A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 67-year-old man presents to his primary care provider for routine follow-up. He complains of mild fatigue and occasional tingling in both feet. He reports that this numbness and tingling has led to him having 3 falls over the last month. He has had type 2 diabetes mellitus for 23 years and hypertension for 15 years, for which he takes metformin and enalapril. He denies tobacco or alcohol use. His blood pressure is 126/82 mm Hg, the heart rate is 78/min, and the respiratory rate is 15/min. Significant laboratory results are shown:
Hemoglobin 10 g/dL
Hematocrit 30%
Mean corpuscular volume (MCV) 110 fL
Serum B12 level 210 picograms/mL
Which of the following is the best next step in the management of this patient’s condition?
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A
Intrinsic factor antibodyIncorrect. Intrinsic factor antibodies are useful to diagnose pernicious anemia, but only after vitamin B12 deficiency has been confirmed — the borderline B12 level here requires first measuring methylmalonic acid.
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B
Schilling testIncorrect. The Schilling test (historically used to differentiate causes of B12 malabsorption) is not the first step — it is reserved for patients with confirmed deficiency to identify the cause; many institutions no longer perform it.
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C
Folic acid supplementationIncorrect. Folate supplementation could partially correct the macrocytic anemia but would mask and not correct the neurologic damage of B12 deficiency — it is contraindicated as a first step in this scenario.
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D
Methylmalonic acid levelCorrect. Methylmalonic acid (MMA) is the most sensitive and specific test for confirming functional vitamin B12 deficiency when serum B12 is in the borderline range — MMA accumulates when methylmalonyl-CoA mutase activity is impaired by B12 deficiency.
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E
Empiric vitamin B12 supplementationIncorrect. Empiric B12 supplementation without confirmatory testing would obscure the diagnostic workup and delay identification of the underlying cause (e.g., pernicious anemia); MMA should be checked first to confirm functional B12 deficiency.
↑ Tap an answer to reveal the reasoning
Answer: D. This 67-year-old diabetic has paresthesias and falls (peripheral neuropathy), macrocytic anemia (Hgb 10, MCV 110), and a low-normal serum B12 (210 pg/mL — typically the "borderline" range, with definitive deficiency below 200). The question is how to confirm or rule out vitamin B12 deficiency.
The serum B12 level alone is insensitive in the borderline range (200–400 pg/mL): some patients with true tissue B12 deficiency have "normal" levels, and conversely some patients with low levels are not clinically deficient. To resolve this ambiguity, measure methylmalonic acid (MMA) — and often homocysteine — which are upstream metabolites that accumulate when B12 is functionally deficient.
Mechanistically: B12 is a cofactor for two reactions:
1. Methionine synthase (cytosolic): converts homocysteine to methionine, requires methylcobalamin. Deficiency raises homocysteine.
2. Methylmalonyl-CoA mutase (mitochondrial): converts methylmalonyl-CoA to succinyl-CoA, requires adenosylcobalamin. Deficiency raises methylmalonic acid.
Elevated MMA is more specific to B12 deficiency than elevated homocysteine (which can also be elevated in folate deficiency, renal failure, and inborn errors). If MMA is elevated, B12 deficiency is confirmed, and the next steps are determining the cause (intrinsic factor antibodies for pernicious anemia, Schilling test in some cases, evaluation for dietary deficiency, malabsorption, metformin use — relevant here, since metformin causes B12 deficiency by interfering with ileal absorption).
Intrinsic factor antibodies and the Schilling test are useful once deficiency is established to determine the cause (pernicious anemia vs malabsorption), but should not be the first step before deficiency is confirmed. Folate supplementation could mask but not correct the neurologic damage of B12 deficiency.
**Why each option:**
**A.** Intrinsic factor antibodies are useful to diagnose pernicious anemia, but only after vitamin B12 deficiency has been confirmed — the borderline B12 level here requires first measuring methylmalonic acid.
**B.** The Schilling test (historically used to differentiate causes of B12 malabsorption) is not the first step — it is reserved for patients with confirmed deficiency to identify the cause; many institutions no longer perform it.
**C.** Folate supplementation could partially correct the macrocytic anemia but would mask and not correct the neurologic damage of B12 deficiency — it is contraindicated as a first step in this scenario.
**D.** Correct. Methylmalonic acid (MMA) is the most sensitive and specific test for confirming functional vitamin B12 deficiency when serum B12 is in the borderline range — MMA accumulates when methylmalonyl-CoA mutase activity is impaired by B12 deficiency.