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Subject: Vitamin B12 Deficiency
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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.
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%
Typical Western diet: 5 to 30 μg/day; however, only 1 to 5 μg/day is effectively absorbed.
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
Prevalence by age group
Decreased oral intake
Decreased intrinsic factor (IF)
Decreased ileal absorption
Medications: proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting B12 release from dietary protein; metformin
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.
Underlying disease associated with vitamin B12 deficiency
Falls (due to diminished proprioception)
Loss of sensation in “stocking-glove” distribution
Glossitis/loss of sense of taste and other subtle, nonspecific neurologic symptoms
Measurement of vitamin B12, CBC (MCV)
Measurement of B12 may be low or low normal depending on institution’s cutoff value.
If high suspicion on normal B12 with high/normal MCV, consider testing MMA and homocysteine levels.
MCV often increased
Measurement of MMA
Measurement of homocysteine
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.
Low levels of vitamin B12 are seen in folate deficiency, HIV, and multiple myeloma.
Elevated levels of vitamin B12 are seen in renal disease, occult malignancy, and alcoholic liver disease and as a result of technical error.
Macrocytosis may be due to folate deficiency, reticulocytosis, medications, bone marrow dysplasia, and hypothyroidism or be masked by concomitant microcytic anemia.
Serum homocysteine and MMA
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.
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]
High-dose, daily oral cyanocobalamin at doses of 1,000 to 2,000 μg 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.
Folic acid without vitamin B12 in patients with PA is contraindicated; it will not correct neurologic abnormalities.
Consider blood transfusion for severe anemia.
Draw blood for hematologic parameters before transfusing.
Neurologic: can note improvement within 3 months of treatment; however, maximum improvement noticed at 6 to 12 months. Some symptoms may be irreversible.
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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.
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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
D51.1 Vitamin B12 deficiency anemia due to selective vitamin B12 malabsorption with proteinuria
D51.9 Vitamin B12 deficiency anemia, unspecified
D51.8 Other vitamin B12 deficiency anemias
266.2 Other B-complex deficiencies
281.0 Pernicious anemia
281.1 Other vitamin B12 deficiency anemia
64117007 Vitamin B12 deficiency (non anemic) (disorder)
84027009 Pernicious anemia (disorder)
190634004 Cobalamin deficiency (disorder)
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.