What is the diagnosis and plan for a patient with macrocytosis indicated by elevated MCV and MCH?

Macrocytosis with Normal MCH and Low RDW: Diagnosis and Management

Immediate Diagnosis

This patient has isolated macrocytosis (MCV 104 fL) with normal MCH (34.4 pg/dL) and remarkably low RDW (11.5%), which strongly suggests a non-megaloblastic cause—most likely medication effect, alcohol use, liver disease, or early reticulocytosis rather than vitamin B12 or folate deficiency. 1, 2

The low RDW is particularly important here, as it indicates a uniform population of macrocytic cells rather than the mixed cell populations seen in nutritional deficiencies or combined deficiency states. 1

Diagnostic Algorithm

Step 1: Targeted History and Laboratory Evaluation

Obtain the following information and tests immediately:

• Medication review: Specifically ask about azathioprine, 6-mercaptopurine, methotrexate, hydroxyurea, antiretrovirals, and anticonvulsants, as these commonly cause macrocytosis through myelosuppressive effects rather than vitamin deficiency 1, 3

• Alcohol intake: Quantify consumption over the past 2+ weeks, as alcohol is the most common cause of macrocytosis in hospitalized patients (18-30% of cases) 2, 3

• Reticulocyte count: This is the single most critical test to distinguish between ineffective erythropoiesis (low/normal count) and increased red cell production from hemolysis or recent hemorrhage (elevated count) 1, 4

• Liver function tests: AST, ALT, alkaline phosphatase, and bilirubin to evaluate for chronic liver disease, which accounts for a significant proportion of macrocytosis cases 5, 3

• TSH: Hypothyroidism causes macrocytosis in approximately 3-5% of cases 4, 5

Step 2: Vitamin Assessment (Despite Normal MCH)

Check vitamin B12 and folate levels, even though the normal MCH makes deficiency less likely:

• Serum vitamin B12 (deficiency defined as <150 pmol/L or <203 ng/L) 4
• Serum folate and RBC folate (deficiency: serum folate <10 nmol/L or RBC folate <305 nmol/L) 4
• If B12 is borderline (150-250 pmol/L), obtain methylmalonic acid (>271 nmol/L confirms deficiency) and homocysteine levels, as these may reveal tissue deficiency despite normal serum levels 1, 4

Critical caveat: The normal MCH (34.4 pg/dL) argues against iron deficiency masking B12/folate deficiency, but this should still be considered if the patient has inflammatory conditions. 1

Step 3: Interpretation Based on Reticulocyte Count

If reticulocyte count is elevated (>2% corrected for hematocrit):

• Evaluate for hemolysis: check haptoglobin, LDH, indirect bilirubin, and peripheral blood smear for schistocytes 1, 4
• Consider recent blood loss or response to recent hematinic therapy 6, 5

If reticulocyte count is low or normal:

• Drug effect and alcohol remain most likely if history is positive 3
• Liver disease if transaminases are elevated 2, 5
• Hypothyroidism if TSH is elevated 4
• If all above are negative, consider bone marrow evaluation for myelodysplastic syndrome, particularly if patient is elderly 7

Management Plan

If Cause Identified:

For medication-induced macrocytosis:

• Discuss risk/benefit with prescribing physician; macrocytosis from thiopurines (azathioprine, 6-mercaptopurine) is expected and does not require discontinuation unless other cytopenias develop 1
• Monitor CBC every 3-6 months to ensure stability 1

For alcohol-related macrocytosis:

• Counsel on alcohol cessation 2, 3
• Recheck MCV in 2-3 months after abstinence; MCV should normalize within 2-4 months if alcohol is the sole cause 5

For liver disease:

• Manage underlying hepatic condition 5, 3

For vitamin B12 deficiency (if identified):

• Never initiate folate before ruling out B12 deficiency, as this can precipitate irreversible subacute combined degeneration of the spinal cord 4, 8
• Treat with cyanocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg every 2-3 months for life 4, 8
• Repeat CBC in 4 weeks; expect hemoglobin increase of ≥2 g/dL and reticulocyte response within 5-7 days 4, 8

If No Cause Identified (Unexplained Macrocytosis):

Close monitoring is mandatory, as 11.6% of patients with unexplained macrocytosis develop primary bone marrow disorders (lymphoma, myelodysplastic syndrome, plasma cell disorders) over 2-5 years: 7

• Repeat CBC every 6 months 7
• Reassess B12 and folate periodically, as deficiencies may develop over time 1
• Consider hematology consultation and bone marrow biopsy if:
  • Other cytopenias develop (median time to first cytopenia: 18 months) 7
  • MCV progressively increases 1
  • MCV >120 fL (usually indicates B12 deficiency or myelodysplasia) 3
  • Patient is elderly with persistent unexplained macrocytosis 7

Critical Pitfalls to Avoid

• Do not assume macrocytosis equals B12/folate deficiency: In hospitalized patients, drugs and alcohol are more common causes than megaloblastic anemia, which accounts for <10% of cases 3

• Do not give folate empirically: This can mask B12 deficiency while allowing irreversible neurologic damage to progress 4, 8, 9

• Do not neglect follow-up: Even "benign" unexplained macrocytosis requires monitoring, as bone marrow disorders may emerge years later 7

• Do not overlook the low RDW: This patient's RDW of 11.5% suggests a homogeneous macrocytic population, making mixed deficiency states (which elevate RDW) unlikely 1