Vitamin B12 - Deficiency

Vitamin B₁₂ deficiency is estimated to affect 10%-15% of individuals over the age of 60. Absorption of vitamin B₁₂ from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B₁₂ from food, allowing it to bind to other proteins, known as R proteins. In the alkaline environment of the small intestine, R proteins are degraded by pancreatic enzymes, freeing vitamin B₁₂ to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach. Receptors on the surface of the small intestine take up the IF-B₁₂ complex only in the presence of calcium, which is also supplied by the pancreas. Vitamin B₁₂ can also be absorbed by passive diffusion, but this process is very inefficient, allowing only about 1% absorption of a vitamin B₁₂ dose.

Causes of vitamin B₁₂ deficiency

The most common causes of vitamin B₁₂ deficiency are pernicious anemia and food-bound vitamin B₁₂ malabsorption. Although both causes become more common with age, they are two separate conditions.

Pernicious anemia

Pernicious anemia has been estimated to be present in approximately 2 % of individuals over 60. Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach, resulting in destruction of stomach cells by one's own antibodies. Progressive destruction of the cells that line the stomach cause decreased secretion of acid and enzymes required to release food bound vitamin B₁₂. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B₁₂ complex, further inhibiting vitamin B₁₂ absorption. If the body's vitamin B₁₂ stores are adequate prior to the onset of pernicious anemia, it may take years for symptoms of deficiency to develop. About 20% of the relatives of pernicious anemia patients also have pernicious anemia, suggesting a genetic predisposition. Treatment of pernicious anemia generally requires injections of vitamin B₁₂, bypassing intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 mcg (1 mg)/day of vitamin B₁₂ orally should result in the absorption of about 10 mcg/day (about 1%) by passive diffusion (3).

Food-bound vitamin B₁₂ malabsorption

Food-bound vitamin B₁₂ malabsorption is defined as an impaired ability to absorb food or protein-bound vitamin B₁₂, although the free form is fully absorbable. In the elderly, food-bound vitamin B₁₂ malabsorption is thought to result mainly from atrophic gastritis, a chronic inflammation of the lining of the stomach, which ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production. Because stomach acid is required for the release of vitamin B₁₂ from the proteins in food, vitamin B₁₂ absorption is diminished. Decreased stomach acid production also provides an environment more conducive to the overgrowth of anaerobic bacteria in the stomach, interfering further with vitamin B₁₂ absorption. Because vitamin B₁₂ in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B₁₂ is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B₁₂ malabsorption do not have an increased requirement for vitamin B₁₂; they simply need it in the form of a supplement rather than from food.

Atrophic gastritis

Atrophic gastritis is thought to affect 10% - 30% of people over 60 years of age, and is frequently associated with infection by the bacteria, Heliobacter pylori. H. pylori infection induces a chronic inflammation of the stomach which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals. The relationship of H. pylori infection to atrophic gastritis, gastric cancer, and vitamin B₁₂ deficiency is presently an area of active research.

Other causes of vitamin B₁₂ deficiency

Other causes of deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B₁₂ complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B₁₂ deficiency. Because the pancreas provides critical enzymes as well as calcium required for vitamin B₁₂ absorption, pancreatic insufficiency may contribute to B₁₂ deficiency. Since vitamin B₁₂ is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B₁₂ deficiency. In alcoholics, vitamin B₁₂ intake and absorption are reduced, while elimination is increased. Individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B₁₂ receptor to take up the IF-B₁₂ complex. Long-term use of acid-reducing drugs has also been implicated in vitamin B₁₂ deficiency.

Symptoms of vitamin B₁₂ deficiency

Vitamin B₁₂ deficiency results in impairment of the activities of B₁₂-requiring enzymes. Impaired activity of methionine synthase may result in elevated homocysteine levels, while impaired activity of L-methylmalonyl-CoA mutase results in increased levels of a metabolite of methylmalonyl-CoA, called methylmalonic acid (MMA). Individuals with mild vitamin B₁₂ deficiency may not experience symptoms, although blood levels of homocysteine and/or MMA may be elevated.

Megaloblastic anemia: Diminished activity of methionine synthase in vitamin B₁₂ deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body, resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B₁₂ deficiency, folate is unavailable to participate in DNA synthesis. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, hemoglobin-poor red blood cells. The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named. Supplementation of folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B₁₂ deficiency was the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined.

Neurologic symptoms: The neurologic symptoms of vitamin B₁₂ deficiency include numbness and tingling of the arms and more commonly the legs, difficulty walking, memory loss, disorientation, and dementia, with or without mood changes. Although the progression of neurologic complications is generally gradual, they are not always reversible with treatment of vitamin B₁₂ deficiency, especially if they have been present for a long time. Neurologic complications are not always associated with megaloblastic anemia, and are the only clinical symptom of vitamin B₁₂ deficiency in about 25% of cases. Although vitamin B₁₂ deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in B₁₂ deficiency are not well understood.

Gastrointestinal symptoms: A sore tongue, appetite loss, and constipation have also been associated with vitamin B₁₂ deficiency. Their origins are unclear, but may be related to the stomach inflammation underlying some cases of B₁₂ deficiency, or the increased vulnerability of the rapidly dividing cells along the gastrointestinal tract to impaired DNA synthesis.

The Recommended Dietary Allowance (RDA)

The current RDA was revised by the Food and Nutrition Board (FNB) of the Institute of Medicine in 1998. Because of the increased risk of food-bound vitamin B₁₂ malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B₁₂-containing supplements.

Recommended Dietary Allowance (RDA) for Vitamin B₁₂
Life Stage	Age	Males (mcg/day)	Females (mcg/day)
Infants	0-6 months	0.4 (AI)	0.4 (AI)
Infants	7-12 months	0.5 (AI)	0.5 (AI)
Children	1-3 years	0.9	0.9
Children	4-8 years	1.2	1.2
Children	9-13 years	1.8	1.8
Adolescents	14-18 years	2.4	2.4
Adults	19-50 years	2.4	2.4
Adults	51 years and older	2.4*	2.4*
Pregnancy	all ages	-	2.6
Breastfeeding	all ages	-	2.8

*Vitamin B₁₂ intake should be from supplements or fortified foods, due to the age-related increase in food bound malabsorption.

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