In a 72-year-old woman with fatigue, anemia, macrocytosis, hypersegmented neutrophils, normal‑high ferritin, markedly low vitamin B12 and elevated methylmalonic acid, what is the most likely diagnosis?

Vitamin B12 Deficiency

The most likely diagnosis is vitamin B12 deficiency (option 2). This 72-year-old woman presents with the classic triad of macrocytic anemia (MCV 102), hypersegmented neutrophils on peripheral smear, and markedly low serum B12 (210 pg/mL), confirmed by elevated methylmalonic acid (580 nmol/L, normal <271). 1

Diagnostic Confirmation

The laboratory findings definitively establish functional B12 deficiency:

• Serum B12 of 210 pg/mL falls in the indeterminate range (180-350 pg/mL), but the elevated MMA of 580 nmol/L (>271 nmol/L) confirms true cellular B12 deficiency. 1 MMA has 98.4% sensitivity for detecting B12 deficiency and is the gold standard confirmatory test when serum B12 is borderline. 1

• Hypersegmented neutrophils are pathognomonic for megaloblastic anemia due to B12 or folate deficiency, representing impaired DNA synthesis during cell division. 2 This finding, combined with macrocytosis (MCV 102), strongly points to B12 deficiency rather than other causes of anemia. 2

• The ferritin of 220 ng/mL excludes iron deficiency anemia (option 1), which would present with microcytosis (low MCV) and low ferritin. 1

Why Other Diagnoses Are Excluded

Anemia of chronic disease (option 3) is ruled out because it typically presents with normocytic or microcytic anemia, not macrocytosis, and would not cause hypersegmented neutrophils or elevated MMA. 1

Hemolysis (option 4) is excluded by the absence of typical findings such as elevated reticulocyte count, elevated indirect bilirubin, elevated LDH, or decreased haptoglobin—none of which are mentioned in this case. 1

Myelodysplastic syndrome (option 5) remains a differential for macrocytic anemia with hypersegmented neutrophils in elderly patients, but the markedly low B12 and elevated MMA make B12 deficiency far more likely. 1 MDS would require bone marrow biopsy for diagnosis and would not explain the metabolic derangements (elevated MMA). 1

Understanding the Pathophysiology

Standard serum B12 testing misses functional deficiency in up to 50% of cases. The Framingham Study demonstrated that while 12% had frankly low serum B12, an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" serum levels. 1 This patient's B12 of 210 pg/mL sits in this gray zone, making MMA measurement essential. 1

Elderly patients have particularly high rates of metabolic B12 deficiency: 18.1% of those over 80 years have functional deficiency, often due to atrophic gastritis causing food-cobalamin malabsorption. 1, 3 Atrophic gastritis affects up to 20% of older adults and impairs release of B12 from food proteins while leaving absorption of crystalline B12 intact. 1, 3

Common Pitfalls to Avoid

Do not rely solely on serum B12 to rule out deficiency in elderly patients. Serum B12 between 180-350 pg/mL requires MMA or homocysteine measurement to identify the 5-10% of patients with functional deficiency who would otherwise be missed. 1

Do not confuse the normal ferritin with iron deficiency. In inflammatory conditions, ferritin up to 100 μg/L may still be consistent with iron deficiency, but this patient's ferritin of 220 is well above that threshold and the macrocytosis (not microcytosis) excludes iron deficiency. 1

Never administer folic acid before treating B12 deficiency. Folate can mask the megaloblastic anemia while allowing irreversible neurological damage (subacute combined degeneration of the spinal cord) to progress. 1, 4 Always correct B12 first, then add folate if needed. 4

Immediate Next Steps

Begin treatment immediately without waiting for additional testing. With confirmed B12 deficiency (low B12 + elevated MMA + macrocytic anemia + hypersegmented neutrophils), treatment should not be delayed. 1

For patients without neurological symptoms: Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then 1 mg IM every 2-3 months for life. 4

If neurological symptoms are present (fatigue may represent early neurological involvement): Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then 1 mg IM every 2 months for life. 4

Investigate the underlying cause: Check intrinsic factor antibodies for pernicious anemia, assess for atrophic gastritis with gastrin levels (>1000 pg/mL suggests pernicious anemia), review medications (metformin >4 months, PPIs >12 months), and evaluate dietary intake. 1