Causes of Vitamin B12 Deficiency
Vitamin B12 deficiency in older adults is primarily caused by food-bound malabsorption due to atrophic gastritis (affecting up to 20% of older adults) and widespread use of proton pump inhibitor drugs, rather than inadequate dietary intake. 1
Primary Mechanisms of Deficiency
Malabsorption (Most Common in Older Adults)
- Atrophic gastritis affecting the gastric body is the leading cause of B12 deficiency in older adults, impairing the release of food-bound cobalamin through reduced gastric acid production 1, 2
- Pernicious anemia (autoimmune destruction of parietal cells) causes intrinsic factor deficiency, though this now accounts for a minority of cases compared to food-bound malabsorption 2, 3
- Ileal resection >20 cm or ileal Crohn's disease prevents B12 absorption in the terminal ileum, requiring lifelong intramuscular supplementation 2, 4
- Post-bariatric surgery (sleeve gastrectomy, Roux-en-Y gastric bypass, duodenal switch) reduces both intrinsic factor and gastric acid production 2, 4
Medication-Induced Deficiency
- Proton pump inhibitors (PPIs) or H2 receptor antagonists used for >12 months impair B12 absorption by reducing gastric acid needed to cleave food-bound cobalamin 2, 5, 6
- Metformin use for >4 months increases deficiency risk, particularly important given widespread diabetes treatment 2, 4, 5, 6
- Other medications including colchicine, phenobarbital, pregabalin, primidone, anticonvulsants, sulfasalazine, and methotrexate can contribute to deficiency 2, 4
Dietary Insufficiency
- Vegan or strict vegetarian diets lacking animal products (meat, dairy, eggs) provide inadequate B12, as the vitamin is not present in plant-based foods 2, 7, 5
- Limited consumption of fortified foods in those with restricted diets increases risk 2
- Food allergies to eggs, milk, or fish may limit B12 sources 2
- Eating disorders with severely restricted intake can lead to deficiency 2
High-Risk Populations Requiring Vigilance
Age-Related Risk
- Adults >75 years have 18.1% prevalence of metabolic B12 deficiency, increasing to 25% in those ≥85 years, even with "normal" serum B12 levels 4, 8, 6
- The combination of atrophic gastritis prevalence and medication use makes older adults particularly vulnerable 1, 8
Gastrointestinal Conditions
- Celiac disease impairs B12 absorption and frequently coexists with autoimmune conditions 2
- Inflammatory bowel disease, particularly Crohn's disease affecting the terminal ileum 2, 5
- Gastric or small intestine resections for any reason 5, 6
Autoimmune Associations
- Autoimmune thyroid disease (Hashimoto's, Graves') has 28-68% prevalence of B12 deficiency due to associated autoimmune gastritis 4
- Type 1 diabetes and other autoimmune conditions increase risk through autoimmune gastritis 2, 4
- Sjögren syndrome is associated with increased B12 deficiency risk 2
Critical Clinical Pitfalls
The "Normal" Serum B12 Trap
- Up to 50% of patients with "normal" serum B12 (180-350 pg/mL) have functional metabolic deficiency when measured by methylmalonic acid, meaning standard testing misses half of all cases 2, 4, 9
- Serum B12 measures both active and inactive forms, not reflecting actual cellular availability 2, 4
- In the Framingham Study, 12% had low serum B12, but an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" levels 4
Neurological Damage Precedes Hematological Changes
- Neurological symptoms often appear before anemia develops, and one-third of B12-deficient patients never develop macrocytic anemia 2, 9, 6
- Subacute combined degeneration of the spinal cord can progress to irreversible damage if treatment is delayed, even with normal serum B12 2, 9
- Sensory symptoms (paresthesia, numbness, impaired proprioception) typically precede motor dysfunction 2, 9
Never Give Folic Acid Before B12
- Administering folic acid before treating B12 deficiency masks anemia while allowing irreversible neurological damage to progress 4, 7
- This is a critical error that can precipitate subacute combined degeneration of the spinal cord 1, 7
Diagnostic Algorithm for Suspected Deficiency
When to Test
- Any patient with risk factors (age >75, PPI use >12 months, metformin >4 months, vegan diet, gastric surgery, ileal disease) PLUS clinical features (fatigue, cognitive difficulties, neuropathy, macrocytosis, anemia unresponsive to iron) 2, 4, 6
- All patients with autoimmune thyroid disease at diagnosis and annually thereafter 4
- Post-bariatric surgery patients require routine monitoring 2, 4
Testing Sequence
Initial test: Total serum B12 (costs £2, rapid turnaround) 4
Confirmatory test for indeterminate results: Methylmalonic acid (MMA) 4, 6
Alternative: Active B12 (holotranscobalamin) if available 2, 4
Identifying the Underlying Cause
- Test for pernicious anemia: Intrinsic factor antibodies (highly specific), gastrin levels (>1000 pg/mL suggests pernicious anemia) 2, 4
- Screen for celiac disease: Tissue transglutaminase (tTG) antibodies and total IgA, found in 13.3% of B12-deficient patients 4
- Helicobacter pylori testing to evaluate for atrophic gastritis 6
Impact on Morbidity and Mortality
- Cardiovascular disease: Metabolic B12 deficiency increases stroke risk through hyperhomocysteinemia; B vitamin supplementation reduced ischemic stroke by 43% in meta-analyses 4
- Cognitive dysfunction and dementia: Lower B12 biomarker status associated with increased risk in older adults 1
- Depression and anxiety: Deficient B12 status linked to increased depression risk; deficient B6 status associated with increased anxiety 1
- Osteoporosis: B vitamin deficiencies associated with higher risk of bone disease 1
- Irreversible neurological damage: Subacute combined degeneration causes permanent spinal cord damage if untreated 2, 9, 7