A 58-year-old Indian woman presents with progressive fatigue, dyspnea on exertion, and paresthesias in her feet for 3 months. She is a strict vegetarian with no meat or dairy intake for the past 15 years. On examination, she has glossitis, angular cheilitis, and a positive Romberg sign. Her hemoglobin is 7.2 g/dL, MCV is 118 fL, and the reticulocyte count is 0.8%. Peripheral blood smear shows hypersegmented neutrophils and macro-ovalocytes. Serum vitamin B12 is 85 pg/mL (normal: 200–900). What is the most likely diagnosis?

Explanation

## Diagnosis: Megaloblastic Anemia — Vitamin B12 Deficiency ### Clinical Presentation **Key Point:** The combination of strict vegetarianism (no animal products), neurological signs (paresthesias, positive Romberg sign), and low serum B12 (85 pg/mL) is pathognomonic for vitamin B12 deficiency. ### Laboratory Findings | Finding | Interpretation | |---------|----------------| | MCV 118 fL | Macrocytic (>100 fL) | | Hypersegmented neutrophils | Nuclear maturation lag — hallmark of megaloblastosis | | Macro-ovalocytes | Large, oval RBCs with immature nuclear pattern | | Low reticulocyte count (0.8%) | Inadequate bone marrow response; ineffective erythropoiesis | | Serum B12 85 pg/mL | Confirmed B12 deficiency (normal >200) | ### Pathophysiology of Megaloblastosis 1. Vitamin B12 is a cofactor for methionine synthase and methylmalonyl-CoA mutase 2. B12 deficiency impairs DNA synthesis (via reduced 5-methyltetrahydrofolate regeneration) 3. RNA synthesis continues → **nuclear-cytoplasmic asynchrony** 4. Nucleus remains immature (open chromatin, hypersegmented) while cytoplasm matures → megaloblast 5. Ineffective erythropoiesis → low reticulocyte count despite severe anemia **Clinical Pearl:** Neurological manifestations (subacute combined degeneration: paresthesias, Romberg sign, ataxia, dementia) are **specific to B12 deficiency** and do NOT occur in folate deficiency alone. ### Why B12 Deficiency, Not Folate? **High-Yield:** Both B12 and folate deficiency cause megaloblastosis, but: - **B12 deficiency** → neurological signs (demyelination of dorsal columns, lateral corticospinal tracts) - **Folate deficiency** → no neurological signs (folate does not affect myelin) - This patient has paresthesias and Romberg sign → **B12 deficiency** ### Source of B12 Deficiency Strict vegetarian diet (no meat, fish, dairy, eggs) for 15 years → dietary B12 deficiency. Intrinsic factor antibodies and parietal cell antibodies are negative (pernicious anemia ruled out). **Mnemonic: ABCDE of B12 Deficiency sources:** - **A**nemia pernicious (IF antibodies) - **B**lind loop syndrome - **C**rohn's disease (terminal ileum) - **D**ietary (vegans) - **E**xtrinsic factor loss (gastrectomy, ileal resection)