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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- Vitamin B12 deficiency causes megaloblastic anemia with macro-ovalocytes and hypersegmented neutrophils
- Neurologic features distinguish B12 deficiency from folate deficiency
- Methylmalonic acid and homocysteine are elevated in B12 deficiency; only homocysteine is elevated in folate deficiency
- Pernicious anemia is autoimmune intrinsic factor deficiency from gastric parietal cell destruction
- Treat B12 deficiency before folate if both are possible, because folate can correct anemia while neurologic injury progresses
Overview
Vitamin B12 is required for DNA synthesis and myelin maintenance. Deficiency causes ineffective hematopoiesis, macrocytosis, and neurologic dysfunction. Causes include pernicious anemia, gastric surgery, terminal ileal disease or resection, Crohn disease, vegan diet without supplementation, chronic metformin or PPI use, Diphyllobothrium latum infection, and pancreatic insufficiency.
Epidemiology
Risk increases with older age, autoimmune disease, gastric bypass, gastrectomy, ileal disease, strict vegan diet, and long-term metformin or acid suppression. Pernicious anemia is associated with other autoimmune conditions and increased risk of gastric adenocarcinoma and type I gastric carcinoids.
Clinical Features
Symptoms
Fatigue, weakness, exertional dyspnea
Paresthesias, numbness, gait instability, or falls
Cognitive changes, depression, irritability, or psychosis
Glossitis, anorexia, weight loss, diarrhea
Infertility or recurrent pregnancy loss in severe deficiency
Signs
Pallor, mild jaundice from ineffective erythropoiesis
Beefy red glossitis
Loss of vibration and proprioception, positive Romberg, sensory ataxia
Spasticity or upper motor neuron signs from subacute combined degeneration
Peripheral neuropathy with decreased sensation
Investigations
First-line
CBC and peripheral smearMacrocytic anemia, elevated MCV, macro-ovalocytes, hypersegmented neutrophils; pancytopenia can occur
Serum vitamin B12Low level supports diagnosis, but borderline values require MMA/homocysteine
Methylmalonic acid and homocysteineBoth elevated in B12 deficiency; MMA is more specific for B12
Second-line
Anti-intrinsic factor antibodyHighly specific for pernicious anemia
Anti-parietal cell antibodyMore sensitive but less specific than intrinsic factor antibody
LDH, bilirubin, reticulocyte countIneffective erythropoiesis can mimic hemolysis: high LDH, indirect bilirubin, low retic response
Specialist
Endoscopic evaluationConsider in pernicious anemia for gastric cancer risk and if gastrointestinal symptoms or iron deficiency coexist
Neurologic assessment or MRIReserved for diagnostic uncertainty; dorsal column changes may be seen
1
Replace vitamin B12
- High-dose oral cyanocobalamin can be effective if absorption is partly intact
- IM cyanocobalamin is preferred for severe deficiency, neurologic signs, pernicious anemia, or malabsorption
- Treat promptly when neurologic features are present
2
Address the cause
- Pernicious anemia usually requires lifelong replacement
- Review metformin, PPI use, bariatric surgery, vegan diet, ileal disease, and fish tapeworm risk
- Check for concurrent iron deficiency, especially in autoimmune gastritis
3
Monitor response
- Reticulocytosis begins within about 1 week
- Hemoglobin improves over weeks; neurologic recovery may take months and may be incomplete if prolonged
Complications
- Subacute combined degeneration: Dorsal column and corticospinal tract dysfunction
- Irreversible neuropathy: Risk increases with delayed treatment
- Pancytopenia: Severe ineffective hematopoiesis can mimic marrow failure
- Gastric malignancy: Pernicious anemia increases gastric adenocarcinoma and carcinoid risk
USMLE Step 2 CK Exam Tips
- 1Macrocytosis + neurologic symptoms = vitamin B12 deficiency, not folate deficiency
- 2B12 deficiency: elevated methylmalonic acid and homocysteine
- 3Folate deficiency: normal methylmalonic acid with elevated homocysteine
- 4Pernicious anemia: anti-intrinsic factor antibody is highly specific
- 5Do not treat presumed folate deficiency alone until B12 deficiency is excluded
- 6Terminal ileum disease or resection causes B12 deficiency; proximal jejunal disease causes folate/iron problems
practicetest your knowledge on vitamin b12 deficiencyApply what you've learnt with USMLE Step 2 CK-style questions from the iatroX Q-Bank — hematology & oncology and beyond.
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