What is the diagnosis and recommended treatment for a 51-year-old woman with severe macrocytic anemia (hemoglobin 6.9 g/dL, mean corpuscular volume 101 fL, mean corpuscular hemoglobin 33.3 pg) and labs showing blood urea nitrogen 8 mg/dL, total cholesterol 203 mg/dL, LDL cholesterol 121 mg/dL?

Severe Macrocytic Anemia: Vitamin B12 or Folate Deficiency

This 51-year-old woman has severe macrocytic anemia (hemoglobin 6.9 g/dL, MCV 101 fL) requiring immediate investigation for vitamin B12 and folate deficiency, followed by urgent treatment with parenteral vitamin B12 while awaiting confirmatory laboratory results. 1

Immediate Diagnostic Workup

Order the following tests immediately:

• Serum vitamin B12 level – Deficiency is defined as <150 pmol/L or <203 ng/L; if borderline, measure methylmalonic acid (>271 nmol/L confirms deficiency). 1
• Serum folate and RBC folate – Deficiency indicated by serum folate <10 nmol/L (4.4 μg/L) or RBC folate <305 nmol/L (<140 mg/L). 1
• Reticulocyte count – A low or normal count confirms decreased RBC production typical of megaloblastic anemia, while an elevated count would suggest hemolysis or hemorrhage. 1, 2
• Peripheral blood smear – Look for macro-ovalocytes and hypersegmented neutrophils, which are pathognomonic for megaloblastic anemia from B12 or folate deficiency. 3, 4
• TSH and free T4 – Hypothyroidism can cause macrocytic anemia and must be excluded. 1
• Liver function tests – Liver disease is a common cause of macrocytosis, though typically milder (MCV rarely >110 fL). 5, 6

The combination of severe anemia (Hb 6.9 g/dL) with macrocytosis (MCV 101 fL) strongly suggests megaloblastic anemia from vitamin deficiency rather than liver disease or hypothyroidism, which typically produce milder macrocytosis. 5, 4

Critical Diagnostic Considerations

• Do not wait for laboratory confirmation before starting treatment – Severe anemia with hemoglobin 6.9 g/dL requires immediate therapy while diagnostic workup proceeds. 1
• Check for combined deficiencies – Iron deficiency can coexist with B12 or folate deficiency; an elevated RDW suggests this possibility. 1
• Evaluate for underlying cause – In a 51-year-old woman, investigate for pernicious anemia (autoimmune gastritis), celiac disease, inflammatory bowel disease with ileal involvement, dietary insufficiency, or medications (methotrexate, hydroxyurea). 1, 6

Treatment Algorithm

If Vitamin B12 Deficiency is Confirmed or Strongly Suspected:

Start parenteral vitamin B12 immediately – The FDA-approved regimen for pernicious anemia is: 7

1. Initial phase: Cyanocobalamin 100 mcg intramuscularly or deep subcutaneous daily for 6-7 days
2. Consolidation phase: 100 mcg on alternate days for seven doses (if clinical improvement and reticulocyte response observed)
3. Continuation phase: 100 mcg every 3-4 days for another 2-3 weeks (until hematologic values normalize)
4. Maintenance phase: 100 mcg monthly for life 7

Alternative regimen from guidelines: Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months. 1

Critical rule: Always treat vitamin B12 deficiency BEFORE initiating folate supplementation to prevent precipitating subacute combined degeneration of the spinal cord. 1, 7

If Folate Deficiency is Confirmed (After Excluding B12 Deficiency):

• Oral folic acid 5 mg daily for a minimum of 4 months. 1
• Folate should be administered concomitantly with B12 if both deficiencies are present. 7

Expected Response to Treatment:

• Reticulocyte response should occur within 3-7 days, peaking at 5-7 days. 4
• Hemoglobin rise of ≥10 g/L within 2 weeks confirms the diagnosis of vitamin deficiency. 1
• Complete normalization of hematologic values should occur within 2-3 weeks of appropriate therapy. 7

Monitoring and Follow-Up

• Weekly hemoglobin checks until treatment is complete, then less frequently. 1
• Repeat complete blood count at 4-6 weeks to confirm adequate response. 1
• If no response occurs within 2-4 weeks, consider alternative diagnoses such as myelodysplastic syndrome, medication-induced bone marrow suppression, or combined deficiencies. 1, 2

When to Consider Bone Marrow Examination

Bone marrow aspiration and biopsy are indicated if: 1

• Unexplained pancytopenia or other cytopenias are present
• Peripheral smear shows dysplastic features or blasts
• Progressive anemia despite optimal vitamin replacement
• Concern for myelodysplastic syndrome, particularly with leucopenia and/or thrombocytopenia

Common Pitfalls to Avoid

• Never use the intravenous route for vitamin B12 – Almost all of the vitamin will be lost in the urine. 7
• Never start folate before excluding B12 deficiency – This can precipitate irreversible neurologic damage. 1, 7
• Do not assume dietary insufficiency alone – In adults, investigate for malabsorption (pernicious anemia, celiac disease, inflammatory bowel disease) as the underlying cause. 1, 6
• Do not overlook combined deficiencies – Iron deficiency can coexist with B12 or folate deficiency, recognizable by elevated RDW. 1