- 1 What is Vitamin B12
- 1.1 Vitamin B12 Supplements
- 1.2 What are some Benefits of Vitamin B12 on Health ?
- 1.3 How much vitamin B12 do you need ?
- 1.4 What foods provide vitamin B12 ?
- 1.5 Are you getting enough vitamin B12 ?
- 1.6 What happens if you don’t get enough vitamin B12 ?
- 1.7 Vitamin B12 Deficiency
- 1.8 Causes of Vitamin B12 Deficiency
- 1.9 Groups at Risk of Vitamin B12 Deficiency
- 1.10 Symptoms and Signs of Vitamin B12 Deficiency
- 1.11 Diagnosis of Vitamin B12 Deficiency
- 1.12 Treatment of Vitamin B12 Deficiency
- 1.13 Vitamin B12 Side Effects and Toxicity – Health Risks from Excessive Vitamin B12
What is Vitamin B12
Vitamin B12 is also known as Cyanocobalamin is a nutrient that helps keep the body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. Vitamin B12 also helps prevent a type of anemia called megaloblastic anemia that makes people tired and weak.
Vitamin B12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 exists in several forms and contains the mineral cobalt 1), 2), 3), 4), so compounds with vitamin B12 activity are collectively called “cobalamins”. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 that are active in human metabolism 5).
Two steps are required for the body to absorb vitamin B12 from food.
- First, food-bound vitamin B12 is released in the stomach’s acid environment (hydrochloric acid and and gastric protease in the stomach separate vitamin B12 from the protein to which vitamin B12 is attached in food) and is bound to R protein (haptocorrin) 6). When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and thus, does not require this separation step.
- Second, pancreatic enzymes cleave this B12 complex (B12-R protein) in the small intestine. After cleavage, intrinsic factor (a protein made by the stomach), secreted by parietal cells in the gastric mucosa, binds with the free vitamin B12. Intrinsic factor is required for absorption of vitamin B12, which takes place in the terminal ileum 7), 8). Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12) 9). Some people have pernicious anemia, a condition where they cannot make intrinsic factor. As a result, they have trouble absorbing vitamin B12 from all foods and dietary supplements.
Pernicious anemia is an autoimmune disease that affects the gastric mucosa and results in gastric atrophy. This leads to the destruction of parietal cells, achlorhydria, and failure to produce intrinsic factor, resulting in vitamin B12 malabsorption 10), 11), 12), 13), 14). If pernicious anemia is left untreated, it causes vitamin B12 deficiency, leading to megaloblastic anemia and neurological disorders, even in the presence of adequate dietary intake of vitamin B12. For more details see below – Groups at Risk of Vitamin B12 Deficiency.
In the blood plasma, vitamin B12 is bound to transcobalamins I and II. Transcobalamin II is responsible for delivering vitamin B12 to tissues. The liver stores large amounts of vitamin B12. Enterohepatic reabsorption helps retain vitamin B12. Liver vitamin B12 stores can normally sustain physiologic needs for 3 to 5 yr if B12 intake stops (eg, in people who become vegans) and for months to 1 yr if enterohepatic reabsorption capacity is absent.
Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis 15), 16), 17), 18), 19). Vitamin B12 functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase catalyzes the conversion of homocysteine to methionine 20), 21). Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate 22), 23), 24), an essential biochemical reaction in fat and protein metabolism. Succinyl-CoA is also required for hemoglobin synthesis.
Large amounts of vitamin B12 seem to be nontoxic but are not recommended for regular use (ie, as a general tonic).
Vitamin B12 Supplements
In dietary supplements, vitamin B12 is usually present as cyanocobalamin 25), a form that the body readily converts to the active forms methylcobalamin and 5-deoxyadenosylcobalamin. Dietary supplements can also contain methylcobalamin and other forms of vitamin B12.
Existing evidence does not suggest any differences among forms with respect to absorption or bioavailability. However the body’s ability to absorb vitamin B12 from dietary supplements is largely limited by the capacity of intrinsic factor. For example, only about 10 mcg of a 500 mcg oral supplement is actually absorbed in healthy people 26).
In addition to oral dietary supplements, vitamin B12 is available in sublingual preparations as tablets or lozenges. These preparations are frequently marketed as having superior bioavailability, although evidence suggests no difference in efficacy between oral and sublingual forms 27), 28).
Vitamin B12 Prescription Medications
Vitamin B12, in the form of cyanocobalamin and occasionally hydroxocobalamin, can be administered parenterally as a prescription medication, usually by intramuscular injection 29). Parenteral administration is typically used to treat vitamin B12 deficiency caused by pernicious anemia and other conditions that result in vitamin B12 malabsorption and severe vitamin B12 deficiency 30).
Vitamin B12 is also available as a prescription medication in a gel formulation applied intranasally, a product marketed as an alternative to vitamin B12 injections that some patients might prefer 31). This formulation appears to be effective in raising vitamin B12 blood levels 32), although it has not been thoroughly studied in clinical settings.
What are some Benefits of Vitamin B12 on Health ?
Scientists are studying vitamin B12 to understand how it affects health. Here are several examples of what this research has shown:
Cardiovascular disease is the most common cause of death in industrialized countries, such as the United States, and is on the rise in developing countries. Risk factors for cardiovascular disease include elevated low-density lipoprotein (LDL) levels, high blood pressure, low high-density lipoprotein (HDL) levels, obesity, and diabetes 33).
Elevated homocysteine levels have also been identified as an independent risk factor for cardiovascular disease 34), 35), 36). Homocysteine is a sulfur-containing amino acid derived from methionine that is normally present in blood. Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation 37), 38), 39). Evidence from retrospective, cross-sectional, and prospective studies links elevated homocysteine levels with coronary heart disease and stroke 40), 41), 42), 43), 44).
Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to inadequate function of methionine synthase 45). Results from several randomized controlled trials indicate that combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels in people with vascular disease or diabetes and in young adult women 46), 47), 48), 49), 50), 51), 52). In another study, older men and women who took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels 53).
Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular disease 54), 55), 56), 57), 58), 59), 60). In the Women’s Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular disease who took daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid, and 50 mg vitamin B6 for 7.3 years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels 61).
The Heart Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54 years with vascular disease or diabetes, found that daily treatment with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for an average of 5 years reduced homocysteine levels and the risk of stroke but did not reduce the risk of major cardiovascular events 62). In the Western Norway B Vitamin Intervention Trial, which included 3,096 patients undergoing coronary angiography, daily supplements of 0.4 mg vitamin B12 and 0.8 mg folic acid with or without 40 mg vitamin B6 for 1 year reduced homocysteine levels by 30% but did not affect total mortality or the risk of major cardiovascular events during 38 months of follow-up 63). The Norwegian Vitamin (NORVIT) trial 64) and the Vitamin Intervention for Stroke Prevention trial had similar results 65).
The American Heart Association has concluded that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk 66).
- Dementia and Cognitive Function
As they get older, some people develop dementia. These people often have high levels of homocysteine in the blood. Vitamin B12 (with folic acid and vitamin B6) can lower homocysteine levels, but scientists don’t know yet whether these vitamins actually help prevent or treat dementia.
Researchers have long been interested in the potential connection between vitamin B12 deficiency and dementia 67), 68). A deficiency in vitamin B12 causes an accumulation of homocysteine in the blood 69) and might decrease levels of substances needed to metabolize neurotransmitters 70). Observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer’s disease and dementia 71), 72), 73). Low vitamin B12 status has also been positively associated with cognitive decline 74).
Despite evidence that vitamin B12 lowers homocysteine levels and correlations between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent effect on cognition 75), 76), 77), 78), 79). In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older with no or moderate cognitive impairment received 1,000 mcg vitamin B12, 1,000 mcg vitamin B12 plus 400 mcg folic acid, or placebo for 24 weeks 80). Treatment with vitamin B12 plus folic acid reduced homocysteine concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved cognitive function.
Women at high risk of cardiovascular disease who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study were randomly assigned to receive daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid and 50 mg vitamin B6, or placebo 81). After a mean of 1.2 years, B-vitamin supplementation did not affect mean cognitive change from baseline compared with placebo. However, in a subset of women with low baseline dietary intake of B vitamins, supplementation significantly slowed the rate of cognitive decline. In a trial conducted by the Alzheimer’s Disease Cooperative Study consortium that included individuals with mild-to-moderate Alzheimer’s disease, daily supplements of 1 mg vitamin B12, 5 mg folic acid, and 25 mg vitamin B6 for 18 months did not slow cognitive decline compared with placebo 82). Another study found similar results in 142 individuals at risk of dementia who received supplements of 2 mg folic acid and 1 mg vitamin B12 for 12 weeks 83).
The authors of two Cochrane reviews and a systematic review of randomized trials of the effects of B vitamins on cognitive function concluded that insufficient evidence is available to show whether vitamin B12 alone or in combination with vitamin B6 or folic acid has an effect on cognitive function or dementia 84), 85), 86). Additional large clinical trials of vitamin B12 supplementation are needed to assess whether vitamin B12 has a direct effect on cognitive function and dementia 87).
- Energy and athletic performance
Due to its role in energy metabolism, vitamin B12 is frequently promoted as an energy enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit 88).
Vitamin B12 has not been shown to cause any harm.
How much vitamin B12 do you need ?
The amount of vitamin B12 you need each day depends on your age. Average daily recommended amounts for different ages are listed below in micrograms (mcg):
Table 1 lists the current RDAs for vitamin B12 in micrograms (mcg). For infants aged 0 to 12 months, the Food and Nutrition Board established an adequate intake (AI) for vitamin B12 that is equivalent to the mean intake of vitamin B12 in healthy, breastfed infants.
Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
|Life Stage||Recommended Amount|
|Birth to 6 months||0.4 mcg|
|Infants 7–12 months||0.5 mcg|
|Children 1–3 years||0.9 mcg|
|Children 4–8 years||1.2 mcg|
|Children 9–13 years||1.8 mcg|
|Teens 14–18 years||2.4 mcg|
|Pregnant teens and women||2.6 mcg|
|Breastfeeding teens and women||2.8 mcg|
What foods provide vitamin B12 ?
Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, but fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability for vegetarians 90), 91), 92), 93). Some nutritional yeast products also contain vitamin B12. Fortified foods vary in formulation, so it is important to read product labels to determine which added nutrients they contain.
The U.S. Department of Agriculture’s (USDA’s) Nutrient Database Web site 94) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B12 arranged by nutrient content 95) and by food name 96).
Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Infants of vegan mothers should receive supplemental vitamin B12 from birth. Deficiency causes megaloblastic anemia, damage to the white matter of the spinal cord and brain, and peripheral neuropathy. Diagnosis is usually made by measuring serum vitamin B12 levels. The Schilling test helps determine etiology 97).
Vitamin B12 is found naturally in a wide variety of animal foods and is added to some fortified foods. Plant foods have no vitamin B12 unless they are fortified. You can get recommended amounts of vitamin B12 by eating a variety of foods including the following:
- Beef liver and clams, which are the best sources of vitamin B12.
- Fish, meat, poultry, eggs, milk, and other dairy products, which also contain vitamin B12.
- Some breakfast cereals, nutritional yeasts and other food products that are fortified with vitamin B12. To find out if vitamin B12 has been added to a food product, check the product labels.
Several food sources of vitamin B12 are listed in Table 2.
Table 2: Selected Food Sources of Vitamin B12
|Clams, cooked, 3 ounces||84.1||1,402|
|Liver, beef, cooked, 3 ounces||70.7||1,178|
|Breakfast cereals, fortified with 100% of the DV for vitamin B12, 1 serving||6.0||100|
|Trout, rainbow, wild, cooked, 3 ounces||5.4||90|
|Salmon, sockeye, cooked, 3 ounces||4.8||80|
|Trout, rainbow, farmed, cooked, 3 ounces||3.5||58|
|Tuna fish, light, canned in water, 3 ounces||2.5||42|
|Cheeseburger, double patty and bun, 1 sandwich||2.1||35|
|Haddock, cooked, 3 ounces||1.8||30|
|Breakfast cereals, fortified with 25% of the DV for vitamin B12, 1 serving||1.5||25|
|Beef, top sirloin, broiled, 3 ounces||1.4||23|
|Milk, low-fat, 1 cup||1.2||18|
|Yogurt, fruit, low-fat, 8 ounces||1.1||18|
|Cheese, Swiss, 1 ounce||0.9||15|
|Beef taco, 1 soft taco||0.9||15|
|Ham, cured, roasted, 3 ounces||0.6||10|
|Egg, whole, hard boiled, 1 large||0.6||10|
|Chicken, breast meat, roasted, 3 ounces||0.3||5|
*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers determine the level of various nutrients in a standard serving of food in relation to their approximate requirement for it. The DV for vitamin B12 is 6.0 mcg. However, the FDA does not require food labels to list vitamin B12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.[Source 98)]
Are you getting enough vitamin B12 ?
Most people in the United States get enough vitamin B12 from the foods they eat. But some people have trouble absorbing vitamin B12 from food. As a result, vitamin B12 deficiency affects between 1.5% and 15% of the public. Your doctor can test your vitamin B12 level to see if you have a deficiency.
Certain groups may not get enough vitamin B12 or have trouble absorbing it:
- Many older adults, who do not have enough hydrochloric acid in their stomach to absorb the vitamin B12 naturally present in food. People over 50 should get most of their vitamin B12 from fortified foods or dietary supplements because, in most cases, their bodies can absorb vitamin B12 from these sources.
- People with pernicious anemia whose bodies do not make the intrinsic factor needed to absorb vitamin B12. Doctors usually treat pernicious anemia with vitamin B12 shots, although very high oral doses of vitamin B12 might also be effective.
- People who have had gastrointestinal surgery, such as weight loss surgery, or who have digestive disorders, such as celiac disease or Crohn’s disease. These conditions can decrease the amount of vitamin B12 that the body can absorb.
- Some people who eat little or no animal foods such as vegetarians and vegans. Only animal foods have vitamin B12 naturally. When pregnant women and women who breastfeed their babies are strict vegetarians or vegans, their babies might also not get enough vitamin B12.
What happens if you don’t get enough vitamin B12 ?
Vitamin B12 deficiency causes tiredness, weakness, constipation, loss of appetite, weight loss, and megaloblastic anemia. Nerve problems, such as numbness and tingling in the hands and feet, can also occur. Other symptoms of vitamin B12 deficiency include problems with balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue. Vitamin B12 deficiency can damage the nervous system even in people who don’t have anemia, so it is important to treat a deficiency as soon as possible.
In infants, signs of a vitamin B12 deficiency include failure to thrive, problems with movement, delays in reaching the typical developmental milestones, and megaloblastic anemia.
Large amounts of folic acid can hide a vitamin B12 deficiency by correcting megaloblastic anemia, a hallmark of vitamin B12 deficiency. But folic acid does not correct the progressive damage to the nervous system that vitamin B12 deficiency also causes. For this reason, healthy adults should not get more than 1,000 mcg of folic acid a day.
Vitamin B12 Deficiency
Vitamin B12 deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss 99), 100), 101). Neurological changes, such as numbness and tingling in the hands and feet, can also occur 102), 103). Additional symptoms of vitamin B12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue 104). The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage 105). During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia 106). Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B12 deficiency.
Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 may also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration 107), 108). Overall, an individual patient’s ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection 109). In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged 110).
Folic Acid and Vitamin B12 Deficiency
Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency 111), 112) without correcting the neurological damage that also occurs 113), 114). Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency 115), 116). Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults 117).
Causes of Vitamin B12 Deficiency
Vitamin B12 deficiency can result from
- Inadequate intake
- Inadequate absorption
- Decreased utilization
- Use of certain drugs
Inadequate vitamin B12 intake is possible in vegans but is otherwise unlikely. Breastfed babies of vegan mothers may develop vitamin B12 deficiency by age 4 to 6 mo because in these babies, liver stores (which are normally extensive in other babies) are limited and their rapid growth rate results in high demand.
Inadequate vitamin B12 absorption is the most common cause of deficiency. In the elderly, inadequate absorption most commonly results from decreased acid secretion. In such cases, crystalline vitamin B12 (such as that available in vitamin supplements) can be absorbed, but food-bound vitamin B12 is not liberated and absorbed normally.
Inadequate absorption may occur in blind loop syndrome (with overgrowth of bacteria) or fish tapeworm infestation; in these cases, bacteria or parasites use ingested vitamin B12 so that less is available for absorption.
Vitamin B12 absorption may be inadequate if ileal absorptive sites are destroyed by inflammatory bowel disease or are surgically removed.
Less common causes of inadequate vitamin B12absorption include chronic pancreatitis, gastric or bariatric surgery, malabsorption syndromes, AIDS, use of certain drugs (eg, antacids, metformin), repeated exposure to nitrous oxide, and a genetic disorder causing malabsorption in the ileum (Imerslund-Graesbeck syndrome).
Less commonly, decreased utilization of vitamin B12 or use of certain drugs causes vitamin B12 deficiency.
Groups at Risk of Vitamin B12 Deficiency
The main causes of vitamin B12 deficiency include vitamin B12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency 118). However, in many cases, the cause of vitamin B12 deficiency is unknown.
The following groups are among those most likely to be vitamin B12 deficient.
- Older adults
Atrophic gastritis, a condition affecting 10%–30% of older adults, decreases secretion of hydrochloric acid in the stomach, resulting in decreased absorption of vitamin B12 119), 120), 121), 122), 123), 124), 125). Decreased hydrochloric acid levels might also increase the growth of normal intestinal bacteria that use vitamin B12, further reducing the amount of vitamin B12 available to the body 126).
Individuals with atrophic gastritis are unable to absorb the vitamin B12 that is naturally present in food. Most, however, can absorb the synthetic vitamin B12 added to fortified foods and dietary supplements. As a result, the Institute of Medicine recommends that adults older than 50 years obtain most of their vitamin B12 from vitamin supplements or fortified foods 127). However, some elderly patients with atrophic gastritis require doses much higher than the RDA to avoid subclinical deficiency 128).
- Individuals with pernicious anemia
Pernicious anemia, a condition that affects 1%–2% of older adults 129), is characterized by a lack of intrinsic factor. Individuals with pernicious anemia cannot properly absorb vitamin B12 in the gastrointestinal tract 130), 131), 132), 133). Pernicious anemia is usually treated with intramuscular vitamin B12. However, approximately 1% of oral vitamin B12 can be absorbed passively in the absence of intrinsic factor 134), suggesting that high oral doses of vitamin B12 might also be an effective treatment.
- Individuals with gastrointestinal disorders
Individuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores 135), 136). Subtly reduced cognitive function resulting from early vitamin B12 deficiency might be the only initial symptom of these intestinal disorders, followed by megaloblastic anemia and dementia.
- Individuals who have had gastrointestinal surgery
Surgical procedures in the gastrointestinal tract, such as weight loss surgery or surgery to remove all or part of the stomach, often result in a loss of cells that secrete hydrochloric acid and intrinsic factor 137), 138), 139). This reduces the amount of vitamin B12, particularly food-bound vitamin B12 140), that the body releases and absorbs. Surgical removal of the distal ileum also can result in the inability to absorb vitamin B12. Individuals undergoing these surgical procedures should be monitored preoperatively and postoperatively for several nutrient deficiencies, including vitamin B12 deficiency 141).
Strict vegetarians and vegans are at greater risk than lacto-ovo vegetarians and nonvegetarians of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods 142). Fortified breakfast cereals are one of the few sources of vitamin B12 from plants and can be used as a dietary source of vitamin B12 for strict vegetarians and vegans.
- Pregnant and lactating women who follow strict vegetarian diets and their infants
Vitamin B12 crosses the placenta during pregnancy and is present in breast milk. Exclusively breastfed infants of women who consume no animal products may have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency within months of birth 143), 144). Undetected and untreated vitamin B12 deficiency in infants can result in severe and permanent neurological damage.
The American Dietetic Association recommends supplemental vitamin B12 for vegans and lacto-ovo vegetarians during both pregnancy and lactation to ensure that enough vitamin B12 is transferred to the fetus and infant 145). Pregnant and lactating women who follow strict vegetarian or vegan diets should consult with a pediatrician regarding vitamin B12 supplements for their infants and children 146).
Symptoms and Signs of Vitamin B12 Deficiency
Anemia usually develops insidiously. It is often more severe than its symptoms indicate because its slow evolution allows physiologic adaptation.
Occasionally, splenomegaly and hepatomegaly occur. Various GI symptoms, including weight loss and poorly localized abdominal pain, may occur. Glossitis, usually described as burning of the tongue, is uncommon.
Neurologic symptoms develop independently from and often without hematologic abnormalities.
Subacute combined degeneration refers to degenerative changes in the nervous system due to vitamin B12 deficiency; they affect mostly brain and spinal cord white matter. Demyelinating or axonal peripheral neuropathies can occur 147).
In early stages, decreased position and vibratory sensation in the extremities is accompanied by mild to moderate weakness and hyporeflexia. In later stages, spasticity, extensor plantar responses, greater loss of position and vibratory sensation in the lower extremities, and ataxia emerge. These deficits may develop in a stocking-glove distribution. Tactile, pain, and temperature sensations are usually spared but may be difficult to assess in the elderly.
Some patients are also irritable and mildly depressed. Paranoia (megaloblastic madness), delirium, confusion, and, at times, postural hypotension may occur in advanced cases. The confusion may be difficult to differentiate from age-related dementias, such as Alzheimer disease.
Diagnosis of Vitamin B12 Deficiency
- Complete blood test checking for anemia and vitamin B12 and folate levels
- Sometimes methylmalonic acid levels or Schilling test
It is important to remember that severe neurologic disease may occur without anemia or macrocytosis.
Diagnosis of vitamin B12 deficiency is based on complete blood count and vitamin B12 and folate levels. Complete blood count usually detects megaloblastic anemia. Tissue deficiency and macrocytic indexes may precede the development of anemia. A vitamin B12 level < 200 pg/mL (< 145 pmol/L) indicates vitamin B12 deficiency. The folate level is measured because vitamin B12 deficiency must be differentiated from folate deficiency as a cause of megaloblastic anemia; folate supplementation can mask vitamin B12 deficiency and may alleviate megaloblastic anemia but allow the neurologic deficits to progress or even accelerate.
When clinical judgment suggests vitamin B12 deficiency but the vitamin B12 level is low-normal (200 to 350 pg/mL [145 to 260 pmol/L]) or hematologic indexes are normal, other tests can be done. They include measuring the following:
- Serum methylmalonic acid (MMA) levels: An elevated MMA level supports vitamin B12 deficiency but may be due to renal failure. MMA levels can also be used to monitor the response to treatment. MMA levels remain normal in folate deficiency.
- Homocysteine levels: Levels may be elevated with either vitamin B12 or folate deficiency.
- Less commonly, holotranscobalamin II (transcobalamin II–B12 complex) content: When holotranscobalamin II is < 40 pg/mL (< 30 pmol/L), vitamin B12 is deficient.
After vitamin B12 deficiency is diagnosed, additional tests (eg, Schilling test) may be indicated for younger adults but usually not for the elderly. Unless dietary vitamin B12 is obviously inadequate, serum gastrin levels or autoantibodies to intrinsic factor may be measured; sensitivity and specificity of these tests may be poor.
- Schilling test
The Schilling test is useful only if diagnosing intrinsic factor deficiency is important, as in classic pernicious anemia. This test is not necessary for most elderly patients. The Schilling test measures absorption of free radiolabeled vitamin B12. Radiolabeled vitamin B12 is given orally, followed in 1 to 6 h by 1000 mcg (1 mg) of parenteral vitamin B12, which reduces uptake of radiolabeled vitamin B12 by the liver. Absorbed radiolabeled vitamin B12 is excreted in urine, which is collected for 24 h. The amount excreted is measured, and the percentage of total radiolabeled vitamin B12 is determined. If absorption is normal, ≥ 9% of the dose given appears in the urine. Reduced urinary excretion (< 5% if kidney function is normal) indicates inadequate vitamin B12 absorption. Improved absorption with the subsequent addition of intrinsic factor to radiolabeled vitamin B12 confirms the diagnosis of pernicious anemia.
The test is often difficult to do or interpret because of incomplete urine collection or renal insufficiency. In addition, because the Schilling test does not measure absorption of protein-bound vitamin B12, the test does not detect defective liberation of vitamin B12 from foods, which is common among the elderly. The Schilling test repletes vitamin B12 and can mask deficiency, so it should be done only after all other diagnostic tests and therapeutic trials.
If malabsorption is identified, the Schilling test can be repeated after a 2-wk trial of an oral antibiotic. If antibiotic therapy corrects malabsorption, the likely cause is intestinal overgrowth of bacteria (eg, blind-loop syndrome).
Treatment of Vitamin B12 Deficiency
- Supplemental Vitamin B12
Vitamin B12 1000 to 2000 mcg po can be given once/day to patients who do not have severe deficiency or neurologic symptoms or signs. A nasal gel preparation of vitamin B12is available at a higher price. Large oral doses can be absorbed by mass action, even when intrinsic factor is absent. If the MMA level (sometimes used to monitor treatment) does not decrease, patients may not be taking vitamin B12.
For more severe deficiency, vitamin B12 1 mg IM is usually given 1 to 4 times/wk for several weeks until hematologic abnormalities are corrected; then it is given once/mo.
Although hematologic abnormalities are usually corrected within 6 wk (reticulocyte count should improve within 1 wk), resolution of neurologic symptoms may take much longer. Neurologic symptoms that persist for months or years become irreversible. In most elderly people with vitamin B12 deficiency and dementia, cognition does not improve after treatment.
Vitamin B12 treatment must be continued for life unless the pathophysiologic mechanism for the deficiency is corrected.
Infants of vegan mothers should receive supplemental vitamin B12 from birth.
Vitamin B12 Side Effects and Toxicity – Health Risks from Excessive Vitamin B12
The Institute of Medicine did not establish a UL for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the Institute of Medicine states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals” 148).
Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial) 149), 150).
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