Vitamin B12 Deficiency

Definition and Pathophysiology

Megaloblastic anemia resulting from impaired DNA synthesis.
Characterized by macrocytosis, dyssynchrony between nuclear and cytoplasmic maturation, and hypersegmented neutrophils.
Dietary Sources: Synthesized exclusively by microorganisms; humans rely on animal products (meat, eggs, fish, milk).
Absorption Pathway:
- Dietary cobalamin (Cbl) released by gastric proteases.
- Binds Intrinsic Factor (IF) secreted by gastric parietal cells.
- IF-Cbl complex absorbed via cubam receptors in proximal ileum.
Transport: Released into portal circulation bound to Transcobalamin II (TC II).
Intracellular Metabolism: Converted to active coenzymes.
- Adenosylcobalamin (AdoCbl): Cofactor for methylmalonyl-CoA mutase. Deficiency causes elevated methylmalonic acid (MMA).
- Methylcobalamin (MeCbl): Cofactor for methionine synthase. Deficiency causes elevated homocysteine.

Category	Specific Disorders & Mechanisms
Inadequate Intake	- Maternal deficiency: Exclusively breastfed infants of B12-deficient/vegan mothers.- Strict vegetarian or vegan diet.- Malnutrition or poorly controlled PKU diet.
Defective Absorption (Gastric)	- Hereditary Intrinsic Factor Deficiency (HIFD): Autosomal recessive; absent/defective IF; normal gastric mucosa and acid secretion.- Juvenile Pernicious Anemia: Autoimmune destruction of parietal cells; antibodies against IF/parietal cells; associated endocrinopathies.- Gastric surgery/bypass, Helicobacter pylori infection.
Defective Absorption (Intestinal)	- Imerslund-Gräsbeck Syndrome: Defective ileal receptor (CUBN or AMN mutations); associated with benign proteinuria.- Celiac disease, Crohn disease, terminal ileum resection.- Bacterial Overgrowth: Intestinal diverticula, blind loops.- Parasitic Infection: Diphyllobothrium latum (fish tapeworm).
Defective Transport	- Transcobalamin II (TC II) Deficiency: Autosomal recessive; failure to transport B12 to tissues.
Disorders of Metabolism	- Intracellular Defects: Complementation groups cblA through cblX.- Inadequate synthesis of AdoCbl, MeCbl, or both.
Inactivation	- Nitrous Oxide Abuse: Inactivates cobalamin (recreational “Whippets” or anesthesia).

Neurologic problems may precede hematologic abnormalities or occur in isolation.
Infants: Developmental delay, loss of motor milestones (head control, sitting), hypotonia, athetoid movements, seizures, brain atrophy.
Older Children/Adolescents: Subacute combined degeneration of spinal cord (posterior and lateral columns).
Loss of vibration and position sense, ataxic gait, positive Romberg sign.
Peripheral neuropathy: Paresthesia, hyporeflexia, clonus, Babinski responses.
Neuropsychiatric changes, dementia.

Complete Blood Count: Macrocytic anemia (MCV >100 fL, often 110-140 fL).
Elevated Red Cell Distribution Width (RDW).
Leukopenia and thrombocytopenia (simulating aplastic anemia or leukemia in advanced cases).
Inappropriately low absolute reticulocyte count.
Peripheral Smear:
- Macro-ovalocytes.
- Hypersegmented neutrophils (>5 lobes in >5% of cells).
- Marked anisocytosis, poikilocytosis, teardrop cells.
- Cabot rings, Howell-Jolly bodies, punctate basophilia.
Bone Marrow Aspirate:
- Hypercellular with erythroid predominance (reversed myeloid:erythroid ratio).
- Megaloblastic changes: Nuclear-cytoplasmic dyssynchrony (retarded nuclear condensation).
- Giant metamyelocytes with horseshoe-shaped nuclei.

Serum Vitamin B12: Typically <80 pg/mL (normal 200-800 pg/mL). May be falsely normal in TC II deficiency or metabolic defects.
Metabolites (Confirmatory):
- Methylmalonic Acid (MMA): Markedly elevated (>280 nmol/L); specific for B12 deficiency. Excessive urinary MMA excretion.
- Homocysteine: Elevated (non-specific; also raised in folate deficiency).
Hemolysis Markers: Markedly elevated Lactate Dehydrogenase (LDH), moderate indirect hyperbilirubinemia (2-3 mg/dL), decreased haptoglobin (reflecting ineffective erythropoiesis and apoptosis of megaloblastic cells).
Iron/Folate Profile: Serum iron and serum folic acid typically normal or elevated.

Disorder	Differentiating Features
Folic Acid Deficiency	Elevated homocysteine, but normal methylmalonic acid (MMA). Low serum/RBC folate.
Thiamine-Responsive Megaloblastic Anemia	Autosomal recessive (SLC19A2). Triad: Megaloblastic anemia, sensorineural deafness, diabetes mellitus. Marrow shows ringed sideroblasts.
Orotic Aciduria	Defect in pyrimidine synthesis. Normal B12/folate. Orotic acid in urine. Uridine-responsive.
Lesch-Nyhan Syndrome	Hypoxanthine phosphoribosyltransferase deficiency. Mental retardation, choreoathetosis, self-mutilation. Adenine-responsive.
Drug-Induced Macrocytosis	Use of purine/pyrimidine analogs (methotrexate, 6-mercaptopurine, azathioprine, 5-fluorouracil) or ribonucleotide reductase inhibitors (hydroxyurea).
Bone Marrow Failure / MDS	Aplastic anemia, Fanconi anemia, or Myelodysplastic syndromes. Distinguished by marrow cellularity, cytogenetics, and absence of hypersegmented neutrophils.

Formulations: Cyanocobalamin (CNCbl) or Hydroxocobalamin (OHCbl). OHCbl preferred for HIFD and metabolic defects.
Standard Dosing:
- Initial: 25-100 mcg daily (oral, intramuscular, or deep subcutaneous) for 1 week.
- Taper: Weekly doses, followed by monthly maintenance (200-1000 mcg IM).
Neurologic Complications: Higher dosing required. 1000 mcg daily for 2 weeks, then every 2 weeks for 6 months, followed by lifelong monthly administration.
Disease-Specific Dosing:
- TC II Deficiency: Requires massive doses (1000 mcg 2-3 times weekly) to force Cbl into cells.
- Intracellular Defects (cblA-X): High-dose OHCbl, betaine, and specific metabolic management.
- Imerslund-Gräsbeck / HIFD: Lifelong IM or intranasal Cbl bypasses the absorption defect.

Contraindication: Folic acid supplementation without B12 is strictly contraindicated. It may partially correct anemia but rapidly accelerates irreversible neurologic degeneration.
Hematologic Response:
- Bone marrow megaloblastosis reverses to normoblastic within 3 days.
- Reticulocytosis begins by day 3-4, peaks at days 6-8, and normalizes by 3 weeks.
Neurologic Response: Alertness improves within 48 hours. However, long-term cognitive deficits and severe neurologic sequelae often remain irreversible despite therapy.