Mechanisms of Vitamin B12 Malabsorption
Vitamin B12 malabsorption arises from disruption at any point along a complex absorption pathway requiring gastric acid, intrinsic factor, pancreatic proteases, and intact terminal ileum function. 1, 2
Physiological Absorption Pathway
The normal absorption of vitamin B12 involves multiple sequential steps, each vulnerable to disruption:
Gastric phase: Dietary B12 is released from food proteins by gastric acid and pepsin, then binds to haptocorrin (R-binder) secreted by salivary glands and gastric mucosa. 1, 2
Duodenal phase: Pancreatic proteases degrade haptocorrin in the duodenum, releasing B12 to bind intrinsic factor (IF) secreted by gastric parietal cells; this transfer requires adequate pancreatic enzyme activity and appropriate pH. 1, 3
Ileal phase: The B12-IF complex is absorbed in the terminal ileum via the cubilin-amnionless receptor complex, which mediates cellular uptake. 1, 2
Enterohepatic circulation: A portion of hepatic B12 is excreted in bile and reabsorbed in the ileum, creating a recycling pathway that can be disrupted by ileal disease. 1
Major Categories of Malabsorption
1. Gastric Causes
Pernicious anemia results from autoimmune destruction of gastric parietal cells, eliminating intrinsic factor production and causing lifelong malabsorption requiring parenteral B12 replacement. 4, 1, 2
Atrophic gastritis affects up to 20% of older adults, impairing both acid secretion (needed to release food-bound B12) and intrinsic factor production. 5
Gastrectomy (total or partial) removes the source of intrinsic factor and acid, mandating lifelong B12 supplementation at 1000 mcg intramuscularly monthly. 4, 1
Proton pump inhibitors and H2-receptor antagonists used for >12 months impair release of B12 from dietary proteins by suppressing gastric acid, creating food-bound B12 malabsorption. 5
2. Pancreatic Causes
Pancreatic insufficiency prevents degradation of haptocorrin by pancreatic proteases, blocking transfer of B12 to intrinsic factor; approximately 30% of adults with exocrine pancreatic insufficiency show abnormal Schilling tests, though clinical B12 deficiency remains rare. 3
Cystic fibrosis produces abnormal Schilling tests in nearly all cases due to pancreatic enzyme deficiency and gastric hyperacidity, yet overt B12 deficiency is uncommon. 3
Zollinger-Ellison syndrome causes gastric hyperacidity that may interfere with B12-IF binding. 1
3. Small Intestinal Causes
Ileal resection >20 cm removes the absorption site for the B12-IF complex, requiring prophylactic hydroxocobalamin 1000 mcg intramuscularly monthly for life. 6, 1
Crohn disease involving >30–60 cm of ileum impairs B12 absorption even without resection, necessitating annual screening and prophylactic supplementation. 7, 6
Celiac disease and tropical sprue damage the ileal mucosa, reducing cubilin-amnionless receptor function; gluten-free diet or antibiotics may restore absorption. 4, 1
Bacterial overgrowth in the small bowel allows bacteria to consume dietary B12 before absorption; treatment with antibiotics may eliminate the need for long-term supplementation. 4, 1
Fish tapeworm (Diphyllobothrium latum) competes for dietary B12; expulsion of the parasite resolves malabsorption. 4, 1
Chronic radiation enteritis of the distal ileum damages the absorptive surface. 1
4. Bariatric Surgery
Roux-en-Y gastric bypass and biliopancreatic diversion eliminate intrinsic factor production and bypass the ileal absorption site, requiring 1000–2000 mcg/day oral or 1000 mcg/month intramuscular B12 indefinitely. 5, 6
Sleeve gastrectomy reduces parietal cell mass and acid secretion, necessitating 250–350 mcg/day oral or 1000 mcg/week sublingual B12. 6
5. Medication-Induced Malabsorption
Metformin used for >4 months disrupts calcium-dependent ileal receptors and may promote bacterial overgrowth, causing dose-dependent reductions in serum B12 (−53.93 pmol/L; 95% CI: −81.44, −26.42) and increasing deficiency risk 2.92-fold (adjusted OR: 2.92; 95% CI: 1.26,6.78). 7
Colchicine, anticonvulsants, sulfasalazine, and methotrexate interfere with B12 absorption or utilization. 5
6. Inherited Disorders
Imerslund-Gräsbeck syndrome results from mutations in cubilin (CUBN) or amnionless (AMN) genes, abolishing ileal B12 uptake; this autosomal recessive disorder presents in childhood with megaloblastic anemia and proteinuria. 1, 2
Intrinsic factor deficiency is a rare autosomal recessive disorder causing congenital pernicious anemia. 1, 2
Transcobalamin deficiency (TCN2 mutations) and intracellular cobalamin metabolism defects (MMACHC, MMADHC, MTRR, MTR genes) impair cellular B12 delivery and utilization despite normal absorption. 5
Diagnostic Work-Up
Initial Laboratory Testing
Measure serum total B12 or active B12 (holotranscobalamin) first; total B12 costs £2 with rapid turnaround, whereas active B12 costs £18 but measures the biologically active fraction. 5
Interpretation of total B12: <180 pg/mL (133 pmol/L) confirms deficiency and mandates immediate treatment without further testing; 180–350 pg/mL (133–258 pmol/L) is indeterminate and requires methylmalonic acid (MMA) measurement; >350 pg/mL (258 pmol/L) makes deficiency unlikely unless clinical suspicion is high. 5
Interpretation of active B12: <25 pmol/L confirms deficiency; 25–70 pmol/L is indeterminate and requires MMA; >70 pmol/L excludes deficiency. 5
Confirmatory Functional Testing
Methylmalonic acid (MMA) >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity, detecting an additional 5–10% of patients with deficiency missed by serum B12 alone; MMA testing costs £11–£80 and is cost-effective (£3,946 per quality-adjusted life year) when used after indeterminate B12 results. 5
Homocysteine >15 µmol/L supports B12 deficiency but is less specific than MMA, as it also rises in folate deficiency, renal impairment, and hypothyroidism. 5
Standard serum B12 testing misses functional deficiency in up to 50% of cases; the Framingham Study found that while 12% had low serum B12, an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" serum levels. 5
Etiologic Testing
Intrinsic factor antibodies are highly specific (>95%) for pernicious anemia; positive results confirm the diagnosis and indicate lifelong parenteral B12 therapy is required. 5
Gastric parietal cell antibodies are sensitive but less specific for pernicious anemia. 8
Gastrin levels >1000 pg/mL suggest pernicious anemia or Zollinger-Ellison syndrome. 5
Genetic testing for TCN2, MMACHC, MMADHC, MTRR, and MTR genes should be considered in patients with elevated MMA and normal serum B12, particularly with a strong family history of B12 deficiency. 5
Special Population Screening
Screen all patients with autoimmune hypothyroidism for B12 deficiency at diagnosis and annually thereafter, as prevalence ranges from 28–68% and is strongly associated with positive thyroid antibodies. 5
Screen patients with ileal Crohn disease or ileal resection annually for B12 deficiency. 7, 6
Screen post-bariatric surgery patients at 3,6, and 12 months in the first year, then at least annually thereafter. 6
Screen patients on metformin >4 months, PPIs >12 months, or age >75 years for B12 deficiency. 5
Treatment Approaches
Intramuscular Therapy (Preferred for Malabsorption)
For neurological involvement: Administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement (may require weeks to months), then 1 mg intramuscularly every 2 months for life. 6
Without neurological involvement: Give hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then 1 mg intramuscularly every 2–3 months for life. 6
Post-bariatric surgery: Initiate prophylactic hydroxocobalamin 1 mg intramuscularly every 3 months indefinitely, regardless of documented deficiency. 6
Ileal resection >20 cm or ileal Crohn disease: Administer prophylactic hydroxocobalamin 1000 mcg intramuscularly monthly for life, even without documented deficiency. 6
Oral Therapy (Effective for Dietary Deficiency)
Oral B12 1000–2000 mcg daily is as effective as intramuscular administration for most patients, including those with malabsorption, because approximately 1% of oral B12 is absorbed by passive diffusion independent of intrinsic factor. 5, 4
Oral therapy is appropriate for dietary insufficiency in vegetarians, vegans, or elderly patients with food-bound B12 malabsorption from atrophic gastritis. 5
Formulation Selection
Hydroxocobalamin is the guideline-recommended first-line injectable due to superior tissue retention and established dosing protocols. 6
In patients with renal dysfunction (eGFR <50 mL/min), use methylcobalamin or hydroxocobalamin instead of cyanocobalamin, as cyanocobalamin requires renal clearance of the cyanide moiety and is associated with doubled cardiovascular event risk (hazard ratio 2.0) in diabetic nephropathy. 6
Critical Safety Considerations
Never administer folic acid before correcting B12 deficiency, as folic acid can mask megaloblastic anemia while allowing irreversible subacute combined degeneration of the spinal cord to progress. 6, 9
After B12 repletion, add folic acid 5 mg daily only if folate deficiency is documented, and continue for at least 4 months. 6
Monitoring
Recheck serum B12 at 3,6, and 12 months in the first year, then annually thereafter to detect treatment failures or recurrence. 6
Target homocysteine <10 µmol/L for optimal cardiovascular outcomes. 6
Check complete blood count, ferritin, and folate concurrently at each monitoring visit, as deficiencies often coexist. 6
For patients on intramuscular injections, measure serum B12 directly before the next scheduled injection (trough level) to identify potential under-dosing. 6
Common Pitfalls
Relying solely on serum B12 to rule out deficiency misses up to 50% of cases with functional deficiency; always measure MMA when B12 is indeterminate (180–350 pg/mL) or clinical suspicion is high despite normal B12. 5
Stopping monitoring after one normal result risks missing relapse in patients with malabsorption or dietary insufficiency who require ongoing supplementation. 6
Failing to screen high-risk populations (autoimmune thyroid disease, ileal Crohn disease, post-bariatric surgery, metformin >4 months, age >75 years) delays diagnosis until irreversible neurological damage occurs. 5
Using cyanocobalamin in renal dysfunction increases cardiovascular risk; always choose hydroxocobalamin or methylcobalamin in patients with eGFR <50 mL/min. 6