What is the appropriate workup and treatment for a patient with macrocytic anemia, characterized by a low Red Blood Cell (RBC) count, high Mean Corpuscular Volume (MCV), high Mean Corpuscular Hemoglobin (MCH), and high Red Cell Distribution Width (RDW)?

Workup for Macrocytic Anemia with High RDW

Begin immediately with vitamin B12 and folate testing, as these are the most common treatable causes and delays beyond 3 months can cause irreversible neurologic damage. 1

Initial Laboratory Panel

Order the following tests without delay:

• Vitamin B12 level – essential first-line test for macrocytic anemia 1
• Red blood cell folate level – must be checked concurrently with B12 1
• Reticulocyte count – distinguishes production failure (low/normal) from hemolysis or hemorrhage (elevated) 1
• Peripheral blood smear – look specifically for macro-ovalocytes and hypersegmented neutrophils indicating megaloblastic changes 2
• Thyroid function tests (TSH) – hypothyroidism is a common cause 1, 2
• Liver function tests – liver disease and alcohol are leading causes of macrocytosis 1, 2

The high RDW in your patient is a critical clue suggesting either a nutritional deficiency (B12 or folate) or a mixed deficiency state, as RDW elevation indicates significant variation in red blood cell size. 3, 4

Critical History Elements to Elicit

• Alcohol intake – quantify precisely, as alcoholism is the most common cause of macrocytic anemia in hospitalized patients 5, 6
• Medication exposures – specifically ask about chemotherapy agents (thiopurines, methotrexate, hydroxyurea), anticonvulsants, and azathioprine 1, 2
• Dietary history – vegetarian or vegan diet suggests B12 deficiency 7
• Neurologic symptoms – paresthesias, ataxia, or cognitive changes indicate B12 deficiency with potential irreversible damage 7
• Evidence of blood loss or hemolysis – jaundice, dark urine, or bleeding 8

Algorithmic Approach Based on Reticulocyte Count

If Reticulocyte Count is Low or Normal (Production Failure):

This indicates bone marrow dysfunction or nutritional deficiency. 1

• If B12 is low or borderline – order methylmalonic acid (MMA) and homocysteine levels, as MMA has greater sensitivity than serum B12 alone and is more specific for B12 deficiency 2
• If folate is low – this confirms folate deficiency 1
• If both B12 and folate are normal – proceed to extended workup below 1

If Reticulocyte Count is Elevated:

This suggests hemolysis or recent hemorrhage. 1

• Order hemolysis panel: indirect bilirubin, LDH, haptoglobin, and direct antiglobulin test 8

Extended Workup If Initial Tests Unrevealing

If vitamin levels, thyroid, and liver function are normal:

• Haptoglobin, LDH, indirect bilirubin – evaluate for hemolysis 1
• Transferrin saturation and ferritin – assess for combined iron deficiency, as mixed deficiencies can present with high RDW 1
• Bone marrow aspirate and biopsy with cytogenetics – necessary if myelodysplastic syndrome is suspected, especially in elderly patients with additional cytopenias 1, 2

Myelodysplastic syndrome should be strongly considered if the patient is elderly, has other cytopenias, or has MCV persistently >114 fL without clear cause. 9

Critical Pitfall to Avoid

Never give folic acid alone without confirming B12 status first. Folic acid doses >0.1 mg daily can produce hematologic remission in B12 deficiency while allowing irreversible neurologic damage to progress. 7 If folate deficiency is confirmed, administer folic acid 1 mg daily orally only after ensuring B12 is repleted or given concomitantly. 1, 7

Treatment Initiation

If B12 Deficiency Confirmed:

• Cyanocobalamin 100 mcg intramuscularly daily for 6-7 days, then alternate days for seven doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life 7
• Avoid intravenous route as almost all vitamin is lost in urine 7
• Administer folic acid 1 mg daily concomitantly if folate is also deficient 1, 7

If Folate Deficiency Confirmed:

• Folic acid 1 mg daily orally (only after excluding B12 deficiency) 1

Monitoring During Treatment

• Monitor hemoglobin and reticulocyte count – reticulocytes should increase by day 5-7 of B12 therapy and remain at least twice normal until hematocrit normalizes 7
• Check serum potassium closely in first 48 hours of B12 treatment in pernicious anemia, as rapid cell production can cause hypokalemia 7
• If reticulocytes fail to increase or hematocrit doesn't improve, reassess diagnosis and check for complicating conditions like concurrent iron deficiency 7

When to Refer to Hematology

• Cause remains unclear after comprehensive initial workup 8
• Bone marrow examination is being considered 8
• Suspected primary hematologic disorder (myelodysplastic syndrome, aplastic anemia) 8, 9
• Additional cytopenias present 2