulocyte count Hemolysis testing^*
Excess alcohol	Unknown, likely multifactorial (liver disease, bone marrow toxicity, folate deficiency, bleeding)	Alcohol history Stigmata of alcohol use	Liver function testing Response to discontinuation
Liver disease	Changes in serum lipids increase RBC membrane deposition	Stigmata of liver disease	Liver function testing Cytopenias Blood smear for target cells and other morphologic changes
Hypothyroidism	Unknown, may be multifactorial and include changes in serum lipids increase RBC membrane deposition	Associated symptoms Associated examination findings	TSH
Myelodysplastic syndrome	Bone marrow dysfunction; in some cases, hemolysis with reticulocytosis	Cytopenia-associated symptoms or findings	CBC for cytopenias Bone marrow evaluation Disease-specific genetic or other testing
Acquired aplastic anemia	Bone marrow dysfunction	Cytopenia-associated symptoms or findings	CBC for cytopenias Bone marrow evaluation
Acquired pure red cell aplasia	Bone marrow dysfunction	Parvovirus infection	Parvovirus testing Bone marrow evaluation
Acquired sideroblastic anemia (copper deficiency)	Bone marrow dysfunction	Use of excess zinc products History of gastric bypass surgery	Serum copper level
Hematologic malignancies (multiple myeloma, LGL leukemia, others)	Unknown, likely multifactorial (bone marrow dysfunction, medications)		CBC for cytopenias and immature forms SPEP or flow cytometry Bone marrow evaluation

Testing for the cause can be done sequentially or simultaneously and is based on history, examination, prevalence of the condition, and clinical features that would necessitate a more rapid diagnosis. Refer to UpToDate for additional details.

CBC: complete blood count; EMA: eosin-5-maleimide; FA: Fanconi anemia; G6PD: glucose-6-phosphate dehydrogenase; HE: hereditary elliptocytosis; HSt: hereditary stomatocytosis; LDH: lactate dehydrogenase; LGL: large granular lymphocyte; MLASA: myopathy, lactic acidosis, and sideroblastic anemia; PK: pyruvate kinase; RBC: red blood cell; SPEP: serum protein electrophoresis; TRMA: thiamine-responsive megaloblastic anemia; TSH: thyroid stimulating hormone; XLSA: X-linked sideroblastic anemia.

* Hemolysis testing includes LDH, haptoglobin, bilirubin, and reticulocyte count. Blood smear review may be useful for identifying specific RBC changes in certain forms of hemolysis. Coombs testing is appropriate for suspected immune hemolysis.

¶ This is only a partial list. Refer to UpToDate for a longer list or to a drug information resource for the likelihood of anemia or macrocytosis with specific medications.

Graphic 148062 Version 1.0

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Differential diagnosis of macrocytosis