What should be given to a patient with macrocytic anemia?

Treatment of Macrocytic Anemia

For macrocytic anemia, immediately administer vitamin B12 (1000 mcg intramuscularly) and folic acid (5 mg orally daily), but always treat vitamin B12 deficiency before or simultaneously with folate to prevent precipitating irreversible neurological damage. 1, 2, 3

Immediate Treatment Algorithm

Step 1: Confirm Macrocytosis and Check Vitamin Levels

• Macrocytosis is defined as MCV >100 fL, and when present with anemia, vitamin B12 and folate deficiency are the most common causes requiring immediate evaluation. 2, 4, 5
• Measure serum vitamin B12 first (deficiency defined as <150 pmol/L or <203 pg/mL), along with serum and red blood cell folate levels. 1, 2, 6
• If B12 is 180-350 pg/mL (indeterminate range), measure methylmalonic acid (MMA) to confirm functional deficiency; MMA >271 nmol/L confirms true B12 deficiency. 1, 7

Step 2: Initiate Vitamin B12 Replacement

For confirmed B12 deficiency (<180 pg/mL):

• Administer cyanocobalamin 100-1000 mcg intramuscularly daily for 6-7 days, then alternate days for seven doses, then every 3-4 days for 2-3 weeks until hematologic values normalize. 3
• After initial correction, continue 100-1000 mcg intramuscularly monthly for life, as the underlying cause (usually malabsorption) persists. 7, 2, 3
• Oral B12 (1000-2000 mcg daily) is equally effective for most patients except those with severe neurological symptoms or confirmed malabsorption, where intramuscular administration is mandatory. 7

Critical warning: Avoid intravenous administration of B12, as almost all will be lost in urine. 3

Step 3: Add Folate Supplementation

• After confirming B12 deficiency is being treated, administer folic acid 5 mg orally daily for at least 4 months. 2
• Never give folate before treating B12 deficiency, as folate may mask the anemia while allowing irreversible subacute combined degeneration of the spinal cord to progress. 7, 2, 8
• Folate deficiency is defined as serum folate <10 nmol/L (4.4 μg/L) or RBC folate <305 nmol/L (<140 mg/L). 2

Step 4: Address Neurological Symptoms Urgently

If neurological symptoms are present (paresthesias, ataxia, cognitive changes):

• Administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months for life. 2
• Neurological symptoms often appear before hematologic changes and can become irreversible if untreated, making urgent treatment essential even with borderline B12 levels. 7

Additional Causes to Address

Exclude Other Reversible Causes

• Check TSH and free T4 to exclude hypothyroidism, which causes macrocytic anemia and requires thyroid hormone replacement. 2, 6, 5
• Review all medications, particularly methotrexate, azathioprine, hydroxyurea, and anticonvulsants, which cause macrocytosis and may require discontinuation. 7, 2, 6
• Assess alcohol use, as chronic alcoholism is one of the three most common causes of macrocytosis and impairs B12 absorption. 2, 9, 5
• Evaluate liver function, as liver disease causes mild, uniform macrocytosis with round RBCs (MCV rarely >110 fL). 9, 5

Identify Coexisting Iron Deficiency

• Check red cell distribution width (RDW) and ferritin, as elevated RDW suggests coexisting iron deficiency even when MCV is elevated, because microcytosis and macrocytosis can mask each other. 2, 6
• In inflammatory conditions, ferritin up to 100 μg/L may still indicate iron deficiency, so check transferrin saturation (<20% confirms iron deficiency). 1, 2

Monitoring Response to Treatment

• Expect reticulocytosis within 3-7 days and hemoglobin increase of ≥2 g/dL within 4 weeks of treatment. 2, 3
• Monitor hemoglobin weekly until treatment is complete, then less frequently. 2
• Recheck B12 levels after 3-6 months to confirm normalization, and continue annual screening in high-risk patients (age >75, metformin use >4 months, PPI use >12 months, post-bariatric surgery, inflammatory bowel disease). 7

When to Refer to Hematology

• If pancytopenia is present (leukopenia and/or thrombocytopenia with anemia), suspect myelodysplastic syndrome and obtain bone marrow aspiration with cytogenetic analysis. 2, 4, 5
• If reticulocyte count is low/normal and no vitamin deficiency is found, consider bone marrow examination to evaluate for MDS or other primary bone marrow disorders. 6, 10
• If cytopenias persist despite correcting vitamin deficiencies, proceed with bone marrow evaluation to assess for treatment-related myelodysplastic syndrome. 2

Critical Pitfalls to Avoid

• Never delay B12 treatment while waiting for MMA or intrinsic factor antibody results when B12 is <180 pg/mL and macrocytic anemia is present. 7
• Never rely solely on serum B12 to rule out deficiency, especially in patients >60 years, where up to 50% with "normal" serum B12 have metabolic deficiency when MMA is measured. 7
• Never give folate alone without first treating B12 deficiency, as this can precipitate irreversible neurological damage. 7, 2, 8