What's the next step in evaluating a patient with confirmed increased Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Volume (MCV) on a complete blood count (CBC) test?

Evaluation of Elevated MCH and MCV

The next step is to measure serum vitamin B12, red blood cell folate, and reticulocyte count, as these are the most common and treatable causes of macrocytosis, with delays beyond 3 months potentially causing irreversible neurologic damage. 1

Initial Laboratory Assessment

The diagnostic workup should include the following tests immediately 1:

• Vitamin B12 level - Most critical to rule out B12 deficiency, which can cause irreversible neurologic complications if treatment is delayed 1
• Red blood cell folate level - Folate deficiency is the most likely nutritional cause when B12 is normal 2
• Reticulocyte count - Distinguishes between production failure (low/normal count) versus hemolysis or hemorrhage (elevated count) 1
• Peripheral blood smear - Essential for identifying morphologic abnormalities and ruling out hemolytic causes 1, 3
• Thyroid function tests (TSH) - Hypothyroidism can cause macrocytosis without anemia 2, 1
• Liver function tests - Chronic liver disease is a common cause of macrocytosis 1

Critical History Elements

Obtain a focused history targeting specific causes 2, 1:

• Medication review - Specifically ask about thiopurines, anticonvulsants, methotrexate, and other chemotherapy agents that cause myelosuppression 2, 1
• Alcohol consumption - Chronic alcohol use causes macrocytosis independent of nutritional deficiencies 2
• Symptoms of hypothyroidism - Fatigue, cold intolerance, weight gain 2
• Neurologic symptoms - Paresthesias, ataxia, cognitive changes suggesting B12 deficiency 1

Interpretation Based on Initial Results

If B12 and Folate Are Normal

When nutritional deficiencies are excluded, pursue these additional causes 2:

• Measure homocysteine levels - Provides additional information on tissue deficiency even when serum levels appear normal 2
• Assess for medication effects - Review all current medications, particularly those known to interfere with DNA synthesis 2, 1
• Evaluate thyroid function - If not already done 2
• Consider alcohol-related macrocytosis - Even with normal liver enzymes 2

If Extended Workup Remains Unrevealing

Order second-tier tests 1:

• Haptoglobin, LDH, and indirect bilirubin - To evaluate for hemolysis 1
• Transferrin saturation and ferritin - To assess for combined iron deficiency masking the picture 1
• Bone marrow aspirate and biopsy with cytogenetics - Consider if myelodysplastic syndrome is suspected, especially in elderly patients with cytopenias or unexplained macrocytosis 1

Common Pitfalls to Avoid

• Do not delay B12 testing - Neurologic damage from B12 deficiency can become irreversible after 3 months 1
• Do not assume normal B12 rules out deficiency - Tissue deficiency can exist with borderline-normal serum levels; measure homocysteine and methylmalonic acid if clinical suspicion is high 2
• Do not overlook medication history - Many commonly prescribed drugs cause macrocytosis without anemia 2, 1
• Do not forget to check reticulocyte count - This simple test distinguishes production problems from hemolysis/hemorrhage and guides the entire diagnostic approach 1

Treatment Considerations

If folate deficiency is confirmed 1:

• Administer folic acid 1 mg daily orally 1
• Always give concomitantly with vitamin B12 if both are deficient - Treating folate deficiency alone in the presence of unrecognized B12 deficiency can precipitate irreversible neurologic progression 1