A 55-year-old woman presents with fatigue, pallor, and macrocytosis (MCV 118 fL). Serum vitamin B12 is 88 pg/mL (normal 200–900). Gastric parietal cell antibodies are positive. Bone marrow shows hypersegmented neutrophils and megaloblastic changes. Which laboratory parameter confirms impaired B12 metabolism at the cellular level even when total B12 is borderline low?

• A Elevated total serum B12 with normal MMA
• B Low serum folate with normal MMA
• C Elevated LDH with normal MMA
• D Elevated serum methylmalonic acid (MMA) and homocysteine ✓

Explanation

Methylmalonic acid (MMA) and homocysteine are the most sensitive functional markers of intracellular B12 deficiency. B12 is required as a cofactor for methionine synthase (converting homocysteine to methionine) and methylmalonyl-CoA mutase (converting MMA to succinyl-CoA). Both MMA and homocysteine are elevated in B12 deficiency. In folate deficiency, homocysteine is elevated but MMA is normal (MMA requires B12, not folate). Elevated LDH reflects haemolysis/ineffective erythropoiesis but is not specific for B12 deficiency.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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