How do I differentiate between vitamin B12 deficiency and folate deficiency in a patient with macrocytosis?

To differentiate between vitamin B12 deficiency and folate deficiency in a patient presenting with macrocytosis, initial clinical and laboratory assessment is essential. Both deficiencies cause macrocytic anemia characterized by enlarged red blood cells, but certain biochemical tests and clinical features help distinguish them.

Laboratory differentiation: Measure serum vitamin B12 and serum folate levels as initial tests. A low serum vitamin B12 concentration (<180 ng/L or <133 pmol/L) suggests vitamin B12 deficiency, while low serum folate indicates folate deficiency NICE NG239. However, serum vitamin B12 alone may be insufficient due to indeterminate results; in such cases, measuring serum methylmalonic acid (MMA) and plasma homocysteine levels is recommended. Elevated MMA is specific for vitamin B12 deficiency, whereas homocysteine is elevated in both deficiencies but more markedly in folate deficiency NICE NG239.

Clinical features: Vitamin B12 deficiency often presents with neurological symptoms such as peripheral neuropathy, balance issues, cognitive difficulties, and subacute combined degeneration of the spinal cord, which are not typical in folate deficiency NICE NG239. Folate deficiency usually lacks neurological manifestations but may present with similar hematological findings including macrocytosis and anemia Kaferle & Strzoda 2009Nagao & Hirokawa 2017.

Additional considerations: Risk factors for vitamin B12 deficiency include dietary insufficiency (e.g., vegan diet), malabsorption (e.g., gastrectomy, terminal ileal resection), and certain medications, whereas folate deficiency is often related to poor dietary intake, increased requirements (e.g., pregnancy), or malabsorption (Marchi et al., 2020; NICE NG239).

In summary, differentiation relies on combined clinical assessment and targeted biochemical testing: low serum vitamin B12 with elevated MMA and neurological signs supports vitamin B12 deficiency, while low serum folate with elevated homocysteine but normal MMA and absence of neurological symptoms supports folate deficiency NICE NG239 Kaferle & Strzoda 2009Nagao & Hirokawa 2017Marchi et al. 2020.