What is the workup for macrocytosis without anemia in a patient with a history of smoking, renal cell carcinoma, and nephrectomy?

Workup for Macrocytosis Without Anemia in a 51-Year-Old Female Smoker with History of Renal Cell Carcinoma

In this patient with macrocytosis but no anemia, you should obtain a reticulocyte count, peripheral blood smear, vitamin B12, folate, TSH, liver function tests, and assess for medication effects and alcohol use, followed by close monitoring with CBC every 6 months. 1, 2

Initial Laboratory Evaluation

The diagnostic approach must distinguish between ineffective erythropoiesis and increased red cell production:

• Reticulocyte count is the critical first test—a low or normal count suggests vitamin deficiency or bone marrow disorder, while an elevated count suggests hemolysis or recent hemorrhage 1
• Peripheral blood smear to evaluate red cell morphology, looking specifically for macro-ovalocytes (suggesting megaloblastic anemia), schistocytes (suggesting hemolysis), and hypersegmented neutrophils (one of the most sensitive signs of megaloblastic anemia) 1, 3
• Vitamin B12 and folate levels to exclude deficiency, even though these are common causes, they must be ruled out first 4, 1
• Mean corpuscular hemoglobin (MCH) is particularly important—if MCH is reduced despite macrocytosis, this suggests concurrent iron deficiency that the elevated MCV is masking 1

Additional Essential Tests

• Thyroid-stimulating hormone (TSH) to exclude hypothyroidism as a cause of nonmegaloblastic macrocytosis 4, 3
• Liver function tests including gamma-glutamyl transpeptidase (GGT), as liver disease is a common cause of macrocytosis 3, 5
• Comprehensive metabolic panel including creatinine, given her history of nephrectomy and potential for renal insufficiency contributing to anemia 4
• Lactate dehydrogenase (LDH), haptoglobin, and indirect bilirubin if hemolysis is suspected based on reticulocyte count 4, 1

Critical History and Medication Review

Given this patient's specific risk factors, focus on:

• Detailed smoking history—quantify pack-years, as smoking is associated with macrocytosis 1
• Alcohol consumption—this is one of the most common causes of macrocytosis in clinical practice, and abstinence can lead to spontaneous resolution 6, 3, 5
• Complete medication list—many drugs cause macrocytosis through myelosuppressive activity, including hydroxyurea, azathioprine, and antiretroviral medications 4, 1
• Cancer treatment history—any prior chemotherapy or radiation could affect bone marrow function 4

When B12 and Folate Are Normal

If initial B12 and folate levels are normal but clinical suspicion remains:

• Methylmalonic acid (MMA) is specific for B12 deficiency with better sensitivity than serum B12 measurement 1
• Homocysteine levels may reveal tissue deficiency of B12 or folate despite normal serum levels 1
• Red cell distribution width (RDW) elevation suggests mixed nutrient deficiencies—microcytosis from iron deficiency coexisting with macrocytosis can result in falsely normal MCV 1

Surveillance Strategy

For unexplained macrocytosis without anemia, follow-up with CBC every 6 months is recommended. 2 This is critical because:

• 11.6% of patients with unexplained macrocytosis develop primary bone marrow disorders (lymphomas, myelodysplastic syndrome, plasma cell disorders) over time 2
• 16.3% develop worsening cytopenias, with median time to first cytopenia of 18 months 2
• Mean time to diagnosis of bone marrow disorder is 31.6 months 2

Indications for Bone Marrow Biopsy

Do not perform bone marrow biopsy initially in this patient without anemia. The diagnostic yield is only 33.3% in macrocytosis without anemia compared to 75% when anemia is present 2. Instead, perform bone marrow biopsy when:

• Cytopenias develop during follow-up 2
• Macrocytosis is severe (MCV >120 fL), which is usually caused by vitamin B12 deficiency but warrants more aggressive evaluation 5
• Other concerning hematologic abnormalities appear, such as progressive worsening of macrocytosis or development of additional cytopenias 1
• The cause remains unclear after comprehensive workup and the patient has other risk factors for myelodysplastic syndrome 4

Bone Marrow Evaluation Components (When Indicated)

If bone marrow biopsy becomes necessary:

• Bone marrow aspirate and biopsy with cytomorphology to evaluate for dysplasia (≥10% of cells in any lineage suggests MDS) 4
• Cytogenetics of bone marrow cells to detect clonal abnormalities 4
• Flow cytometry can be useful in experienced hands for diagnosis 4
• Next-generation sequencing to demonstrate clonality in difficult cases 4

Special Considerations for This Patient

Given her history of renal cell carcinoma and nephrectomy:

• Erythropoietin (EPO) level may be relevant if anemia develops, as nephrectomy can affect EPO production 4
• Exclude paroxysmal nocturnal hemoglobinuria (PNH) if clinical suspicion arises, as small PNH clones can accompany bone marrow disorders 4
• Reassess B12 and folate periodically even with initially normal levels, as deficiencies may develop over time 1

Common Pitfalls to Avoid

• Do not neglect follow-up—even unexplained macrocytosis requires monitoring, as a significant percentage develop primary bone marrow disorders over time 1, 2
• Do not assume normal B12/folate excludes deficiency—tissue deficiency can exist with normal serum levels, requiring MMA and homocysteine testing 1
• Do not overlook medication effects—review all medications, as drug-induced macrocytosis is the most common cause in hospitalized patients 5
• Do not miss concurrent iron deficiency—check MCH and consider iron studies even with macrocytosis, as mixed deficiencies can mask each other 1

Hematology Consultation

Consider hematology referral if:

• The cause remains unclear after initial comprehensive workup 1
• Severe or progressively worsening macrocytosis develops 1
• Any cytopenias develop during surveillance 2
• Bone marrow biopsy is being considered 2