Vitamin B12 Deficiency
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- Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B12)
- Cobalamin is critical for central nervous system 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 (2)[C].
- 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 is a water-soluble vitamin present in animal-source foods (meat, fish, eggs, milk) and foods (cereals and supplements) 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 μg/day; however, only 1 to 5 μg/day is effectively absorbed.
- Recommend 2.4 μg/day for adults and 2.6 μg/day during pregnancy and 2.8 μg/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 B12deficient 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 (3)
- <60 years old: prevalence 6%
- >60 years old: prevalence 20%
Etiology and Pathophysiology
- Decreased oral intake
- Vegetarians and vegans: B12 is found in animal source 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 number 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 B12haptocorrin bond to allow vitamin B12 to bind to IF.
- 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
- Metformin usage
- Chronic metformin usage leads to vitamin B12 deficiency. Caused by calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption. Years on metformin is the only predictive factor for B12 deficiency.
- Metformin usage
- Hereditary (rare)
- Imerslünd-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
- 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
- Antigastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test
- Anti-IF antibodies: sensitivity 50%
- Associated with other autoimmune diseases
- Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
- Infants born to vitamin B12deficient mothers may have deficiency or may 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 IF
- 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
- Food-cobalamin malabsorption syndrome
Imerslünd-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 >60 years, female, chronic atrophic gastritis, Crohn disease or other ileal disorders, chronic medication use including PPI, metformin, H2 antagonists