A 38-year-old man with a 10-year history of celiac disease presents with fatigue and macrocytic anemia (MCV 112 fL). Serum B12 is normal, but serum folate is low. Which investigation best confirms folate deficiency as the cause of megaloblastosis?

Explanation

## Confirmation of Folate Deficiency in Megaloblastosis **Key Point:** Red cell folate (RBC folate) is the gold standard for confirming true folate deficiency because it reflects long-term folate stores (120-day RBC lifespan), whereas serum folate fluctuates with recent dietary intake. ### Why Red Cell Folate? Folate metabolism occurs in two compartments: | Compartment | Marker | Reflects | Interpretation | |---|---|---|---| | **Serum folate** | Serum folate level | Recent dietary intake (days) | Fluctuates; low in poor intake but normalizes quickly with supplementation | | **Intracellular (RBC)** | **Red cell folate** | **Long-term stores (120 days)** | **Stable; true deficiency state** | **High-Yield:** In this patient, serum folate is low (confirming recent deficiency) but RBC folate would be **very low**, confirming **tissue depletion**. Celiac disease causes mucosal atrophy → impaired folate absorption. ### Why Not the Other Tests? **Methylmalonic acid:** Elevated ONLY in B12 deficiency (this patient has normal B12), so it will be normal. **Homocysteine:** Elevated in both B12 and folate deficiency; non-specific. It would be elevated here, but does not confirm folate as the sole cause. **Deoxyuridine suppression test:** Functional test that detects impaired DNA synthesis (positive in both B12 and folate deficiency); not specific to folate. ### Clinical Pearl In malabsorption syndromes (celiac, tropical sprue, Crohn's disease), RBC folate is often depleted before serum folate becomes critically low. RBC folate is the **most sensitive marker of true tissue folate depletion**. [cite:Harrison 21e Ch 100]