Vitamin B12

Vitamin B12, also known as cobalamin or extrinsic factor, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor in DNA synthesis and both fatty acid and amino acid metabolism. It plays an essential role in the nervous system by supporting myelin synthesis and is critical for the maturation of red blood cell

Vitamin B12, also known as cobalamin or extrinsic factor, is a water-soluble vitamin involved in metabolism.[2] One of eight B vitamins, it serves as a vital cofactor in DNA synthesis and both fatty acid and amino acid metabolism.[3] It plays an essential role in the nervous system by supporting myelin synthesis and is critical for the maturation of red blood cells in the bone marrow.[2][4] Animals require B12 but plants do not, relying instead on alternative enzymatic pathways.[5]

Vitamin B12 is the most chemically complex of all vitamins,[2][6][7] and is synthesized exclusively by certain archaea and bacteria.[8] Natural food sources include meat, shellfish, liver, fish, poultry, eggs, and dairy products.[2] It is also added to many breakfast cereals through food fortification and is available in dietary supplement and pharmaceutical forms.[2] Supplements are commonly taken orally but may be administered via intramuscular injection to treat deficiencies.[2][6]

In healthy adults, vitamin B12 deficiency is not common, mainly because body stores of the vitamin are substantial and turnover is slow, with relatively low dietary requirements.[3] However, B12 deficiency in the elderly is a significant concern, and is related to dementia.[3]: 313  The most common cause in developed countries is impaired absorption due to loss of gastric intrinsic factor (IF), required for absorption.[9] A related cause is reduced stomach acid production with age or from long-term use of proton-pump inhibitors,[10] H2 blockers, or other antacids,[11] and interaction with metformin. Elderly people due to impaired intestinal absorption, and children, premenopausal women, and pregnant women whose diets are low in animal foods are at increased risk.[2][12]

Deficiency is especially harmful in pregnancy, childhood, and older adults. It can lead to neuropathy, megaloblastic anemia, and pernicious anemia,[2][13] causing symptoms including fatigue, paresthesia, depression, 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.

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.[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 as vitamers having vitamin activity as a coenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.[16][17]

• 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 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 vitamin B
12 are methylcobalamin in cytosol and adenosylcobalamin in mitochondria.[18]

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.[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]

Pseudovitamins and antivitamins

Pseudovitamin B12 refers to compounds that are corrinoids with a structure similar to the vitamin, but without vitamin activity.[22][18] Pseudovitamin B12 is the majority corrinoid in spirulina, 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 with rhodium, nickel, or zinc, 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]

Deficiency

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 or tingling, poor appetite, heartburn, poor balance, difficulty walking, poor reflexes, blurred vision, memory problems, depression, irritability, inattention, cognitive decline, dementia, and even psychosis.[26][27][28] Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur.[29] It has also been linked to optic nerve atrophy and neuritis.[30]

The main type of vitamin B12 deficiency anemia is pernicious anemia,[31] characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia).[32] This is due to the inhibition of DNA synthesis (specifically purines and thymidine).[medical citation needed]
2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control.[33] 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.[34]
3. Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) and subacute combined degeneration of the spinal cord.[32][35] Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.[36]

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.[37] 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.[38] 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.[39] 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.[2]

Nitrous oxide overdose or overuse converts the active monovalent form of vitamin B12 to the inactive bivalent form.[40]

Pregnancy, lactation, and early childhood

The U.S. Recommended Dietary Allowance (RDA) for pregnancy is 2.6 micrograms per day (μg/d), for lactation 2.8 μg/d. Determination of these values was based on an RDA of 2.4 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][41]: 972  However, looking at the same scientific evidence, the European Food Safety Authority (EFSA) sets adequate intake (AI) at 4.5 μg/d for pregnancy and 5.0 μg/d for lactation.[42] 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.[43][41] During pregnancy the placenta 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][44]

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.[44][41] 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[45][46] especially for pregnant mothers who follow a vegetarian or vegan diet.[47]

Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products.[41]: 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.[48] 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.[41]: 973  Breast milk B12 decreases over months of nursing in both well-nourished and vitamin-deficient mothers.[41]: 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.[41]: 974–975 

The risk of deficiency persists if the post-weaning diet is low in animal products.[41]: 974–975  Signs of low vitamin levels in infants and young children can include anemia, poor physical growth, and neurodevelopmental delays.[41]: 975  Children diagnosed with low serum B12 can be treated with intramuscular injections, then transitioned to an oral dietary supplement.[41]: 976 

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.[49][50][51] For post-operative oral supplementation, 1000 μg/d may be needed to prevent vitamin deficiency.[51]

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."[52] 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.[53] 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 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.[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.[54] In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such as methylmalonic acidemia.[55] If nervous system damage is present and blood testing is inconclusive, a lumbar puncture may be carried out to measure cerebrospinal fluid B12 levels.[56]

Serum haptocorrin binds 80-90% of circulating B12, rendering it unavailable for cellular delivery by transcobalamin II. This is conjectured to be a circulating storage function.[57] 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.[58]