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Vitamin B12 Deficiency
Justin D. Chaltry, DO
Katie L. Westerfield, DO
image BASICS
  • Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B12)
  • Cobalamin is critical for CNS myelination and normal functioning.
  • Deficiency can cause a multitude of symptoms and disorders including megaloblastic anemia, bone marrow dysfunction, and diverse and potentially irreversible neuropsychiatric changes.
  • Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; demyelination of white matter; and demyelination of cranial and peripheral nerves (1)[C].
  • Low vitamin B12 level can lead to elevated methylmalonic acid (MMA) and homocysteine levels.
  • Elevated MMA causes abnormality in fatty acid synthesis affecting neuronal membrane.
  • Elevated homocysteine is neurotoxic through overstimulation of the N-methyl-D-aspartate (NMDA) receptor and toxic to vasculature through activation of coagulation system and effects on endothelium.
Normal B12 absorption
  • B12 present in animal-source foods (meat, fish, eggs, milk) and foods fortified with B12
  • Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin (commonly known as R-factor).
  • Duodenal proteases cleave B12 from haptocorrin.
  • In duodenum, B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
  • B12 -IF complex is absorbed by terminal ileum into portal circulation.
  • Body's B12 stored in liver = 50-90%
    • B12 secreted into bile from liver recycled via enterohepatic circulation
    • Delay 5 to 10 years from onset of B12 deficiency to clinical symptoms due to hepatic stores and enterohepatic circulation
  • Typical Western diet: 5 to 30 &mgr;g/day; however, only 1 to 5 &mgr;g/day is effectively absorbed.
    • Recommend 2.4 &mgr;g/day for adults and 2.6 &mgr;g/day during pregnancy and 2.8 &mgr;g/day during lactation (most prenatal vitamins contain B12)
  • Endemic area: Northern Europe, including Scandinavia; more common in those of African ancestry
  • Increasing recognition in breastfed-only infant populations with vitamin B12 deficient mothers
  • Prevalence 5-20% in developed countries
    • 12% in elderly living in community
    • 30-40% in elderly in institutions, sick, or malnourished
    • 5% patients in tertiary reference hospitals
  • Prevalence by age group
    • 20 to 39 years old: prevalence 3%
    • 40 to 59 years old: prevalence 4%
    • >70 years old: prevalence 6%
  • Decreased oral intake
    • Vegetarians and vegans: B12 is found in animalsource foods; however, strict vegetarians uncommonly develop deficiency because only 1 mg/day is needed, with adequate amounts present in legumes.
  • Decreased IF
    • Pernicious anemia (PA): can be associated with autoantibodies directed against gastric parietal cells and/or IF
    • 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 decreases amount of parietal cells.
  • Decreased ileal absorption
    • Crohn disease: Terminal ileal inflammation decreases body's ability to absorb B12.
    • Chronic alcoholism: decreases body's ability to absorb B12
    • Ileal resection
    • Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B12-haptocorrin bond to allow vitamin B12 to bind to intrinsic factor.
    • Helicobacter pylori infection impairs release of B12 from bound proteins.
  • Medications: Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting B12 release from dietary protein; metformin
  • Hereditary (rare)
    • Imerslund-Grasbeck disease (juvenile megaloblastic anemia)
    • Congenital deficiency of transcobalamin
    • Severe methylene tetrahydrofolate reductase deficiency
    • Abnormalities of methionine synthesis
  • Food-cobalamin malabsorption syndrome
    • As many as 60-70% of cases
    • Primary cause in elderly
    • Pathophysiology: inability to release cobalamin from food or binding protein, especially if in the setting of hypochlorhydria
    • Seen in atrophic gastritis, long-term ingestion of antacids and biguanides, possible relationship to H. pylori infection
  • PA
    • 15-30% of all cases; most frequent cause of severe disease. Neurologic disorders are common presenting complaints.
    • Common in elderly, as high as 20%, with mild atrophic gastritis, hypochlorhydria, and impaired release of dietary vitamin B12
    • Autoimmune disease with destruction of gastric fundal mucosa cells via a cell-mediated process
    • Anti-gastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test
    • Anti-intrinsic factor antibodies: sensitivity 50%
    • Associated with other autoimmune diseases
  • Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
  • Infants born to vitamin B12-deficient mothers may have deficiency or develop it if breastfed exclusively.
  • Intestinal causes:
    • 1% of cases; prevalence depends on risk factors, such as surgical conditions
    • Gastrectomy: due to decreased production of intrinsic factor
    • Gastric bypass: appears 1 to 9 years after surgery, prevalence 12-33%
    • Ileal resection or disease
    • Fish tapeworm
    • Severe pancreatic insufficiency
  • Undetermined etiology
    • 1/10 of cases
Imerslund-Grasbeck 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 B12-IF complex and B12 renal protein reabsorption
Risk factors: vegan diet, age >65 years, female, chronic atrophic gastritis, Crohn disease or other ileal disorders, chronic medication use including PPI, metformin, H2 antagonists
Symptoms and physical exam findings:
  • Asymptomatic patients may be diagnosed by the incidental finding of anemia or an elevated mean corpuscular volume (MCV) during routine testing or evaluation of unassociated disorders.
  • Hematologic
    • Frequent: macrocytosis, neutrophil hypersegmentation, spinal cord medullar megaloblastosis (blue spinal cord)
    • Rare: isolated thrombocytopenia and neutropenia, pancytopenia
    • Very rare: hemolytic anemia, thrombotic microangiopathy with schistocytes
  • Neuropsychiatric
    • Frequent: sensory polyneuritis, paresthesias, positive Babinski sign, weakness, gait unsteadiness, loss of proprioception (impaired vibratory sensation, positive Romberg, ataxia, hyperreflexia)
    • Classic, but uncommon: subacute combined degeneration of spinal cord associated with PA; myelin degeneration in the lateral and posterior columns; ataxia, proprioception and vibration loss, bowel and bladder incontinence, orthostatic hypotension, decreased memory, mania, delirium, psychosis, depression
  • Digestive
    • Classic: Hunter glossitis, jaundice, and high lactate dehydrogenase and bilirubin
    • Possible: abdominal pain, dyspepsia, nausea, vomiting, diarrhea
    • Rare: mucocutaneous ulcers
  • Other
    • Frequent: pallor, edema, jaundice
    • Under investigation: chronic vaginal and urinary infections, atrophy of vaginal mucosa, hypofertility, venous thromboembolism, angina, miscarriages
    • Commonly insidious and nonspecific; thus, delay in diagnosis is common.

  • Measurement of vitamin B12, CBC (MCV)
  • Measurement of B12 may be low or low normal depending on institution's cutoff value.
    • 65-95% sensitivity levels <200 pg/mL
    • May need additional tests such as MMA and homocysteine if vitamin B12 level is low normal (<350 pg/mL) and no evidence of anemia depending on clinical suspicion
  • If high suspicion on normal B12 with high/normal MCV, consider testing MMA and homocysteine levels.
  • MCV often increased
  • Measurement of MMA
    • More sensitive and specific than homocysteine
    • Levels increased in renal failure and volume depletion
  • Measurement of homocysteine
    • Levels increased in folate deficiency, renal failure, and homocystinuria
  • MMA and homocysteine levels only reliable in an untreated patient, as levels fall with supplementation
  • Other tests: folate and other markers of anemia (iron studies)
  • MCV may be normal, decreased, or increased if vitamin B12 deficiency coexists with other forms of anemia, such as iron deficiency or hemolysis. Thus, RBCs may be normochromic, normocytic, or hypochromic microcytic.
Pregnancy Considerations
  • Because B12 crosses the placenta, pregnant women with low levels of B12 are at higher risk of having children with neural tube defects, congenital heart defects, developmental delay, and failure to thrive.
  • Exclusively breastfed infants of mothers who are B12 deficient are at risk of developing B12 deficiency. Infants breastfed from B12-deficient mothers might not show signs or symptoms until 4 to 6 months of age, which may include developmental regression, feeding difficulties, lethargy, or hypotonia.
Diagnostic Procedures/Other
  • Bone marrow exam is usually unnecessary in the evaluation of B12 deficiency because of the inability to differentiate from folate deficiency.
  • Spinal cord imaging is not standard; MRI in selected cases, especially with severe myelopathy
  • Parenteral cyanocobalamin replacement recommended in patients with severe neurologic symptoms: IM cyanocobalamin (2)[C]
    • 1,000 &mgr;g/day for 7 days, then
    • 1,000 &mgr;g weekly for 4 weeks, then
    • 1,000 &mgr;g monthly for life
  • High-dose, daily oral cyanocobalamin at doses of 1,000 to 2,000 &mgr;g are as effective as monthly intramuscular injection and is the preferred route of initial therapy in most circumstances because it is cost-effective and convenient (3)[A]. Requires greater patient compliance. Transnasal and buccal preparations of cyanocobalamin are also available; however, further study is needed.
Admission Criteria/Initial Stabilization
  • Consider blood transfusion for severe anemia.
  • Draw blood for hematologic parameters before transfusing.
Patient Monitoring
  • Hematologic
    • Reticulocytosis in 1 week
    • Rise in hemoglobin beginning at 10 days; usually will return to normal in 6 to 8 weeks
    • Monitor potassium in profoundly anemic patients (hypokalemia due to potassium use).
    • Serum MMA decreases with replacement therapy.
  • Neurologic: can note improvement within 3 months of treatment; however, maximum improvement noticed at 6 to 12 months. Some symptoms may be irreversible.
Meat, animal protein, and legumes unless contraindicated
1. Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12 deficiency in elderly patients. J Neuropsychiatry Clin Neurosci. 2012;24(1):5-15.
2. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-160.
3. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655.
Additional Reading
  • Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. 2009;89(2):693S-696S.
  • Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014; 13(4-5):565-568.
  • Fernández-Bañares F, Monzón H, Forné M. A short review of malabsorption and anemia. World J Gastroenterol. 2009;15(37):4644-4652.
  • Langan RC, Zawistoski KJ. Update on vitamin B12 deficiency. Am Fam Physician. 2011;83(12):1425-1430.
  • Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):359-367.
  • Oberley MJ, Yang DT. Laboratory testing for cobalamin deficiency in megaloblastic anemia. Am J Hematol. 2013;88(6):522-526.
  • E53.8 Deficiency of other specified B group vitamins
  • D51.0 Vitamin B12 defic anemia due to intrinsic factor deficiency
  • D51.3 Other dietary vitamin B12 deficiency anemia
Clinical Pearls
  • Consider screening for B12 deficiency in high-risk patients including the elderly and monitoring B12 levels annually if on metformin or on chronic PPIs.
  • Correcting folate deficiency without treating with cyanocobalamin in megaloblastic anemia may correct hematologic but not neurologic disorders.
  • Vitamin B12 deficiency can coexist with other causes of anemia, including iron deficiency or hemolysis; thus, MCV can be normal, decreased, or increased.
  • For patients with PA, cyanocobalamin replacement must be lifelong.
  • Patients with PA are at increased risk for other autoimmune conditions as well as gastric malignancy.