Vitamin B12 Deficiency
Basics
- Vitamin B12 deficiency is related to inadequate intake or absorption of cobalamin.
- Cobalamin is critical for central nervous system myelination, red blood cell production, immune cell cytogenesis, and DNA synthesis (1).
- Deficiency can cause megaloblastic anemia, bone marrow dysfunction, cytopenia including lymphopenia, and diverse and potentially irreversible neuropsychiatric changes.
- Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; white matter; and cranial and peripheral nerves.
- Elevated MMA and homocysteine levels MMA are more sensitive and specific and persist for several days even after treatment.
Description
Normal vitamin B12 absorption and diet recommendations
- Vitamin B12 is a water-soluble vitamin present in animal-source foods and foods fortified with vitamin B12.
- Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin that are secreted in saliva (commonly known as R-factor).
- Pancreatic proteases cleave vitamin B12 from haptocorrin.
- In duodenum, vitamin B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
- Vitamin B12-IF complex is absorbed by terminal ileum into portal circulation.
- Small amount of ingested vitamin B12 (<1 percent) can be absorbed by passive diffusion and is the basis for use of high dose oral vitamin B12 in pernicious anemia (PA).
- Total body stores of vitamin B12 are in 2 to 5 mg range. Most of it are stored in liver.
- Vitamin B12 excreted in bile is effectively reabsorbed through enterohepatic circulation.
- Typical Western diet: 5 to 30 mg/day; however, only 1 to 5 mg/day is effectively absorbed.
- Recommend 2.4 mg/day for adults and 2.6 mg/day during pregnancy and 2.8 mg/day during lactation (most prenatal vitamins contain vitamin B12).
Epidemiology
Prevalence
- National Health and Nutrition Examination Survey documented 6.9% and 15% prevalence of B12 deficiency in U.S. adults aged 51 to 70 and >70 years, respectively (2).
- Morbidity increases vitamin B12 deficiency occurrence, ranging from 4% to 5% in community-living elderly to about 30–40% in institutionalized subjects with multiple comorbidities.
- Prevalence in those <60 years old is 6% versus 20% in those >60 years.
- Increasing recognition in breastfed-only infants with vitamin B12deficient mothers
- Among patients with clinical macrocytosis (defined as a mean corpuscular volume [MCV] >100), 18–20% were due to vitamin B12 deficiency (3).
- Vitamin B12 deficiency due to PA is more common in people of Northern European ancestry and lower in people of African descent.
Etiology and Pathophysiology
- Decreased oral intake
- Vegetarians and vegans: Vitamin B12 is found in animal-source foods.
- Decreased IF
- PA: can be associated with autoantibodies directed against gastric parietal cells and/or IF; 15–30% of all cases; most frequent cause of severe disease; neurologic disorders are common presenting complaints.
- Chronic atrophic gastritis: autoimmune attack on gastric parietal cells causing autoimmune gastritis and leading to decreased IF production
- Gastrectomy: removal of entire or part of stomach
- Decreased absorption
- Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb vitamin B12.
- Chronic alcoholism: decreases body’s ability to absorb vitamin B12
- Gluten hypersensitivity (celiac disease) intestinal villi atrophy and subsequent malabsorption
- Ileal resection
- Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B12haptocorrin bond to allow vitamin B12 to bind to IF.
- Helicobacter pylori infection: impairs release of vitamin B12 from bound proteins
- Medications:
- Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting vitamin B12 release from dietary protein; metformin
- Metformin usage can cause calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption.
- Hereditary (rare): transcobalamin II deficiency
Genetics
Imerslund-Gräsbeck disease (juvenile megaloblastic anemia) caused by mutations in the amnionless (AMN) or cubilin (CUBN) genes with autosomal recessive pattern of inheritance; inadequate ileal uptake of vitamin B12-IF complex and decreased vitamin B12 renal protein reabsorption.
Commonly Associated Conditions
- Gastric abnormalities: PA, gastritis, gastrectomy/bariatric surgery
- Small bowel disease: malabsorption syndrome, ileal resection, IBD, celiac disease
- Pancreatic insufficiency
- Diet: breastfed infant in vitamin B12 deficient mother, strict vegan diet
- Medications: neomycin, metformin, PPI, histamine 2 receptor antagonists, nitrous oxide (N2O) abuse
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Citation
Domino, Frank J., et al., editors. "Vitamin B12 Deficiency." 5-Minute Clinical Consult, 33rd ed., Wolters Kluwer, 2025. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688647/all/Vitamin_B12_Deficiency.
Vitamin B12 Deficiency. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2025. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688647/all/Vitamin_B12_Deficiency. Accessed December 10, 2024.
Vitamin B12 Deficiency. (2025). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (33rd ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688647/all/Vitamin_B12_Deficiency
Vitamin B12 Deficiency [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2025. [cited 2024 December 10]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688647/all/Vitamin_B12_Deficiency.
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