Cobalamin Skeletal

Vitamin B₁₂, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It is important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the circulatory system in the maturation of red blood cells in the bone marrow. Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it.

Vitamin B₁₂ is the most chemically complex of all vitamins, and for humans, the only vitamin that must be sourced from animal-derived foods or from supplements. Only some archaea and bacteria can synthesize vitamin B₁₂. Most people in developed countries get enough B₁₂ from the consumption of meat or foods with animal sources. Foods containing vitamin B₁₂ include meat, clams, liver, fish, poultry, eggs, and dairy products. Many breakfast cereals are fortified with the vitamin. Supplements and medications are available to treat and prevent vitamin B₁₂ deficiency. They are taken by mouth, but for the treatment of deficiency may also be given as an intramuscular injection.

The most common cause of vitamin B₁₂ deficiency in developed countries is impaired absorption due to a loss of gastric intrinsic factor (IF) which must be bound to a food-source of B₁₂ in order for absorption to occur. A second major cause is age-related decline in stomach acid production (achlorhydria), because acid exposure frees protein-bound vitamin. For the same reason, people on long-term antacid therapy, using proton-pump inhibitors, H2 blockers or other antacids are at increased risk. The diets of vegetarians and vegans may not provide sufficient B₁₂ unless a dietary supplement is consumed. A deficiency in vitamin B₁₂ may be characterized by limb neuropathy or a blood disorder called pernicious anemia, a type of megaloblastic anemia, causing a feeling of tiredness and weakness, lightheadedness, headache, breathlessness, loss of appetite, abnormal sensations, changes in mobility, severe joint pain, muscle weakness, memory problems, decreased level of consciousness, brain fog, and many others. If left untreated in infants, deficiency may lead to neurological damage and anemia. Folate levels in the individual may affect the course of pathological changes and symptomatology of vitamin B₁₂ deficiency.

Vitamin B₁₂ was discovered as a result of pernicious anemia, an autoimmune disorder in which the blood has a lower than normal number of red blood cells, due to a deficiency in vitamin B₁₂. The ability to absorb the vitamin declines with age, especially in people over 60 years old.

Definition

Vitamin B₁₂ is a coordination complex of cobalt, which occupies the center of a corrin ligand and is further bound to a benzimidazole ligand and adenosyl group. It is a deep red solid that dissolves in water to give red solutions.

A number of related species are known and these behave similarly, in particular all function as vitamins. This collection of compounds, of which vitamin B₁₂ is one member, are often 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 as vitamers. The vitamin activity is as a coenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.
* adenosylcobalamin
* cyanocobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by cyanide.
* hydroxocobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by hydroxide.
* methylcobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by methyl.

Cyanocobalamin is a manufactured form of B₁₂. Bacterial fermentation creates AdoB₁₂ and MeB₁₂, which are converted to cyanocobalamin by 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 vitamin are methylcobalamin in cytosol and adenosylcobalamin in mitochondria.

Cyanocobalamin is the most common form used in dietary supplements and food fortification because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement. There is no advantage to the use of adenosylcobalamin or methylcobalamin for treatment of vitamin B₁₂ deficiency.

Hydroxocobalamin can be injected intramuscularly to treat vitamin B₁₂ deficiency. 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.

"Pseudovitamin B₁₂" refers to compounds that are corrinoids with a structure similar to the vitamin but without vitamin activity. Pseudovitamin B₁₂ is the majority corrinoid in spirulina, an algal health food sometimes erroneously claimed as having this vitamin activity.

Deficiency

Vitamin B₁₂ deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as feeling tired, weak, feeling like one may faint, dizziness, breathlessness, headaches, mouth ulcers, upset stomach, decreased appetite, difficulty walking (staggering balance problems), muscle weakness, depression, poor memory, poor reflexes, confusion, and pale skin, feeling abnormal sensations, among others, may be experienced, especially in people over age 60. Vitamin B₁₂ deficiency can also cause symptoms of mania and psychosis. Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur.

The main type of vitamin B12 deficiency anemia is pernicious anemia. It is characterized by a triad of symptoms:
# Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine).
# Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. 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 the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with gastric antral vascular ectasia (which can be referred to as watermelon stomach), and pernicious anemia.
# Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) and subacute combined degeneration of the spinal cord. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.

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. 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. 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. 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, and nutritional yeast as a regular part of their diet. The elderly are at increased risk because they tend to produce less stomach acid as they age, a condition known as achlorhydria, thereby increasing their probability of B₁₂ deficiency due to reduced absorption.

Pregnancy, lactation and early childhood

The U.S. Recommended Dietary Allowance (RDA) for pregnancy is 2.6 µg/day, for lactation 2.8 µg/day. Determination of these values was based on the RDA of 2.4 µg/day for non-pregnant women plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk. However, looking at the same scientific evidence, the European Food Safety Authority (EFSA) sets adequate intake (AI) at 4.5μg/day for pregnancy and 5.0 μg/day for lactation. 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. During pregnancy the placenta concentrates B₁₂, so that newborn infants have a higher serum concentration than their mothers. 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. 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.

Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products. 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. 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. Breast milk B₁₂ decreases over months of nursing in both well-nourished and vitamin-deficient mothers. 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 was poor during the pregnancy and if the early-introduced foods fed to the still breastfeeding infant are vegan. Risk of deficiency persists if the post-weaning diet is low in animal products. Signs of low vitamin levels in infants and young children can include anemia, poor physical growth and neurodevelopmental delays. Children diagnosed with low serum B₁₂ can be treated with intramuscular injections, then transitioned to an oral dietary supplement.

Gastric bypass surgery

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. For post-operative oral supplementation, 1000 μg/day may be needed to prevent vitamin deficiency.

Diagnosis

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." The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevated mean corpuscular volume (MCV). In addition, on the peripheral blood smear, macrocytes and hypersegmented polymorphonuclear leukocytes may be seen. Diagnosis is supported based on vitamin B₁₂ blood levels below 150–180 pmol/L (200–250 pg/mL) in adults. 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. For this reason, elevated serum homocysteine over 15 micromol/L and methylmalonic 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. However, elevated MMA is not conclusive, as it is seen in people with B₁₂ deficiency, but also in elderly people who have renal insufficiency, and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency. In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such as methylmalonic acidemia. If nervous system damage is present and blood testing is inconclusive, a lumbar puncture may be carried out to measure cerebrospinal fluid B₁₂ levels.

Medical uses

Repletion of deficiency

Severe vitamin B₁₂ deficiency is corrected with frequent intramuscular injections of large doses of the vitamin, followed by maintenance doses of injections or oral dosing at longer intervals. In the UK, standard initial therapy consists of intramuscular injections of 1000 μg of hydroxocobalamin three times a week for two weeks or until neurological symptoms improve, followed by 1000 μg every two or three months. Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness.

Cyanide poisoning

For cyanide poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with sodium thiosulfate. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted in urine.

Dietary recommendations

Most people in the United States and the United Kingdom consume sufficient vitamin B₁₂. However, proportions of people with low or marginal levels of vitamin B₁₂ reach up to 40% in the Western world. Grain-based foods can be fortified 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 by intramuscular injection. Since there are few non-animal sources of the vitamin, vegans are advised to consume a dietary supplement or fortified foods for B₁₂ intake, or risk serious health consequences. Children in some regions of developing countries are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.

The US National Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B in 1998. The EAR for vitamin B for women and men ages 14 and up is 2.0μg/day; the RDA is 2.4μg/day. RDA is higher than EAR so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6μg/day. RDA for lactation equals 2.8 μg/day. 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 B naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B or a supplement containing vitamin B. 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 B 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 as dietary reference intakes (DRIs).

The European 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, for lactation 5.0μg/day. For children aged 1–17 years the AIs increase with age from 1.5 to 3.5μg/day. These AIs are higher than the U.S. RDAs. 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 B.

The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4μg/day. The World Health Organization also uses 2.4μg/day as the adult recommended nutrient intake for this vitamin.

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 B labeling purposes 100% of the daily value was 6.0μg, but on May 27, 2016, it was revised downward to 2.4μg. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Bacteria and archaea

Vitamin B₁₂ is produced in nature by certain bacteria, and archaea. It is synthesized by some bacteria in the gut microbiota in humans and other animals, but it has long been thought that humans cannot absorb this as it is made in the colon, downstream from the small intestine, where the absorption of most nutrients occurs. Ruminants, such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in the rumen before entering the true stomach (abomasum), and thus they are absorbing vitamin B₁₂ produced by bacteria. Other mammalian species (examples: rabbits, pikas, beaver, guinea pigs) consume high-fibre plants which pass through the intestinal system and undergo bacterial fermentation in the cecum and large intestine. The first-passage of feces produced by this hindgut fermentation

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