Vitamin B12 Deficiency / Pernicious Anemia

Risk factors

• Age >60
• Autoimmune disease (type 1 diabetes, thyroid disease, vitiligo) — pernicious anemia association
• Strict vegan diet (years of inadequate intake)
• Gastrectomy, bariatric surgery, gastric bypass
• Terminal ileum disease/resection (Crohn disease)
• Prolonged metformin or PPI/H2 blocker use
• Chronic alcohol use
• Pancreatic insufficiency, Diphyllobothrium latum (fish tapeworm) infection
• Nitrous oxide exposure (recreational or anesthesia in marginal patients)

Pathophysiology

Dietary B12 binds R-factor in the stomach, is released by pancreatic enzymes in the duodenum, and then complexes with intrinsic factor (from gastric parietal cells) for absorption in the terminal ileum. In pernicious anemia, autoantibodies destroy parietal cells and/or intrinsic factor, blocking absorption. B12 deficiency impairs DNA synthesis (megaloblastic erythropoiesis) and myelin maintenance (subacute combined degeneration of dorsal columns and lateral corticospinal tracts).

Clinical presentation

Differential diagnosis

• Folate deficiency — Identical megaloblastic anemia on smear and labs; NO neurologic features; serum folate low, methylmalonic acid normal
• Myelodysplastic syndrome — Elderly, macrocytic with dysplasia, persistent cytopenias, blasts on smear/marrow
• Hypothyroidism — Macrocytic anemia without megaloblastic features; elevated TSH
• Alcohol use disorder — Macrocytic anemia from direct marrow toxicity, often coexists with B12/folate deficiency
• Drug-induced macrocytosis — Hydroxyurea, methotrexate, zidovudine, phenytoin, sulfasalazine
• Reticulocytosis — Hemolysis or recent blood loss; reticulocytes are large and raise MCV; LDH, haptoglobin, bilirubin differentiate
• Liver disease — Round macrocytes, not oval; target cells; abnormal LFTs

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Permanent neurologic deficits if untreated >6 months (dorsal column and corticospinal tract damage)
• Increased gastric adenocarcinoma and carcinoid risk in pernicious anemia (EGD surveillance debated; baseline endoscopy recommended)
• Severe pancytopenia with risk of bleeding and infection
• Hyperhomocysteinemia — associated with arterial/venous thrombosis
• Refeeding hypokalemia after starting therapy

PANCE pearls

• Neurologic deficits can occur with normal hemoglobin — do not exclude B12 deficiency in a patient with paresthesias and ataxia just because the CBC is normal.
• Folate replacement WITHOUT B12 in a B12-deficient patient corrects the anemia but allows neurologic disease to progress — always check B12 before treating presumed folate deficiency.
• Methylmalonic acid is more reliable than serum B12 for diagnosis; serum B12 has high false-negative and false-positive rates.
• Schilling test is obsolete (radioisotope and intrinsic factor unavailable); diagnosis now relies on antibody testing.
• Nitrous oxide irreversibly oxidizes cobalamin and can precipitate fulminant deficiency — important in recreational use ('whippets') and in marginal patients undergoing anesthesia.
• Hypersegmented neutrophils on smear are a clue even before macrocytosis develops.

References

• BSH 2014 — British Society for Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders (Devalia et al., Br J Haematol 2014)
• Stabler — Vitamin B12 Deficiency (Stabler, NEJM 2013)
• Green et al. — Vitamin B12 deficiency from the perspective of a practicing hematologist (Green, Blood 2017)
• Andres et al. — Oral cobalamin (daily dose of 1000 μg) for the treatment of severe cobalamin deficiencies (J Am Geriatr Soc 2001)