In a 72-year-old woman with fatigue, hemoglobin 10.2 g/dL, macrocytic anemia (mean corpuscular volume 102 fL), hypersegmented neutrophils, ferritin 220 ng/mL, vitamin B12 210 pg/mL, folate 12 ng/mL, and methylmalonic acid 580 µmol/L, what is the most likely diagnosis?

Vitamin B12 Deficiency

The most likely diagnosis is (b) vitamin B12 deficiency. The elevated methylmalonic acid (MMA) of 580 µmol/L (normal <360) confirms functional B12 deficiency despite a serum B12 level that sits at the lower end of the normal range (210 pg/mL, normal 200-900). 1

Diagnostic Reasoning

Why B12 Deficiency Is Confirmed

• Elevated MMA is the key finding. MMA >271 nmol/L (or >360 µmol/L in this lab's units) confirms functional B12 deficiency with 98.4% sensitivity, even when serum B12 appears "normal." 1
• Serum B12 of 210 pg/mL is borderline-low. While technically within the reference range, levels <258 pg/mL (approximately 190 pmol/L) with elevated MMA define metabolic B12 deficiency. 1 Standard serum B12 testing misses functional deficiency in up to 50% of cases. 1
• Macrocytosis (MCV 102 fL) and hypersegmented neutrophils are classic megaloblastic features. These findings indicate impaired DNA synthesis from B12 deficiency. 2, 3
• Folate is normal (12 ng/mL), ruling out folate deficiency as the cause of macrocytosis. 2

Why Other Options Are Excluded

(a) Iron deficiency anemia is ruled out by:

• Normal-to-elevated ferritin (220 ng/mL). In the absence of inflammation, ferritin <30 µg/L defines iron deficiency; even with inflammation, ferritin up to 100 µg/L may indicate deficiency, but 220 is clearly replete. 2
• Macrocytic (not microcytic) anemia. Iron deficiency causes microcytosis. 2

(c) Anemia of chronic disease is unlikely because:

• Ferritin >100 µg/L with transferrin saturation <20% defines anemia of chronic disease, but this patient has macrocytosis, not the normocytic or microcytic pattern typical of ACD. 2
• No clinical evidence of active inflammation is mentioned. 2

(d) Hemolysis is excluded by:

• Absence of elevated reticulocyte count (not provided but implied by the presentation as non-hemolytic). 2
• Hypersegmented neutrophils point to megaloblastic, not hemolytic, anemia. 2

(e) Myelodysplastic anemia is less likely because:

• MDS typically presents with refractory cytopenias, often affecting multiple cell lines (leukopenia, thrombocytopenia). 2, 3
• The elevated MMA definitively confirms B12 deficiency as the cause. 1
• MDS should be considered if B12 deficiency is treated and anemia persists, but it is not the primary diagnosis here. 2

Clinical Significance in a 72-Year-Old

• Age >60 years is a major risk factor. Metabolic B12 deficiency affects 18.1% of adults >80 years, and 25% of those ≥85 years have B12 <170 pmol/L. 1
• Atrophic gastritis is common in the elderly (up to 20%), causing food-bound B12 malabsorption while crystalline B12 absorption remains intact. 1, 4
• Neurological symptoms often precede anemia and can become irreversible if untreated. Fatigue, cognitive difficulties, peripheral neuropathy, and gait disturbances are common. 1, 5

Immediate Next Steps

1. Initiate treatment without delay. With confirmed B12 deficiency (MMA >271 nmol/L), do not wait for additional testing. 1
2. Assess for neurological involvement. Ask about paresthesias, numbness, gait disturbances, cognitive changes, or glossitis. 1, 5
3. Choose the appropriate regimen:
   • If neurological symptoms are present: Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then 1 mg IM every 2 months for life. 5
   • If no neurological symptoms: Hydroxocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg IM every 2–3 months for life. 5
   • Oral B12 (1000–2000 mcg daily) is an acceptable alternative for most patients without severe neurological involvement or confirmed malabsorption. 1, 6

Critical Pitfalls to Avoid

• Never give folic acid before treating B12 deficiency. Folic acid can mask megaloblastic anemia while allowing irreversible subacute combined degeneration of the spinal cord to progress. 5, 7
• Do not rely solely on serum B12 to rule out deficiency, especially in elderly patients. MMA testing is essential when B12 is borderline (180–350 pg/mL). 1
• Do not stop treatment after symptoms improve. Patients with malabsorption (atrophic gastritis, pernicious anemia) require lifelong supplementation. 5, 7

Further Workup

• Test for intrinsic factor antibodies to diagnose pernicious anemia if the cause is unclear. 1, 6
• Check gastrin levels if pernicious anemia is suspected (markedly elevated >1000 pg/mL). 1
• Evaluate for other causes of malabsorption: Helicobacter pylori (atrophic gastritis), celiac disease (tissue transglutaminase antibodies), or medication use (metformin >4 months, PPIs >12 months). 1, 6
• Monitor response: Recheck B12, MMA, and CBC at 3 months, then at 6 and 12 months in the first year, followed by annual monitoring. 5