Vitamin B₁₂ Status in Health and Disease

Food High in VB₁₂

VB₁₂ is rich in animal tissues, rendering it exclusive to animal-derived sources. The main dietary sources of VB₁₂ include meat, milk and its products (liver, 26-58 μg/100g; beef and lamb, 1-3 μg/100g; eggs, 1-2.5 μg/100g; and dairy products, 0.3-2.4 μg/100g; and chicken, trace-1 μg/100g), various species of fish (salmon, sardines, trout, tuna, etc., 3.0-8.9 μg/100g) and shellfish (10 μg/100g), and fortified ready-to-eat cereals. Liver is a rich source of VB₁₂ followed by kidney and heart. The content of VB₁₂ in milk is not high, but drinking milk frequently is related to the high concentration of VB₁₂ in serum of healthy elderly. Some trace amounts of plant-derived VB₁₂ analogs have been reported to exist in addition to animal-derived foods, such as certain microalgae species, mushrooms, soy-based fermented foods, and soil-contaminated vegetables, but these plant-derived compounds do not provide a reliable source of VB₁₂ activity for humans.

For most people, the dietary intake of VB₁₂ exceeds the metabolic requirement, resulting in the accumulation of 1-5 mg of VB₁₂ in the liver. The typical Western diet provides 4–6 μg/d of VB₁₂, from which 1–5 μg is absorbed. For healthy adults with normal absorption, the bioavailability of VB₁₂ in food is assumed to be 50%, while the absorption rate of crystal VB₁₂ in supplements and fortified foods is 55% to 74%. Absorption rates vary considerably between different types of food, for example, 24%-36% for egg products, 42% for fish and 65% for lean meat. The dietary intake of VB₁₂ also varies with sex and age. In order to maintain normal blood values and normal serum concentrations of VB₁₂, the recommended intake of VB₁₂ is set, assuming that 50% of vitamin B₁₂ can be absorbed from the diet. The recommended intake for adults is 4 μg/d in the European Union and 2.4 μg/d in the United States, with higher intakes during pregnancy and lactation (2.6 and 2.8 μg/d, respectively). The recommended intake for children in the United States ranges from 0.4 μg/d to 1.8 μg/d.

What Causes Deficiency

The causes of cellular VB₁₂ deficiency include inadequate intake, malabsorption, chemical inactivation or disruption of VB₁₂ transport in the blood or intracellular metabolism.

Individuals consuming large amounts of animal products or supplements can easily meet VB₁₂ requirements, but vegetarians consume only 0-0.25 μg/day. A low intake of foods of animal origin may be involuntary due to a limited food supply, or it may be voluntary due to cultural, religious, or personal constraints. The requirements for VB₁₂ intake vary according to age and physiological condition. Factors affecting bioavailability should be considered in addition to recommended intakes. Different people, different gastrointestinal conditions, different sources of food, and different total intakes of VB₁₂ will all affect its bioavailability. To some degree, bioavailability is related to the release of VB₁₂ from food. The bioavailability of VB₁₂ in milk is higher than in other foods of animal origin. The anesthetic gas nitrous oxide chemically inactivates VB₁₂ by irreversible oxidation of its coenzyme form, methylcobalamin, at the active site of the VB₁₂-dependent methionine synthase reaction. Depending on the VB₁₂ status of the individual exposed to the gas, the frequency of use, and the duration of use, the degree of VB₁₂ deficiency will vary. Levels may drop precipitously or gradually.

Pernicious anemia causes VB₁₂ malabsorption in patients, resulting in gradual depletion of the body's VB₁₂ reserves, which can lead to VB₁₂ deficiency. Mutations in the GIF gene, which encodes the intrinsic factor, also cause hereditary VB₁₂ malabsorption, similar to pernicious anemia, but without the involvement of autoantibodies. Haptocorrin is a VB₁₂-binding protein found in many body fluids that protects VB₁₂ as it passes through the acidic environment of the stomach. Reduced gastric acid secretion associated with chronic gastritis or long-term use of proton pump inhibitors affects the release of dietary VB₁₂ from food proteins.

Some intestinal diseases affect VB₁₂ absorption through villous atrophy and mucosal damage. Pharmacologic interventions may also lead to VB₁₂ malabsorption. Cholestyramine, which is used to treat hypercholesterolemia, can chelate intrinsic factor. Colchicine and several antibiotics (including the antituberculosis drug p-aminosalicylic acid) can act as inhibitors of intrinsic factor-VB₁₂ endocytosis, but these drugs are usually not sufficient to cause clinical VB₁₂ deficiency.

Approximately 20% of total plasma VB₁₂ levels are bound to transcobalamin (holotranscobalamin) and thus can enter cells via receptor-mediated uptake, with the remaining major component bound to a circulating form of haptocorrin. Holotranscobalamin is internalized by receptor CD320 antigen (in the brain and other tissues) or LRP2 (in the luminal portion of renal tubules) and subsequently degraded in lysosomes. In the cell, VB₁₂ is reduced and converted to its coenzyme active form for two intracellular processes: the conversion of homocysteine to methionine and the metabolism of methylmalonyl-CoA to succinyl-CoA by the mitochondria. Several hereditary diseases affect the continuous steps of VB₁₂ assimilation, transport, and intracellular processing. Mutations in TCN2 encoding transcobalamin 2 have been found to cause stunted growth and severe disease in infants. These mutations are associated with severe megaloblastic anemia and neurological problems, which can be fatal if not detected in time and treated with high doses of VB₁₂.

Figure 2. Absorption, enterohepatic circulation and intracellular metabolism of vitamin B₁₂
(Source: Green R, et al. 2017)