Causes of Vitamin B12 Deficiency
Primary Etiologic Categories
Vitamin B12 deficiency results from three main mechanisms: inadequate dietary intake, malabsorption disorders, and medication-induced depletion. 1, 2
Dietary Causes
- Vegan and strict vegetarian diets are the most common dietary cause, with deficiency prevalence ranging from 0-86.5% in adults, and vegans showing higher rates than lacto-ovo vegetarians 3
- Limited consumption of fortified foods increases risk in individuals avoiding animal products 1
- Food allergies to eggs, milk, or fish may restrict B12-containing foods 1
- Eating disorders with severely restricted diets can lead to inadequate intake 1
Malabsorption Disorders
Food-cobalamin malabsorption is now recognized as the most common cause of B12 deficiency overall, particularly in older adults 4. This category includes:
Gastric Causes
- Atrophic gastritis affecting the gastric body impairs intrinsic factor production and acid secretion needed to release B12 from food proteins 1, 2
- Pernicious anemia (autoimmune gastritis with intrinsic factor antibodies) causes lifelong malabsorption requiring parenteral replacement 5
- Gastrectomy or bariatric surgery (sleeve gastrectomy, Roux-en-Y gastric bypass, duodenal switch) reduces intrinsic factor and gastric acid 1, 6
Small Intestinal Causes
- Ileal resection >20 cm (with or without ileocecal valve) in Crohn's disease causes permanent malabsorption requiring lifelong monthly intramuscular B12 1
- Celiac disease impairs absorption in the distal ileum 1, 2
- Bacterial overgrowth competes for available B12 2
- Parasitic infestations (particularly fish tapeworm) consume dietary B12 2
- Inflammatory bowel disease affecting the terminal ileum 2, 6
- Chronic radiation enteritis of the distal ileum 2
Pancreatic and Biliary Causes
- Pancreatic insufficiency prevents degradation of haptocorrin, blocking B12 transfer to intrinsic factor 2
- Obstructive jaundice disrupts the enterohepatic circulation of B12 2
Genetic Disorders
- Intrinsic factor deficiency (congenital) 2
- Imerslund-Gräsbeck disease (cubilin/amnionless receptor defects) 2
- These genetic causes are likely underestimated in adults with unexplained B12 deficiency 2
Medication-Induced Deficiency
Multiple medications interfere with B12 absorption or utilization:
- Metformin increases risk, especially after >4 months of use 1, 6, 7
- Proton pump inhibitors and H2 receptor antagonists reduce gastric acid needed to release B12 from food proteins, particularly after >12 months of use 1, 6, 7
- Colchicine impairs ileal absorption 1, 8
- Anticonvulsants (phenobarbital, primidone) interfere with B12 metabolism 1, 8
- Pregabalin affects B12 utilization 1, 8
High-Risk Medical Conditions
Certain autoimmune conditions cluster with B12 deficiency:
- Autoimmune thyroid disease (Hashimoto's, Graves') shows 28-68% prevalence of B12 deficiency due to concurrent autoimmune gastritis 5
- Type 1 diabetes increases risk through autoimmune mechanisms 1, 5
- Sjögren syndrome is associated with autoimmune gastritis 1
Age-Related Deficiency
- Adults >60 years have 18.1% prevalence of metabolic B12 deficiency, rising to 25% in those ≥85 years, primarily due to food-cobalamin malabsorption from reduced gastric acid 5, 4, 6
Critical Clinical Pitfall
Up to 50% of patients with functional B12 deficiency have "normal" serum B12 levels, requiring methylmalonic acid testing to identify metabolic deficiency 1, 5. This is particularly important because neurological damage can occur before hematological changes and may become irreversible if treatment is delayed 1, 7.