Vitamin B12 deficiency is prevalent worldwide, particularly among individuals with low or no intake of animal products, such as those followingvegan orvegetarian diets, or those with low socioeconomic status.[9] The most common cause in developed countries is impaired absorption due to loss ofgastric intrinsic factor (IF), required for absorption.[10] A related cause is reducedstomach acid production with age or from long-term use ofproton-pump inhibitors,[11]H2 blockers, or other antacids.[12]
Deficiency is especially harmful inpregnancy,childhood, and older adults. It can lead toneuropathy,megaloblastic anemia, andpernicious anemia,[2][13] causing symptoms such asfatigue,paresthesia, cognitive decline,ataxia, and even irreversible nerve damage. In infants, untreated deficiency may result in neurological impairment and anemia.[2] Maternal deficiency increases the risk of miscarriage,neural tube defects, and developmental delays in offspring.[14]Folate levels may modify the presentation of symptoms and disease course.
Vitamin B12 is acoordination complex ofcobalt, which occupies the center of acorrin ligand and is further bound to abenzimidazole ligand and adenosyl group.[15] Several related species behave similarly to function as vitamins. This collection of compounds is sometimes referred to as "cobalamins". These chemical compounds have a similar molecular structure, each of which shows vitamin activity in a vitamin-deficient biological system. They are referred to asvitamers having vitamin activity as acoenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.[16][17]
Cyanocobalamin is a manufactured form of B12. Bacterial fermentation creates AdoB12 and MeB12, which are converted to cyanocobalamin by the addition of potassium cyanide in the presence of sodium nitrite and heat. Once consumed, cyanocobalamin is converted to the biologically active AdoB12 and MeB12. The two bioactive forms of vitaminB 12 aremethylcobalamin incytosol andadenosylcobalamin inmitochondria.[18]
Cyanocobalamin is the most common form used indietary supplements andfood fortification because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement.[16] There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B12 deficiency.[19][4]
Hydroxocobalamin can be injected intramuscularly to treat vitamin B12 deficiency.[20] It can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.[21]
Pseudovitamin B12 refers to compounds that arecorrinoids with a structure similar to the vitamin, but without vitamin activity.[22][18] Pseudovitamin B12 is the majority corrinoid inspirulina, an algal dietary supplement sometimes erroneously claimed as having this vitamin activity.[23]
Antivitamin B12 compounds (often synthetic B12 analogues) not only have no vitamin action, but also actively interfere with the activity of true vitamin B12. The design of these compounds mainly involves the replacement of the metal ion withrhodium,nickel, orzinc, or may have an inactive ligand attached, such as 4-ethylphenyl. These compounds have the potential for use in analyzing B12 pathways or even attacking B12-dependent pathogens.[24]
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.[6][25] At levels only slightly below normal, deficiency can result in fatigue, headaches, feeling faint, rapid breathing,pale skin,numbness ortingling, poor appetite, heartburn, poor balance, difficulty walking, poor reflexes, blurred vision, memory problems, depression, irritability, cognitive decline,psychosis, and evendementia, especially in older adults.[26][27][28] Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur.[29]
Gastrointestinal symptoms: alteration in bowel motility, such as milddiarrhea orconstipation, and loss of bladder or bowel control.[32] These are thought to be due to defective DNA synthesis inhibiting replication in tissue sites with a high turnover of cells. This may also be due to theautoimmune attack on theparietal cells of the stomach in pernicious anemia. There is an association withgastric antral vascular ectasia (which can be referred to as watermelon stomach), and pernicious anemia.[33]
Vitamin B12 deficiency is most commonly caused by malabsorption, but can also result from low intake, immune gastritis, low presence of binding proteins, or use of certain medications.[6]Vegans—people who choose to not consume any animal-sourced foods—are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency.[36]Vegetarians—people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal—are also at risk. Vitamin B12 deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B12 supplement or consume vitamin-fortified food.[37] In Hong Kong and India, vitamin B12 deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B12 fortified food such as cereal, plant-based milks, andnutritional yeast as a regular part of their diet.[38] The elderly are at increased risk because they tend to produce lessstomach acid as they age, a condition known asachlorhydria, thereby increasing their probability of B12 deficiency due to reduced absorption.[2]
Nitrous oxide overdose or overuse converts the active monovalent form of vitamin B12 to the inactive bivalent form.[39]
The U.S.Recommended Dietary Allowance (RDA) for pregnancy is2.6 micrograms per day (μg/d), for lactation2.8 μg/d. Determination of these values was based on an RDA of2.4 μg/d for non-pregnant women, plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk.[16][40]: 972 However, looking at the same scientific evidence, theEuropean Food Safety Authority (EFSA) sets adequate intake (AI) at4.5 μg/d for pregnancy and5.0 μg/d for lactation.[41] Low maternal vitamin B12, defined as serum concentration less than 148 pmol/L, increases the risk of miscarriage, preterm birth and newborn low birth weight.[42][40] During pregnancy theplacenta concentrates B12, so that newborn infants have a higher serum concentration than their mothers.[16] As it is recently absorbed vitamin content that more effectively reaches the placenta, the vitamin consumed by the mother-to-be is more important than that contained in her liver tissue.[16][43]
Women who consume little animal-sourced food, or who are vegetarian or vegan, are at higher risk of becoming vitamin depleted during pregnancy than those who consume more animal products. This depletion can lead to anemia, and also an increased risk that their breastfed infants become vitamin deficient.[43][40] Vitamin B12 is not one of the supplements recommended by the World Health Organization for healthy women who are pregnant,[14] however, vitamin B12 is often suggested during pregnancy in a multivitamin along with folic acid[44][45] especially for pregnant mothers who follow a vegetarian or vegan diet.[46]
Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products.[40]: 971, 973 Only a few countries, primarily in Africa, have mandatory food fortification programs for either wheat flour or maize flour; India has a voluntary fortification program.[47] What the nursing mother consumes is more important than her liver tissue content, as it is recently absorbed vitamin that more effectively reaches breast milk.[40]: 973 Breast milk B12 decreases over months of nursing in both well-nourished and vitamin-deficient mothers.[40]: 973–974 Exclusive or near-exclusive breastfeeding beyond six months is a strong indicator of low serum vitamin status in nursing infants. This is especially true when the vitamin status is poor during the pregnancy and if the early-introduced foods fed to the still-breastfeeding infant are vegan.[40]: 974–975
The risk of deficiency persists if the post-weaning diet is low in animal products.[40]: 974–975 Signs of low vitamin levels in infants and young children can include anemia, poor physical growth, and neurodevelopmental delays.[40]: 975 Children diagnosed with low serum B12 can be treated with intramuscular injections, then transitioned to an oral dietary supplement.[40]: 976
Various methods of gastric bypass or gastric restriction surgery are used to treat morbid obesity. Roux-en-Y gastric bypass surgery (RYGB) but not sleeve gastric bypass surgery or gastric banding, increases the risk of vitamin B12 deficiency and requires preventive post-operative treatment with either injected or high-dose oral supplementation.[48][49][50] For post-operative oral supplementation,1000 μg/d may be needed to prevent vitamin deficiency.[50]
According to one review: "At present, no 'gold standard' test exists for the diagnosis of vitamin B12 deficiency and as a consequence the diagnosis requires consideration of both the clinical state of the patient and the results of investigations."[51] The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevatedmean corpuscular volume (MCV). In addition, on theperipheral blood smear,macrocytes and hypersegmentedpolymorphonuclear leukocytes may be seen. Diagnosis is supported based on vitamin B12 blood levels below 150–180pmol/L (200–250pg/mL) in adults.[52] However, serum values can be maintained while tissue B12 stores are becoming depleted. Therefore, serum B12 values above the cut-off point of deficiency do not necessarily confirm adequate B12 status.[2] For this reason, elevated serumhomocysteine over 15 micromol/L andmethylmalonic acid (MMA) over 0.271 micromol/L are considered better indicators of B12 deficiency, rather than relying only on the concentration of B12 in blood.[2] However, elevated MMA is not conclusive, as it is seen in people with B12 deficiency, but also in elderly people who have renal insufficiency,[28] and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency.[53] In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such asmethylmalonic acidemia.[54] If nervous system damage is present and blood testing is inconclusive, alumbar puncture may be carried out to measurecerebrospinal fluid B12 levels.[55]
Serumhaptocorrin binds 80-90% of circulating B12, rendering it unavailable for cellular delivery bytranscobalamin II. This is conjectured to be a circulating storage function.[56] Several serious, even life-threatening diseases cause elevated serum haptocorrin, measured as abnormally high serum vitamin B12, while at the same time potentially manifesting as a symptomatic vitamin deficiency because of insufficient vitamin bound to transcobalamin II which transfers the vitamin to cells.[57]
A vitamin B12 solution (hydroxocobalamin) in a multi-dose bottle, with a single dose drawn up into a syringe for injection. Preparations are usually bright red.
Severe vitamin B12 deficiency is initially corrected with daily intramuscular injections of1000 μg of the vitamin, followed by maintenance via monthly injections of the same amount or daily oral dosing of1000 μg. The oral daily dose far exceeds the vitamin requirement because the normal transporter protein-mediated absorption is absent, leaving only very inefficient intestinal passive absorption.[58][59] Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness. There are not enough studies on whether pills are as effective in improving or eliminating symptoms as parenteral treatment.[60]
Forcyanide poisoning, a large amount of hydroxocobalamin may be givenintravenously and sometimes in combination withsodium thiosulfate.[61][62] The mechanism of action is straightforward: the hydroxycobalamin hydroxideligand is displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted inurine.[63]
Some research shows that most people in the United States and the United Kingdom consume sufficient vitamin B12.[2][10] However, other research suggests that the proportion of people with low or marginal levels of vitamin B12 is up to 40% in theWestern world.[2]Grain-based foods can befortified by having the vitamin added to them. Vitamin B12 supplements are available as single or multivitamin tablets.Pharmaceutical preparations of vitamin B12 may be given byintramuscular injection.[6][64] Since there are few non-animal sources of the vitamin,vegans are advised to consume adietary supplement or fortified foods for B12 intake, or risk serious health consequences.[6] Children in some regions ofdeveloping countries are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.
The USNational Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B12 in 1998.[6] The EAR for vitamin B12 for women and men ages 14 and up is 2.0μg/day; the RDA is2.4 μg/d. RDA is higher than EAR to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy equals 2.6μg/day. RDA for lactation equals2.8 μg/d. For infants up to 12 months, the adequate intake (AI) is 0.4–0.5μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years, the RDA increases with age from 0.9 to 1.8μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B12 naturally occurring in foods, those older than 50 years should meet their RDA mainly by consuming foods fortified with vitamin B12 or a supplement containing vitamin B12. As for safety,tolerable upper intake levels (known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B12 there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs, and ULs are referred to asdietary reference intakes (DRIs).[16]
TheEuropean Food Safety Authority (EFSA) refers to the collective set of information as "dietary reference values", with population reference intake (PRI) instead of RDA, and average requirement instead of EAR. AI and UL are defined by EFSA the same as in the United States. For women and men over age 18, the adequate intake (AI) is set at 4.0μg/day. AI for pregnancy is 4.5 μg/day, and for lactation 5.0μg/day. For children aged 1–14 years, the AIs increase with age from 1.5 to 3.5μg/day. These AIs are higher than the U.S. RDAs.[41] The EFSA also reviewed the safety question and reached the same conclusion as in the United States—that there was not sufficient evidence to set a UL for vitamin B12.[65]
The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4μg/day.[66] TheWorld Health Organization also uses 2.4μg/day as the adult recommended nutrient intake for this vitamin.[67]
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a "percent of daily value" (%DV). For vitamin B12 labeling purposes, 100% of the daily value was 6.0μg, but on 27 May 2016, it was revised downward to 2.4μg (seeReference Daily Intake).[68][69] Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers withUS$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.[70][71]
Vitamin B12 is produced in nature by certainbacteria andarchaea.[72][73][74] It is synthesized by some bacteria in thegut microbiota in humans and other animals, but it has long been thought that humans cannot absorb this as it is made in thecolon, downstream from thesmall intestine, where the absorption of most nutrients occurs.[75]Ruminants, such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in therumen before entering the true stomach (abomasum), thus allowing them to absorb the vitamin B12 produced by the bacteria.[75][76]
Other mammalian species (examples:rabbits,pikas,beaver,guinea pigs) consume high-fiber plants which pass through the gastrointestinal tract and undergo bacterial fermentation in thececum andlarge intestine. In thishindgut fermentation, the material from the cecum is expelled as "cecotropes" and are re-ingested, a practice referred to ascecotrophy. Re-ingestion allows for absorption of nutrients made available by bacterial fermentation, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B12.[76]
Non-ruminant, non-hindgut herbivores may have an enlarged forestomach and/or small intestine to provide a place for bacterial fermentation and B-vitamin production, including B12.[76] For gut bacteria to produce vitamin B12, the animal must consume sufficient amounts ofcobalt.[77] Soil that is deficient in cobalt may result in B12 deficiency, and B12 injections or cobalt supplementation may be required for livestock.[78]
Animals store vitamin B12 from their diets in theirlivers andmuscles and some pass the vitamin into theireggs andmilk. Meat, liver, eggs, and milk are therefore sources of the vitamin for other animals, including humans.[64][2][79] For humans, thebioavailability from eggs is less than 9%, compared to 40% to 60% from fish, fowl, and meat.[80] Insects are a source of B12 for animals (including other insects and humans).[79][81] Animal-derived food sources with a high concentration of vitamin B12 includeliver and otherorgan meats fromlamb,veal,beef, andturkey; alsoshellfish andcrab meat.[6][64][82]
There is some evidence that bacterial fermentation of plant foods and symbiotic relationships between algae and bacteria can provide vitamin B12. However, theAcademy of Nutrition and Dietetics considers plant and algae sources "unreliable", stating thatvegans should turn to fortified foods and supplements instead.[36]
Natural plant andalgae sources of vitamin B12 includefermented plant foods such astempeh[83][84] and seaweed-derived foods such asnori andlaverbread.[85][86][87] Methylcobalamin has been identified inChlorella vulgaris.[88] Since only bacteria and some archea possess the genes and enzymes necessary to synthesize vitamin B12, plant and algae sources all obtain the vitamin secondarily from symbiosis with various species of bacteria,[5] or in the case of fermented plant foods, from bacterial fermentation.[83]
Foods for which vitamin B12-fortified versions are available includebreakfast cereals, plant-derivedmilk substitutes such assoy milk andoat milk,energy bars, andnutritional yeast.[82] The fortification ingredient is cyanocobalamin. Microbial fermentation yields adenosylcobalamin, which is then converted to cyanocobalamin by the addition of potassium cyanide or thiocyanate in the presence of sodium nitrite and heat.[89]
As of 2019, nineteen countries require food fortification of wheat flour, maize flour, or rice with vitamin B12. Most of these are in southeast Africa or Central America.[47]
Vegan advocacy organizations, among others, recommend that every vegan consume B12 from either fortified foods or supplements.[6][38][90][91]
Vitamin B12 is included in multivitamin pills; in some countries grain-based foods, such as bread and pasta, are fortified with B12.[2] In the US, non-prescription products can be purchased providing up to 1,000μg each, and it is a common ingredient inenergy drinks andenergy shots, usually at many times the recommended dietary allowance of B12.[2] The vitamin can also be supplied on prescription and delivered via injection or other means.[2]
When used in supplementation, all of the vitamin B12vitamers have been argued to be beneficial, with there not being clear evidence that any are relatively more or less effective.[92][93][94] The amount of cyanide in cyanocobalamin is generally not considered a health risk, since even in a 1,000μg dose, the 20μg of cyanide it contains is less than the daily consumption of cyanide from food.[92]
Injection ofhydroxycobalamin is often used if digestive absorption is impaired,[2] but this course of action may not be necessary with high-dose oral supplements (such as 0.5–1.0mg or more),[95][96] because with large quantities of the vitamin taken orally, even the 1% to 5% of free crystalline B12 that is absorbed along the entire intestine by passive diffusion may be sufficient to provide a necessary amount.[97]
A person with cobalamin C disease, a rare autosomal, recessive, inheritance disease which results in combinedmethylmalonic aciduria andhomocystinuria),[98] can be treated with intravenous or intramuscular hydroxocobalamin.[99]
Nanotechnologies used in vitamin B12 supplementation
Conventional administration does not ensure specific distribution and controlled release of vitamin B12, for example to bone marrow and nerve cells. Nanocarrier strategies for improved vitamin B12 delivery remain embryonic as of 2021.[100]
Gastric acid is needed to release vitamin B12 from protein for absorption. Reduced secretion ofgastric acid andpepsin, from the use ofH2 blocker orproton-pump inhibitor (PPI) drugs, can reduce the absorption of protein-bound (dietary) vitamin B12, although not of supplemental vitamin B12. H2-receptor antagonist examples includecimetidine,famotidine,nizatidine, andranitidine. PPIs examples includeomeprazole,lansoprazole,rabeprazole,pantoprazole, andesomeprazole. Clinically significant vitamin B12 deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition, the person's dietary intake is below recommended levels. Symptomatic vitamin deficiency is more likely if the person is renderedachlorhydric (a complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers.[101]
Reduced serum levels of vitamin B12 occur in up to 30% of people taking long-termanti-diabeticmetformin.[102][103] Deficiency does not develop if dietary intake of vitamin B12 is adequate or prophylactic B12 supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B12 supplements.[104]
Methylcobalamin (shown) is a form of vitamin B12. Physically it resembles the other forms of vitamin B12, occurring as dark red crystals that freely form cherry-colored transparent solutions in water.
Vitamin B12 is the most chemically complex of all the vitamins.[6] The structure of B12 is based on acorrin ring, which is similar to theporphyrin ring found inheme. The central metal ion iscobalt. As isolated as an air-stable solid and available commercially, cobalt in vitamin B12 (cyanocobalamin and other vitamers) is present in its +3 oxidation state. Biochemically, the cobalt center can take part in both two-electron and one-electron reductive processes to access the "reduced" (B12r, +2 oxidation state) and "super-reduced" (B12s, +1 oxidation state) forms. The ability to shuttle between the +1, +2, and +3 oxidation states is responsible for the versatile chemistry of vitamin B12, allowing it to serve as a donor of deoxyadenosyl radical (radical alkyl source) and as a methyl cation equivalent (electrophilic alkyl source).[107]
The structures of the four most common vitamers of cobalamin, together with some synonyms. The structure of the 5'-deoxyadenosyl group, which forms the R group of adenosylcobalamin is also shown.
Four of the six coordination sites are provided by the corrin ring and a fifth by adimethylbenzimidazole group. The sixth coordination site, thereactive center, is variable, being acyano group (–CN), ahydroxyl group (–OH), amethyl group (–CH3) or a 5′-deoxyadenosyl group. Historically, the covalent carbon–cobalt bond is one of the first examples of carbon-metal bonds to be discovered in biology. Thehydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.[108] Animals can convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by enzymatically replacing the cyano or hydroxyl groups.
Several methods have been used to determine the vitamin B12 content in foods including microbiological assays, chemiluminescence assays, polarographic, spectrophotometric, and high-performance liquid chromatography processes.[109] The microbiological assay has been the most commonly used assay technique for foods, utilizing certain vitamin B12-requiring microorganisms, such asLactobacillus delbrueckii subsp.lactis ATCC7830.[80] However, it is no longer the reference method due to the high measurement uncertainty of vitamin B12.[110]
Furthermore, this assay requires overnight incubation and may give false results if any inactive vitamin B12 analogues are present in the foods.[111] Currently, radioisotope dilution assay (RIDA) with labeled vitamin B12 and hog IF (pigs) have been used to determine vitamin B12 content in food.[80] Previous reports have suggested that the RIDA method can detect higher concentrations of vitamin B12 in foods compared to the microbiological assay method.[80][109]
Vitamin B12 functions as acoenzyme, meaning that its presence is required in some enzyme-catalyzed reactions.[16][17] Listed here are the three classes of enzymes that sometimes require B12 to function (in animals):
Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. These use the AdoB12 (adenosylcobalamin) form of the vitamin.[112]
Some species of anaerobic bacteria synthesize B12-dependent dehalogenases, which have potential commercial applications for degrading chlorinated pollutants. The microorganisms may either be capable ofde novo corrinoid biosynthesis or are dependent on exogenous vitamin B12.[114][115]
In humans, two major coenzyme B12-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:
Simplified schematic diagram of the propionate metabolic pathway. Methylmalonyl-CoA mutase requires the coenzyme adenosylcobalamin to convert L-methylmalonyl-CoA into succinyl-CoA. Otherwise, methylmalonic acid accumulates, making it a marker for vitamin B12 deficiency, among other things.
Methylmalonyl coenzyme A mutase (MUT) is an isomerase enzyme that uses the AdoB12 form and reaction type 1 to convertL-methylmalonyl-CoA tosuccinyl-CoA, an important step in the catabolic breakdown of someamino acids into succinyl-CoA, which then enters energy production via thecitric acid cycle.[112] This functionality is lost invitamin B12 deficiency, and can be measured clinically as an increased serummethylmalonic acid (MMA) concentration. The MUT function is necessary for propermyelin synthesis.[4] Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration.[116]
Simplified schematic diagram of the folate methionine cycle. Methionine synthase transfers the methyl group to the vitamin and then transfers the methyl group to homocysteine, converting that to methionine.
Methionine synthase, coded byMTR gene, is a methyltransferase enzyme which uses the MeB12 and reaction type 2 to transfer a methyl group from5-methyltetrahydrofolate tohomocysteine, thereby generatingtetrahydrofolate (THF) andmethionine.[113] This functionality is lost invitamin B12 deficiency, resulting in an increasedhomocysteine level and the trapping offolate as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis, so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B12 deficiency, including themegaloblastic anemia ofpernicious anemia, resolve if sufficient dietary folate is present. Thus the best-known "function" of B12 (that which is involved with DNA synthesis, cell division, and anemia) is afacultative function that is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production.[113] Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H4-MPT, coenzyme M methyltransferase.[117]
Structure of human TCII in complex with Vitamin B12. HC and IF show homologous protein folds.[118]
Vitamin B12 is absorbed by a B12-specific transport proteins or via passive diffusion.[16] Transport-mediated absorption and tissue delivery is a complex process involving three transport proteins:haptocorrin (HC),intrinsic factor (IF) andtranscobalamin II (TC2), and respective membrane receptor proteins (Figure).[118]
HC is present in saliva. As vitamin-containing food is digested byhydrochloric acid andpepsin secreted into the stomach, HC binds the vitamin and protects it from acidic degradation.[16][119] Upon leaving the stomach the hydrochloric acid of thechyme is neutralized in theduodenum bybicarbonate,[120] and pancreatic proteases release the vitamin from HC, making it available to be bound by IF, which is a protein secreted by gastricparietal cells in response to the presence of food in the stomach. IF delivers the vitamin to receptor proteinscubilin andamnionless, which together form thecubam receptor in the distalileum. The receptor is specific to the IF-B12 complex, and so will not bind to any vitamin content that is not bound to IF.[16][119]
Investigations into the intestinal absorption of B12 confirm that the upper limit of absorption per single oral dose is about 1.5μg, with 50% efficiency. In contrast, the passive diffusion process of B12 absorption — normally a very small portion of total absorption of the vitamin from food consumption — may exceed the haptocorrin- and IF-mediated absorption when oral doses of B12 are very large, with roughly 1% efficiency. Thus, dietary supplement B12 supplementation at 500 to 1000μg per day allowspernicious anemia and certain other defects in B12 absorption to be treated with daily oral megadoses of B12 without any correction of the underlying absorption defects.[119]
After the IF/B12 complex binds to cubam the complex is disassociated and the free vitamin is transported into theportal circulation. The vitamin is then transferred to TC2, which serves as the circulating plasma transporter, hereditary defects in the production of TC2 and its receptor may produce functional deficiencies in B12 and infantilemegaloblastic anemia, and abnormal B12 related biochemistry, even in some cases with normal blood B12 levels. For the vitamin to serve inside cells, the TC2-B12 complex must bind to a cell receptor protein and beendocytosed. TC2 is degraded within alysosome, and free B12 is released into the cytoplasm, where it is transformed into the bioactive coenzyme by cellular enzymes.[119][121]
Antacid drugs that neutralize stomach acid, as well as acid-suppressing agents such asproton-pump inhibitors, can inhibit the absorption of vitamin B12 by preventing its release from food in the stomach.[122] Other causes of B12 malabsorption includebariatric surgery,pancreatic insufficiency,obstructive jaundice,tropical sprue,celiac disease, inherited intrinsic factor deficiency, andradiation enteritis affecting the distalileum.[119] Age is also a contributing factor: elderly individuals are oftenachlorhydric due to reduced parietal cell function in the stomach, increasing their risk of vitamin B12 deficiency.[123] The ability to absorb vitamin B12 declines with age, particularly in individuals over 60.[123]
How fast B12 levels change depends on the balance between how much B12 is obtained from the diet, how much is secreted and how much is absorbed. The total amount of vitamin B12 stored in the body is about 2–5mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed.Bile is the main form of B12 excretion; most of the B12 secreted in the bile is recycled viaenterohepatic circulation. Excess B12 beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B12, the liver can store 3 to 5 years' worth of vitamin B12; therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders.[16] In the absence of intrinsic factor or distal ileum receptors, only months to a year of vitamin B12 are stored.[124]
Vitamin B12 through its involvement in one-carbon metabolism plays a key role incellular reprogramming and tissue regeneration and epigenetic regulation. Cellular reprogramming is the process by which somatic cells can be converted to a pluripotent state. Vitamin B12 levels affect the histone modificationH3K36me3, which suppresses illegitimate transcription outside ofgene promoters. Mice undergoing in vivo reprogramming were found to become depleted in B12 and show signs ofmethionine starvation while supplementing reprogramming mice and cells with B12 increased reprogramming efficiency, indicating a cell-intrinsic effect.[125][126]
The complete laboratorysynthesis of B12 was achieved byRobert Burns Woodward[138] andAlbert Eschenmoser in 1972.[139][140] The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (atETH Zurich) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B12 was previously reported. This synthesis of vitamin B12 is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%.[141] Although there have been sporadic synthetic efforts since 1972,[140] the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis.
During the 1920s,George Whipple discovered that ingesting large amounts of rawliver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.[143]Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products.William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.[142] In 1934, George Whipple shared the 1934Nobel Prize in Physiology or Medicine withWilliam P. Murphy andGeorge Minot for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.[142][144]
While working at the Bureau of Dairy Industry, U.S. Department of Agriculture,Mary Shaw Shorb was assigned work on the bacterial strainLactobacillus lactis Dorner (LLD), which was used to make yogurt and other cultured dairy products. The culture medium for LLD required liver extract. Shorb knew that the same liver extract was used to treat pernicious anemia (her father-in-law had died from the disease), and concluded that LLD could be developed as an assay method to identify the active compound. While at the University of Maryland, she received a small grant fromMerck, and in collaboration withKarl Folkers from that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth.[145] Shorb, Folker andAlexander R. Todd, at theUniversity of Cambridge, used the LLD assay to extract the anti-pernicious anemia factor from liver extracts, purify it, and name it vitamin B12.[146] In 1955, Todd helped elucidate the structure of the vitamin. The completechemical structure of the molecule was determined byDorothy Hodgkin based oncrystallographic data and published in 1955[147] and 1956,[148] for which, and for other crystallographic analyses, she was awarded the Nobel Prize in Chemistry in 1964.[149] Hodgkin went on to decipher the structure ofinsulin.[149]
George Whipple, George Minot and William Murphy were awarded the Nobel Prize in 1934 for their work on the vitamin. Three other Nobel laureates, Alexander R. Todd (1957), Dorothy Hodgkin (1964) and Robert Burns Woodward (1965) made important contributions to its study.[150]
Nobel laureates for discoveries relating to vitamin B12
Industrial production of vitamin B12 is achieved throughfermentation of selected microorganisms.[133] As noted above, the completely synthetic laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, though this process has no commercial potential, requiring more than 70 steps and having a yield well below 0.01%.[141]
In the 1970s, John A. Myers, a physician residing in Baltimore, developed a program of injecting vitamins and minerals intravenously for various medical conditions. The formula included1000 μg of cyanocobalamin. This came to be known as theMyers' cocktail. After he died in 1984, other physicians and naturopaths took up prescribing "intravenous micronutrient therapy" with unsubstantiated health claims for treating fatigue, low energy, stress, anxiety, migraine, depression, immunocompromised, promoting weight loss, and more.[151] However, other than a report on case studies[151] there are no benefits confirmed in the scientific literature.[152] Healthcare practitioners at clinics and spas prescribe versions of these intravenous combination products, but also intramuscular injections of just vitamin B12. A Mayo Clinic review concluded that there is no solid evidence that vitamin B12 injections provide an energy boost or aid weight loss.[153]
There is evidence that for elderly people, physicians often repeatedly prescribe and administer cyanocobalamin injections inappropriately, evidenced by the majority of subjects in one large study either having had normal serum concentrations or having not been tested before the injections.[154]
^Yamada K (2013). "Cobalt: Its Role in Health and Disease". In Sigel A, Sigel H, Sigel RK (eds.).Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. Vol. 13. Springer. pp. 295–320.doi:10.1007/978-94-007-7500-8_9.ISBN978-94-007-7499-5.PMID24470095.
^abcdefghij"Vitamin B12". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 4 June 2015.Archived from the original on 29 October 2019. Retrieved5 April 2019.
^abStabler SP (2020). "Vitamin B12". In Marriott BP, Birt DF, Stallings VA, Yates AA (eds.).Present Knowledge in Nutrition, Eleventh Edition. London: Academic Press (Elsevier). pp. 257–272.ISBN978-0-323-66162-1.US survey data from the NHANES What We Eat in America 2013e16 cohort reported the median vitamin B12 consumption for all adult men of 5.1 mcg and women of 3.5 mcg.95b Using the Estimated Average Requirement (EAR) for adults for Vitamin B12 of 2 mcg,93 less than 3% of men and 8% of women in the United States had inadequate diets using this comparator. However, 11% of girls 14e18 years had intakes less than their EAR of 2.0 mcg.
^Choudhury A, Jena A, Jearth V, Dutta AK, Makharia G, Dutta U, et al. (May 2023). "Vitamin B12 deficiency and use of proton pump inhibitors: a systematic review and meta-analysis".Expert Review of Gastroenterology & Hepatology.17 (5):479–487.doi:10.1080/17474124.2023.2204229.PMID37060552.
^Butler P, Kräutler B (2006). "Biological Organometallic Chemistry of B12".Bioorganometallic Chemistry. Topics in Organometallic Chemistry. Vol. 17. pp. 1–55.doi:10.1007/3418_004.ISBN3-540-33047-X.
^abcdefghijkInstitute of Medicine (1998)."Vitamin B12".Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. pp. 306–356.ISBN978-0-309-06554-2. Retrieved7 February 2012.
^Watanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, et al. (November 1999). "Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets".Journal of Agricultural and Food Chemistry.47 (11):4736–4741.Bibcode:1999JAFC...47.4736W.doi:10.1021/jf990541b.PMID10552882.
^van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ (April 2001). "Folate, homocysteine and neural tube defects: an overview".Experimental Biology and Medicine.226 (4):243–270.doi:10.1177/153537020122600402.PMID11368417.S2CID29053617.
^Greenburg M (2010).Handbook of Neurosurgery 7th Edition. New York: Thieme Publishers. pp. 1187–1188.ISBN978-1-60406-326-4.
^Lerner NB (2016). "Vitamin B12 Deficiency". In Kliegman RM, Stanton B, St Geme J, Schor NF (eds.).Nelson Textbook of Pediatrics (20th ed.). Elsevier Health Sciences. pp. 2319–2326.ISBN978-1-4557-7566-8.
^abMelina V, Craig W, Levin S (December 2016). "Position of the Academy of Nutrition and Dietetics: Vegetarian Diets".Journal of the Academy of Nutrition and Dietetics.116 (12):1970–1980.doi:10.1016/j.jand.2016.09.025.PMID27886704.S2CID4984228.Fermented foods (such as tempeh), nori, spirulina, chlorella algae, and unfortified nutritional yeast cannot be relied upon as adequate or practical sources of B-12.39,40 Vegans must regularly consume reliable sources—meaning B-12 fortified foods or B-12 containing supplements—or they could become deficient, as shown in case studies of vegan infants, children, and adults.
^Majumder S, Soriano J, Louie Cruz A, Dasanu CA (2013). "Vitamin B12 deficiency in patients undergoing bariatric surgery: preventive strategies and key recommendations".Surg Obes Relat Dis.9 (6):1013–1019.doi:10.1016/j.soard.2013.04.017.PMID24091055.
^abMahawar KK, Reid A, Graham Y, Callejas-Diaz L, Parmar C, Carr WR, et al. (July 2018). "Oral Vitamin B12 Supplementation After Roux-en-Y Gastric Bypass: a Systematic Review".Obes Surg.28 (7):1916–1923.doi:10.1007/s11695-017-3102-y.PMID29318504.S2CID35209784.
^Graham RM, Deery E, Warren MJ (2009). "18: Vitamin B12: Biosynthesis of the Corrin Ring". In Warren MJ,Smith (eds.).Tetrapyrroles Birth, Life and Death. New York: Springer-Verlag. p. 286.doi:10.1007/978-0-387-78518-9_18.ISBN978-0-387-78518-9.
^ab"Vitamin B-12 (μg)"(PDF).USDA National Nutrient Database for Standard Reference Release 28. 27 October 2015.Archived(PDF) from the original on 26 January 2017. Retrieved6 January 2020.
^Kumudha A, Selvakumar S, Dilshad P, Vaidyanathan G, Thakur MS, Sarada R (March 2015). "Methylcobalamin – a form of vitamin B12 identified and characterised in Chlorella vulgaris".Food Chemistry.170:316–320.doi:10.1016/j.foodchem.2014.08.035.PMID25306351.
^Lane LA, Rojas-Fernandez C (July–August 2002). "Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy".The Annals of Pharmacotherapy.36 (7–8):1268–1272.doi:10.1345/aph.1A122.PMID12086562.S2CID919401.
^Arslan SA, Arslan I, Tirnaksiz F (March 2013). "Cobalamins and Methylcobalamin: Coenzyme of Vitamin B12".FABAD J. Pharm. Sci.38 (3):151–157.S2CID1929961.
^Wang C, Li D, Cai F, Zhang X, Xu X, Liu X, et al. (October 2019). "Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review".Eur J Med Genet.62 (10) 103713.doi:10.1016/j.ejmg.2019.103713.PMID31279840.
^Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, et al. (June 2008). "The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum".Journal of Neurology, Neurosurgery, and Psychiatry.79 (6):725–28.doi:10.1136/jnnp.2007.133025.PMID18245139.S2CID23493993.
^Gilligan MA (February 2002). "Metformin and vitamin B12 deficiency".Archives of Internal Medicine.162 (4):484–485.doi:10.1001/archinte.162.4.484 (inactive 1 July 2025).PMID11863489.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
^Giedyk M, Goliszewska K, Gryko D (June 2015). "Vitamin B12 catalysed reactions".Chemical Society Reviews.44 (11):3391–3404.doi:10.1039/C5CS00165J.PMID25945462.
^Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (December 2009). "Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain".Neuroscience.164 (2):578–587.doi:10.1016/j.neuroscience.2009.08.028.PMID19699272.S2CID34612963.
^abWuerges J, Garau G, Geremia S, Fedosov SN, Petersen TE, Randaccio L (March 2006). "Structural basis for mammalian vitamin B12 transport by transcobalamin".Proceedings of the National Academy of Sciences of the United States of America.103 (12):4386–4391.doi:10.1073/pnas.050909910.PMID16537422.
^Battersby A (2005). "Chapter 11: Discovering the wonder of how Nature builds its molecules". InArcher MD, Haley CD (eds.).The 1702 chair of chemistry at Cambridge: transformation and change. Cambridge University Press. pp. xvi,257–282.ISBN0-521-82873-2.
^Shorb MS (May 10, 2012)."Annual Lecture". Department of Animal & Avian Sciences, University of Maryland. Archived fromthe original on December 12, 2012. RetrievedAugust 2, 2014.
^Hodgkin DC, Pickworth J, Robertson JH, Trueblood KN, Prosen RJ, White JG (1955). "Structure of Vitamin B12: The Crystal Structure of the Hexacarboxylic Acid derived from B12 and the Molecular Structure of the Vitamin".Nature.176 (4477):325–28.Bibcode:1955Natur.176..325H.doi:10.1038/176325a0.PMID13253565.S2CID4220926.
