{"history":[],"article":{"id":"11c533cd-358f-4887-87cc-75ca511cd1c5","title":"Vitamin B12 deficiency","slug":"vitamin-b12-deficiency","content":":::summary\n![Image of the cervical spinal cord in vitamin B12 deficiency showing subacute combined degeneration. (A) The midsagittal T2 weighted image shows linear hyperintensity in the posterior portion of the cervical tract of the spinal cord (black arrows). (B) Axial T2 weighted images reveal the selective involvement of the posterior columns.](https://upload.wikimedia.org/wikipedia/commons/f/fb/VitB12DefFull.jpg)\n**Name:** Vitamin B12 deficiency \n**Synonyms:** Hypocobalaminemia, cobalamin deficiency \n**Field:** [Neurology](https://bliptext.com/articles/neurology), [hematology](https://bliptext.com/articles/hematology) \n**Symptoms:** Decreased ability to think, [feeling tired](https://bliptext.com/articles/fatigue), [depression](https://bliptext.com/articles/depression-mood), irritability, [abnormal sensations](https://bliptext.com/articles/paresthesia), changes in reflexes \n**Complications:** [Megaloblastic anemia](https://bliptext.com/articles/megaloblastic-anemia), irreversible damage to the [brain](https://bliptext.com/articles/brain) and [nervous system](https://bliptext.com/articles/nervous-system) \n**Causes:** Poor absorption, decreased intake, increased requirements \n**Diagnosis:** Blood levels below 148–185 pmol/L (200–250 pg/mL) in adults \n**Prevention:** Supplementation in those at high risk \n**Treatment:** Supplementation by mouth or injection \n**Frequency:** 6% (< 60 years old), 20% (> 60 years old) \n:::\n\n# \n**Vitamin B12 deficiency**, also known as **cobalamin deficiency**, is the medical condition in which the blood and tissue have a lower than normal level of [vitamin B12](https://bliptext.com/articles/vitamin-b12).\nSymptoms can vary from none to severe.\nMild deficiency may have few or absent symptoms.\nIn moderate deficiency, [feeling tired](https://bliptext.com/articles/fatigue), [headaches](https://bliptext.com/articles/headache), [soreness of the tongue](https://bliptext.com/articles/glossitis), [mouth ulcers](https://bliptext.com/articles/aphthous-stomatitis), breathlessness, [feeling faint](https://bliptext.com/articles/presyncope), [rapid heartbeat](https://bliptext.com/articles/tachycardia), [low blood pressure](https://bliptext.com/articles/low-blood-pressure), pallor, hair loss, decreased ability to think and severe [joint pain](https://bliptext.com/articles/arthralgia) and the beginning of [neurological](https://bliptext.com/articles/neurological) symptoms, including [abnormal sensations](https://bliptext.com/articles/paresthesia) such as pins and needles, numbness and tinnitus may occur.\nSevere deficiency may include symptoms of [reduced heart function](https://bliptext.com/articles/cardiomyopathy) as well as more severe neurological symptoms, including changes in [reflexes](https://bliptext.com/articles/reflex), poor muscle function, memory problems, [blurred vision](https://bliptext.com/articles/blurred-vision), irritability, [ataxia](https://bliptext.com/articles/ataxia), decreased [smell](https://bliptext.com/articles/anosmia) and [taste](https://bliptext.com/articles/hypogeusia), [decreased level of consciousness](https://bliptext.com/articles/stupor), depression, anxiety, guilt and [psychosis](https://bliptext.com/articles/psychosis).\nIf left untreated, some of these changes can become permanent.\nTemporary [infertility](https://bliptext.com/articles/infertility), reversible with treatment, may occur.\nA late finding type of anemia known as [megaloblastic anemia](https://bliptext.com/articles/megaloblastic-anemia) is often but not always present.\nIn exclusively breastfed infants of [vegan](https://bliptext.com/articles/vegan) mothers, undetected and untreated deficiency can lead to [poor growth](https://bliptext.com/articles/failure-to-thrive), poor development, and [difficulties with movement](https://bliptext.com/articles/movement-disorder).\nCauses are usually related to conditions that give rise to [malabsorption](https://bliptext.com/articles/malabsorption) of vitamin B12 particularly [autoimmune gastritis](https://bliptext.com/articles/atrophic-gastritis) in [pernicious anemia](https://bliptext.com/articles/pernicious-anemia).\nOther conditions giving rise to malabsorption include [surgical removal of the stomach](https://bliptext.com/articles/gastrectomy), chronic [inflammation of the pancreas](https://bliptext.com/articles/pancreatitis), [intestinal parasites](https://bliptext.com/articles/intestinal-parasite), certain medications such as long-term use of [proton pump inhibitors](https://bliptext.com/articles/proton-pump-inhibitors), [H2-receptor blockers](https://bliptext.com/articles/h2-receptor-blocker), and [metformin](https://bliptext.com/articles/metformin), and some [genetic disorders](https://bliptext.com/articles/genetic-disorder).\nDeficiency can also be caused by inadequate dietary intake such as with the diets of [vegetarians](https://bliptext.com/articles/vegetarian), and [vegans](https://bliptext.com/articles/vegan), and in the [malnourished](https://bliptext.com/articles/malnutrition).\nDeficiency may be caused by increased needs of the body for example in those with [HIV/AIDS](https://bliptext.com/articles/hiv-aids), and [shortened red blood cell lifespan](https://bliptext.com/articles/hemolysis).\nDiagnosis is typically based on blood levels of vitamin B12 below 148–185 [pmol/L](https://bliptext.com/articles/orders-of-magnitude-mass) (200 to 250 pg/mL) in adults.\nDiagnosis is not always straightforward as [serum](https://bliptext.com/articles/serum-vitamin-b12) levels can be falsely high or normal.\nElevated [methylmalonic acid](https://bliptext.com/articles/methylmalonic-acid) levels may also indicate a deficiency.\nIndividuals with low or marginal values of vitamin B12 in the range of 148–221 pmol/L (200–300 pg/mL) may not have classic neurological or hematological signs or symptoms.\nTreatment is by vitamin B12 supplementation, either by mouth or by injection.\nInitially in high daily doses, followed by less frequent lower doses, as the condition improves.\nIf a reversible cause is found, that cause should be corrected if possible.\nIf no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin B12 administration is usually recommended.\nA nasal spray is also available.\nVitamin B12 deficiency is preventable with supplements, which are recommended for pregnant vegetarians and vegans, and not harmful in others.\nRisk of toxicity due to vitamin B12 is low.\nVitamin B12 deficiency in the [US](https://bliptext.com/articles/united-states) and the [UK](https://bliptext.com/articles/united-kingdom) is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60.\nIn [Latin America](https://bliptext.com/articles/latin-america), about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of [Africa](https://bliptext.com/articles/africa) and [Asia](https://bliptext.com/articles/asia).\nMarginal deficiency is much more common and may occur in up to 40% of Western populations.\n\n# Signs, symptoms and complications\nVitamin B12 deficiency appears slowly and worsens over time, and can often be confused with other conditions.\nIt may often go unrecognized, as the body becomes used to feeling unwell.\nVitamin B12 deficiency can lead to anemia, neurologic, and digestive dysfunctions.\nA mild deficiency may not cause any discernible symptoms, but at levels moderately lower than normal, a range of symptoms such as [feeling tired](https://bliptext.com/articles/fatigue), weak, lightheadedness, headaches, dizziness, rapid breathing, rapid heartbeat, cold hands and feet, low-grade [fevers](https://bliptext.com/articles/fever), tremor, [cold intolerance](https://bliptext.com/articles/cold-sensitivity), easy bruising and bleeding, [pale skin](https://bliptext.com/articles/pallor), low blood pressure, [sore tongue](https://bliptext.com/articles/glossitis), [upset stomach](https://bliptext.com/articles/dyspepsia), loss of appetite, weight loss, [constipation](https://bliptext.com/articles/constipation), [diarrhea](https://bliptext.com/articles/diarrhea), severe [joint pain](https://bliptext.com/articles/arthralgia), [feeling abnormal sensations](https://bliptext.com/articles/paresthesia) including numbness or tingling (pins and needles) to the fingers and toes, and tinnitus, may be experienced.\nA wide range of associated symptoms may include [angular cheilitis](https://bliptext.com/articles/angular-cheilitis), mouth ulcers, bleeding gums, hair loss and thinning, premature greying, a look of exhaustion and [dark circles around the eyes](https://bliptext.com/articles/periorbital-dark-circles), as well as brittle nails.\nSevere vitamin B12 deficiency can damage nerve cells.\nIf this happens, vitamin B12 deficiency may result in sense loss, loss of sensation in the feet, [difficulty walking](https://bliptext.com/articles/ataxia), poor balance, blurred vision, changes in reflexes, [muscle weakness](https://bliptext.com/articles/muscle-weakness), decreased smell and taste, [decreased level of consciousness](https://bliptext.com/articles/stupor), mood changes, memory loss, depression, irritability, anxiety, clumsiness, disorientation, psychosis and, in severe cases, dementia.\nTissue deficiencies may negatively affect [nerve cells](https://bliptext.com/articles/nerve-cell), [bone marrow](https://bliptext.com/articles/bone-marrow), and the skin.\nA further complication of severe deficiency is the neurological complex known as [subacute combined degeneration of spinal cord](https://bliptext.com/articles/subacute-combined-degeneration-of-spinal-cord).\nalso myelosis funicularis, or funicular myelosis.\nThis complex consists of the following symptoms:\nThe presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B12 deficiency instead of folate deficiency.\nMethylmalonic acid, if not properly handled by B12, remains in the [myelin sheath](https://bliptext.com/articles/myelin-sheath), causing fragility.\nDementia and depression have been associated with this deficiency as well, possibly from the under-production of [methionine](https://bliptext.com/articles/methionine) because of the inability to convert homocysteine into this product.\nMethionine is a necessary cofactor in the production of several [neurotransmitters](https://bliptext.com/articles/neurotransmitters).\nEach of those symptoms can occur either alone or with others.\nVitamin B12 is essential for the development of the brain.\nIts deficiency can cause neurodevelopmental problems which can be partly reversible with early treatment.\nOnly a small subset of dementia cases have been found to be reversible with vitamin B12 therapy.\n[Tinnitus](https://bliptext.com/articles/tinnitus) may be associated with vitamin B12 deficiency.\nVitamin B12 deficiency may accompany certain eating disorders or restrictive diets.\n\n## Pernicious anemia\n[Pernicious anemia](https://bliptext.com/articles/pernicious-anemia) is a disease caused by an [autoimmune response](https://bliptext.com/articles/autoimmune-disease) that produces [antibodies](https://bliptext.com/articles/antibodies) that attack the [parietal cells](https://bliptext.com/articles/parietal-cell) in the [stomach lining](https://bliptext.com/articles/gastric-mucosa), preventing them from creating [intrinsic factor](https://bliptext.com/articles/intrinsic-factor) needed for the absorption of vitamin B12.\nIt is the main and most common cause of vitamin B12 deficiency anemia in developed countries, and is characterized by a [triad of symptoms](https://bliptext.com/articles/list-of-medical-triads-and-pentads):\nIn babies, neurological symptoms can occur from malnutrition or pernicious anemia in the mother.\nThese include poor growth, apathy, having no desire for food, and developmental regression.\nWhile most symptoms resolve with supplementation, some developmental and cognitive problems may persist.\n\n## Metabolic risk in offspring\nVitamin B12 is a critical micronutrient essential for supporting the increasing metabolic demands of the [foetus](https://bliptext.com/articles/fetus) during pregnancy.\nB12 deficiency in pregnant women is increasingly common and has been shown to be associated with major maternal health implications, including increased obesity, higher body mass index (BMI), insulin resistance, gestational diabetes, and type 2 diabetes (T2D) in later life.\nA study in a pregnant white non-diabetic population in England, found that for every 1% increase in BMI, there was 0.6% decrease in circulating B12.\nFurthermore, an animal study in ewes demonstrated that a B12, folate and methionine restricted diet around conception, resulted in offspring with higher adiposity, blood pressure and insulin resistance which could be accounted for by altered DNA methylation patterns.\nBoth vitamin B12 and folate are involved in the one-carbon metabolism cycle.\nIn this cycle, vitamin B12 is a necessary cofactor for methionine synthase, an enzyme involved in the methylation of homocysteine to methionine.\nDNA methylation is involved in the functioning of genes and is an essential epigenetic control mechanism in mammals.\nThis methylation is dependent on methyl donors such as vitamin B12 from the diet.\nVitamin B12 deficiency has the potential to influence methylation patterns in DNA, besides other epigenetic modulators such as micro (RNAs), leading to the altered expression of genes.\nConsequently, an altered gene expression can possibly mediate impaired foetal growth and the programming of non-communicable diseases.\nVitamin B12 and folate status during pregnancy is associated with the increasing risk of low birth weight, preterm birth, insulin resistance and obesity in the offspring.\nIn addition it has been associated with adverse foetal and neonatal outcomes including [neural tube defects](https://bliptext.com/articles/neural-tube-defect) (NTDs) and delayed myelination or demyelination.\nThe mother's B12 status can be important in determining the later health of the child, as shown in the Pune maternal Nutrition Study, conducted in India.\nIn this study, children born to mothers with high folate concentrations and low vitamin B12 concentrations were found to have higher adiposity and insulin resistance at age 6.\nIn the same study, over 60% of pregnant women were deficient in vitamin B12, which was considered to increase the risk of gestational and later diabetes in the mothers.\nIncreased longitudinal cohort studies or randomised controlled trials are required to understand the mechanisms between vitamin B12 and metabolic outcomes, and to potentially offer interventions to improve maternal and offspring health.\n\n## Cardiometabolic disease outcomes\nMultiple studies have explored the association between vitamin B12 and metabolic disease outcomes, such as [obesity](https://bliptext.com/articles/obesity), [insulin resistance](https://bliptext.com/articles/insulin-resistance) and the development of [cardiovascular disease](https://bliptext.com/articles/cardiovascular-disease).\nA long-term study where vitamin B12 was supplemented across a period of 10 years, led to lower levels of weight gain in overweight or obese individuals (p < 0.05).\nThere are several mechanisms which may explain the relationship between obesity and decreased vitamin B12 status.\nVitamin B12 is a major dietary methyl donor, involved in the one-carbon cycle of [metabolism](https://bliptext.com/articles/metabolism) and a recent genome-wide association (GWA) analysis showed that increased DNA methylation is associated with increased BMI in adults, consequently a deficiency of vitamin B12 may disrupt DNA methylation and increase non-communicable disease risk.\nVitamin B12 is also a co-enzyme which converts methylmalonyl-CoA to succinyl-CoA in the one [carbon cycle](https://bliptext.com/articles/carbon-cycle).\nIf this reaction cannot occur, methylmalonyl-CoA levels elevate, inhibiting the rate-limiting enzyme of fatty acid oxidation (CPT1 – [carnitine palmitoyl transferase](https://bliptext.com/articles/carnitine-o-palmitoyltransferase)), leading to [lipogenesis](https://bliptext.com/articles/lipogenesis) and insulin resistance.\nFurther to this, reduced vitamin B12 concentrations in the obese population is thought to result from repetitive short-term restrictive diets and increased vitamin B12 requirements secondary to increased growth and body surface area.\nIt has also been hypothesised that low vitamin B12 concentrations in obese individuals are a result of wrong feeding habits, where individuals consume a diet low in [micronutrient](https://bliptext.com/articles/micronutrient) density.\nFinally, vitamin B12 is involved in the production of [red blood cells](https://bliptext.com/articles/red-blood-cell), and vitamin B12 deficiency can result in anemia, which causes [fatigue](https://bliptext.com/articles/fatigue) and the lack of motivation to [exercise](https://bliptext.com/articles/exercise).\nThe investigation into the relationship between cardiovascular disease (CVD) and vitamin B12 has been limited, and there is still controversy as to whether primary intervention with vitamin B12 will lower cardiovascular disease.\nDeficiency of vitamin B12 can impair the remethylation of homocysteine in the methionine cycle, and result in raised homocysteine levels.\nThere is much evidence linking elevated homocysteine concentrations with an increased risk of cardiovascular disease, and homocysteine lowering treatments have led to improvements in cardiovascular reactivity and coagulation factors.\nIn adults with metabolic syndrome, individuals with low levels of vitamin B12 had higher levels of homocysteine compared to healthy subjects.\nIt is thus possible that vitamin B12 deficiency enhances the risk of developing cardiovascular disease in individuals who are obese.\nAlternatively, low levels of vitamin B12 may increase the levels of proinflammatory proteins which may induce ischaemic stroke.\nIt is important to screen vitamin B12 deficiency in obese individuals, due to its importance in energy metabolism, and relationship with homocysteine and its potential to modulate weight gain.\nMore studies are needed to test for the causality of vitamin B12 and obesity using genetic markers.\nA few studies have also reported no deficiency of vitamin B12 in obese individuals.\nFinally, a recent literature review conducted over 19 studies, found no evidence of an inverse association between BMI and circulating vitamin B12.\nPrevious clinical and population-based studies have indicated that vitamin B12 deficiency is prevalent amongst adults with type 2 diabetes.\nKaya et al., conducted a study in women with [polycystic ovary syndrome](https://bliptext.com/articles/polycystic-ovary-syndrome), and found that obese women with insulin resistance had lower vitamin B12 concentrations compared to those without insulin resistance.\nSimilarly, in a study conducted in European adolescents, there was an association between high adiposity and higher insulin sensitivity with vitamin B12 concentrations.\nIndividuals with a higher fat mass index and higher insulin sensitivity (high Homeostatic Model Assessment [HOMA] index) had lower plasma vitamin B12 concentrations.\nFurthermore, a recent study conducted in India reported that mean levels of vitamin B12 decreased with increasing levels of glucose tolerance e.g. individuals with type 2 diabetes had the lowest values of vitamin B12, followed by individuals with pre-diabetes and normal glucose tolerance, respectively.\nHowever, B12 levels of middle aged-women with and without [metabolic syndrome](https://bliptext.com/articles/metabolic-syndrome) showed no difference in vitamin B12 levels between those with insulin resistance (IR) and those without.\nIt is believed that malabsorption of vitamin B12 in diabetic patients, is due to individuals taking metformin therapy (an insulin sensitizer used for treating type 2 diabetes).\nFurthermore, obese individuals with type 2 diabetes are likely to develop gastroesophageal reflux disease, and take proton pump inhibitors, which further increased the risk of vitamin B12 deficiency.\nA literature review conducted in 2011 over seven studies, found that there was limited evidence to show that low vitamin B12 status increased the risk of [cardiovascular disease](https://bliptext.com/articles/cardiovascular-disease) and [diabetes](https://bliptext.com/articles/diabetes).\nHowever, the review did not identify any associations between vitamin B12 and cardiovascular disease in the remaining four studies.\nCurrently, no data supports vitamin B12 supplementation on reducing the risk of cardiovascular disease.\nIn a dose-response meta-analysis of five prospective cohort studies, it was reported that the risk of [coronary heart disease](https://bliptext.com/articles/coronary-heart-disease) (CHD) did not change substantially with increasing dietary vitamin B12 intake.\nOf these five studies, three of the studies stated a non-significant positive association and two of the studies demonstrated an inverse association between vitamin B12 supplementation and coronary heart disease (only one of the studies was significant).\n\n## Anemia\nVitamin B12 deficiency is one of the main causes of [anemia](https://bliptext.com/articles/anemia).\nIn countries where B12 deficiency is common, it is generally assumed that there is a greater risk of developing anemia.\nHowever, the overall contribution of vitamin B12 deficiency to the global incidence of anemia may not be significant, except in elderly individuals, [vegetarians](https://bliptext.com/articles/vegetarianism), cases of malabsorption and some genetic disorders.\nAnemia is defined as a condition in which there are not enough [red blood cells](https://bliptext.com/articles/red-blood-cell), as the tissues and organs of the body do not get enough oxygen.\n[Megaloblastic anemia](https://bliptext.com/articles/megaloblastic-anemia) caused by vitamin B12 deficiency is characterized by [red blood cells that are larger than normal](https://bliptext.com/articles/macrocytic-anemia) and are unable to deliver oxygen to the body's organs.\nThe clinical case indicates an altered synthesis of DNA, in which vitamin B12 is essential for the production and maturation of red blood cells in the [bone marrow](https://bliptext.com/articles/bone-marrow).\nAdult patients often report to medical attention symptoms related to anemia, such as feeling tired and weak, breathlessness, [exercise intolerance](https://bliptext.com/articles/exercise-intolerance), feeling faint, headaches, paleness, dry lips and a disturbance of taste.\nPernicious anemia is the most common cause of vitamin B12 deficiency anemia in adults, which results from malabsorption of vitamin B12 due to a lack or loss of [intrinsic factor](https://bliptext.com/articles/intrinsic-factor).\nThere are relatively few studies which have assessed the impact of haematological measures in response to B12 supplementation.\nOne study in 184 premature infants, reported that individuals given monthly vitamin B12 injections (100 μg) or taking supplements of vitamin B12 and folic acid (100 μg/day), had higher haemoglobin concentrations after 10–12 weeks, compared to those only taking folic acid or those taking no vitamin B12 injections.\nIn deficient Mexican adult women and pre-schoolers, it was found that vitamin B12 supplementation did not affect any haematologic parameters.\n\n## Aging\nIn the elderly, vitamin B12 deficiency has been associated with the development of [macular degeneration](https://bliptext.com/articles/macular-degeneration), and the risk of frailty.\nMacular degeneration is the leading cause of severe, irreversible vision loss in older adults.\nSeveral risk factors have been linked to macular degeneration, including family history, genetics, hypercholesterolemia, hypertension, sunlight exposure and lifestyle (smoking and diet).\nIt has been shown that daily supplementation of vitamin B12, B6 and folate over a period of seven years can reduce the risk of age-related macular degeneration by 34% in women with increased risk of vascular disease (n=5,204).\nHowever, another study failed to find an association between age-related macular degeneration and vitamin B12 status in a sample of 3,828 individuals representative of the non-institutionalized US population.\n[Frailty](https://bliptext.com/articles/frailty-syndrome) is a geriatric condition which is characterized by diminished endurance, strength, and reduced physiological function that increases an individual's risk of mortality and impairs an individual from fulfilling an independent lifestyle.\nFrailty is associated with an increased vulnerability to fractures, falls from heights, reduced cognitive function and more frequent hospitalisation.\nThe worldwide prevalence of frailty within the geriatric population is 13.9%, therefore there is an urgent need to eliminate any risk factors associated with frailty.\nPoor vitamin B status has been shown to be associated with an increased risk of frailty.\nTwo cross sectional studies have reported that deficiencies of vitamin B12 were associated with the length of hospital stay, as observed by serum vitamin B12 concentrations and [methylmalonic acid](https://bliptext.com/articles/methylmalonic-acid) (MMA) concentrations.\nFurthermore, another study of elderly women, found that certain genetic variants associated with vitamin B12 status ([tanscobalamin II](https://bliptext.com/articles/tanscobalamin-ii)) may contribute to reduced energy metabolism, consequently contributing to frailty.\nGiven that there are limited studies assessing the relationship between vitamin B12 and frailty status, more longitudinal studies are needed to clarify the relationship.\n\n## Neurological decline\nSevere vitamin B12 deficiency is associated with [subacute combined degeneration of the spinal cord](https://bliptext.com/articles/subacute-combined-degeneration-of-spinal-cord), which involves [demyelination](https://bliptext.com/articles/demyelination) of the posterior and lateral columns of the spinal cord.\nSymptoms include memory and cognitive impairment, sensory loss, motor disturbances, personality changes, disorientation, irritability, dementia, loss of posterior column functions and disturbances in [proprioception](https://bliptext.com/articles/proprioception).\nIn advanced stages of vitamin B12 deficiency, cases of psychosis, paranoia and severe depression have been observed, which may lead to permanent disability if left untreated.\nStudies have shown the rapid reversal of the neurological symptoms of vitamin B12 deficiency, after treatment with high-dose of vitamin B12 supplementation; suggesting the importance of prompt treatment in reversing neurological manifestations.\n\n## Cognitive decline\nElderly individuals are currently assessed on vitamin B12 status during the screening process for dementia.\nStudies investigating the association between vitamin B12 concentrations and cognitive status have produced inconclusive results.\nIt has been shown that elevated MMA concentrations are associated with decreased cognitive decline and [Alzheimer's disease](https://bliptext.com/articles/alzheimer-s-disease).\nIn addition, low vitamin B12 and folate intakes have shown associations with [hyperhomocysteinemia](https://bliptext.com/articles/hyperhomocysteinemia), which is associated with [cerebrovascular disease](https://bliptext.com/articles/cerebrovascular-disease), cognitive decline and an increased risk of dementia in prospective studies.\nThere are limited intervention studies which have investigated the effect of supplementation of vitamin B12 and cognitive function.\nA [Cochrane review](https://bliptext.com/articles/cochrane-review), analysing two studies, found no effect of vitamin B12 supplementation on the cognitive scores of older adults.\nA recent longitudinal study in elderly individuals, found that individuals had a higher risk of brain volume loss over a 5-year period, if they had lower vitamin B12 and holoTC levels and higher plasma tHcy and MMA levels.\nMore intervention studies are needed to determine the modifiable effects of vitamin B12 supplementation on cognition.\n\n## Osteoporosis\nThere has been growing interest on the effect of low serum vitamin B12 concentrations on bone health.\nStudies have found a connection between elevated plasma tHcy and an increased risk of bone fractures, but is unknown whether this is related to the increased levels of tHcy or to vitamin B12 levels (which are involved in homocysteine metabolism).\nResults from the third NHANES conducted in the United States, found that individuals had significantly lower [bone mass density](https://bliptext.com/articles/bone-mass-density) (BMD) and higher osteoporosis rates with each higher quartile of serum MMA (n= 737 men and 813 women).\nGiven that poor bone mineralization has been found in individuals with [pernicious anemia](https://bliptext.com/articles/pernicious-anemia), and that the content of vitamin B12 within bone cells in culture has shown to affect the functioning of bone forming cells (osteoblasts); it is possible that vitamin B12 deficiency is causally related to poor bone health.\nRandomized intervention trials investigating the association of vitamin B12 supplementation and bone health have yielded mixed results.\nOne study conducted on osteoporotic risk patients with [hyperhomocysteinemia](https://bliptext.com/articles/hyperhomocysteinemia) found positive effects between supplementation of B vitamins on BMD.\nHowever, no improvement in BMD was observed in a group of healthy older people.\nFurther, controlled trials are needed to confirm the impact and mechanisms vitamin B12 deficiency has on bone mineralization.\n\n# Causes\nVitamin B12 deficiency can be caused by [impaired absorption](https://bliptext.com/articles/malabsorption), [inadequate dietary intake](https://bliptext.com/articles/malnutrition), or increased requirements.\nImpaired absorption explains most cases of vitamin B12 deficiency, but it can also result from other factors.\n\n## Impaired absorption\n\n## Inadequate intake\nVitamin B12 cannot be produced by the human body, and must be obtained from the diet.\nThe body normally gets enough vitamin B12 from the consumption of foods from animal sources.\nInadequate dietary intake of animal products such as eggs, meat, milk, fish, fowl (and some type of edible algae) can result in a deficiency state.\nVegans, and to a lesser degree vegetarians, are at risk for B12 deficiency if they do not consume either a dietary supplement or vitamin-fortified foods.\nChildren are at a higher risk for B12 deficiency due to inadequate dietary intake, as they have fewer vitamin stores and a relatively larger vitamin need per calorie of food intake.\n\n## Increased need\nIncreased needs by the body can occur due to [AIDS](https://bliptext.com/articles/hiv-aids) and [hemolysis](https://bliptext.com/articles/hemolysis) (the breakdown of red blood cells), which stimulates increased red cell production.\n\n# Mechanism\n# [MRI image of the brain in vitamin B12 deficiency, axial view showing the \"precontrast FLAIR image\": note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology. | upload.wikimedia.org/wikipedia/commons/9/9f/CRIM2010-691563.001.jpg]\n\n## Physiology\nThe total amount of vitamin B12 stored in the body is between two and five milligrams in adults.\nApproximately 50% is stored in the [liver](https://bliptext.com/articles/liver), but approximately 0.1% is lost each day, due to secretions into the gut – not all of the vitamin in the gut is reabsorbed.\nWhile [bile](https://bliptext.com/articles/bile) is the main vehicle for B12 excretion, most of this is recycled via [enterohepatic circulation](https://bliptext.com/articles/enterohepatic-circulation).\nDue to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B12 under normal conditions and functioning.\nHowever, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables.\nThe human physiology of active vitamin B12 absorption from food is complex.\nWhen foods containing B12 are eaten, the vitamin is usually bound to protein and is released by [proteases](https://bliptext.com/articles/protease) released by the [pancreas](https://bliptext.com/articles/pancreas) in the [small intestine](https://bliptext.com/articles/small-intestine).\nFollowing its release, most B12 is absorbed in the [ileum](https://bliptext.com/articles/ileum), the last part of the small intestine, after binding to a protein known as [intrinsic factor](https://bliptext.com/articles/intrinsic-factor).\n\n## Pathophysiology\nVitamin B12 deficiency causes particular changes to the metabolism of two clinically relevant substances in humans:\nMethionine is activated to S-adenosyl methionine, which aids in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production and DNA methylation.\n[5-methyl tetrahydrofolate](https://bliptext.com/articles/levomefolic-acid) provides a methyl group, which is released to the reaction with homocysteine, resulting in methionine.\nThis reaction requires cobalamin as a cofactor.\nThe creation of 5-methyl tetrahydrofolate is an irreversible reaction.\nIf B12 is absent, the forward reaction of homocysteine to methionine does not occur, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops.\nBecause B12 and folate are involved in the [metabolism](https://bliptext.com/articles/metabolism) of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency.\nMethylmalonic acid is used as a test of B12 deficiency, but has a low specificity.\n\n## Nervous system\nEarly changes include a spongiform state of neural tissue, along with [edema](https://bliptext.com/articles/edema) of fibers and deficiency of tissue.\nThe [myelin](https://bliptext.com/articles/myelin) decays, along with axial fiber.\nIn later phases, fibric [sclerosis](https://bliptext.com/articles/sclerosis-medicine) of nervous tissues occurs.\nThose changes occur in dorsal parts of the spinal cord and to pyramidal tracts in lateral cords and are called [subacute combined degeneration of spinal cord](https://bliptext.com/articles/subacute-combined-degeneration-of-spinal-cord).\nPathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.\nIn the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of [astrocytes](https://bliptext.com/articles/astrocyte), usually subcortically located, and also round hemorrhages with a torus of glial cells.\nMRI of the brain may show periventricular white matter abnormalities.\nMRI of the spinal cord may show linear hyperintensity in the posterior portion of the cervical tract of the spinal cord, with selective involvement of the posterior columns.\n\n# Diagnosis\nA diagnosis of vitamin B12 deficiency is determined by blood levels lower than 200 or 250 [picograms](https://bliptext.com/articles/orders-of-magnitude-mass) per ml (148 or 185 picomoles per liter).\nMeasurement of blood [methylmalonic acid](https://bliptext.com/articles/methylmalonic-acid) (MMA), a vitamin B12-associated metabolite, is a commonly used [biomarker](https://bliptext.com/articles/biomarker).\nDeficiency is often suspected first, as diagnosis usually requires several tests.\nThere is no gold standard assay to confirm a vitamin B12 deficiency.\nBlood tests may show low levels of vitamin B12, elevated levels of methylmalonic acid or [homocysteine](https://bliptext.com/articles/homocysteine), and a routine complete blood counts may shows [anemia](https://bliptext.com/articles/anemia) with an elevated [mean cell volume](https://bliptext.com/articles/mean-cell-volume).\nThe presence of antibodies to gastric parietal cells and [intrinsic factor](https://bliptext.com/articles/intrinsic-factor) may indicate [pernicious anemia](https://bliptext.com/articles/pernicious-anemia).\nDeficiency can develop without anemia or within normal vitamin B12 levels, leading to a methylmalonic acid or homocysteine assay.\nIn some cases, a [peripheral blood smear](https://bliptext.com/articles/peripheral-blood-smear) may be used; which may allow to show [macrocytes](https://bliptext.com/articles/macrocyte) and hypersegmented [polymorphonuclear leukocytes](https://bliptext.com/articles/polymorphonuclear-leukocyte).\nNeuropsychiatric symptoms can precede hematological signs and are often the presenting manifestation of B12 deficiency.\nAnemia can be prevented or masked by [folic acid](https://bliptext.com/articles/folate) in which activate [tetrahydrofolate](https://bliptext.com/articles/tetrahydrofolic-acid) (THF) needed for [DNA synthesis](https://bliptext.com/articles/dna-synthesis).\nHowever, elevated methylmalonic acid levels may also be related to metabolic disorders such as [methylmalonic acidemia](https://bliptext.com/articles/methylmalonic-acidemia).\nIf elevated methylmalonic acid levels are further accompanied by elevated malonic acid levels, this may be indicative of [combined malonic and methylmalonic aciduria](https://bliptext.com/articles/combined-malonic-and-methylmalonic-aciduria) (CMAMMA).\nIf nervous system damage is present and blood testing is inconclusive, a [lumbar puncture](https://bliptext.com/articles/lumbar-puncture) to measure [cerebrospinal fluid](https://bliptext.com/articles/cerebrospinal-fluid) B-12 levels may be done.\nOn [bone marrow aspiration](https://bliptext.com/articles/bone-marrow-aspiration) or biopsy, [megaloblasts](https://bliptext.com/articles/megaloblasts) are seen.\nThe [Schilling test](https://bliptext.com/articles/schilling-test) was a radio-isotope method, now outdated, of testing for low vitamin B12.\n# [Schematic representation of the propionate metabolic pathway. Methylmalonyl-CoA mutase requires the coenzyme adenosylcobalamin in order to convert L-methylmalonyl-CoA into succinyl-CoA. Otherwise, methylmalonic acid accumulates, which can be a marker for vitamin B12 deficiency, among other things. | upload.wikimedia.org/wikipedia/commons/e/e6/Propionate///pathway.svg]\n\n## Serum levels\nA blood test shows vitamin B12 levels in the blood.\nVitamin B12 deficiency can be determined, but not always.\nThis means it measures forms of vitamin B12 that are \"active\" and can be used by the body, as well as the \"inactive\" forms, which cannot.\nVitamin B12 deficiency can be found within normal levels, so clinical symptoms should be taken into account when a diagnosis is made.\nNormal blood levels are considered to be at least above 300 pg/mL in adults.\nSome researchers have suggested that current standards for vitamin B12 levels are too low.\n\n# Treatment\nTreatment should take into account the cause and severity of the condition.\nTreatment is done by vitamin B12 supplementation, either by mouth or by injection.\nInitially in high daily doses, followed by less frequent lower doses, as the condition improves.\nIf a reversible cause is found, that cause should be corrected if possible.\nIf no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin B12 administration is usually recommended.\nMore serious vitamin B12 deficiency requires injections initially.\nA 2019 study suggested that oral B12 is inferior to B12 injections in severe cases, as \"there is no proof in large prospective, double-blind studies that oral supplementation is as effective in reducing symptoms associated with vitamin B12 deficiency as parenteral treatment.\"\nThere is risk that folic acid administered to those with untreated B12 deficiency may mask anemia without solving the issue at hand in which, if left untreated, can cause lasting serious side effects that affect the nervous system and brain.\nMeasuring vitamin B12 values during or after treatment, in order to measure the effectiveness of treatment, is useless.\n# [Hydroxocobalamin injection is a clear red liquid solution. | upload.wikimedia.org/wikipedia/commons/6/69/Hydroxocobalamin///Injection.jpg]\n\n# Epidemiology\nVitamin B12 deficiency is common and occurs worldwide.\nIn the US and UK, around 6 percent of the general population have the deficiency; in those over the age of sixty, around 20 percent are deficient.\nIn under-developed countries, the rates are even higher: across Latin America 40 percent are deficient; in some parts of Africa, 70 percent; and in some parts of India, 70 to 80 percent.\nAccording to the [World Health Organization](https://bliptext.com/articles/world-health-organization) (WHO), vitamin B12 deficiency may be considered a global public health problem affecting millions of individuals.\nHowever, the incidence and prevalence of vitamin B12 deficiency worldwide is unknown due to the limited population-based data available (see table below).\nDeveloped countries such as the [United States](https://bliptext.com/articles/united-states), [Germany](https://bliptext.com/articles/germany) and the [United Kingdom](https://bliptext.com/articles/united-kingdom) have relatively constant mean vitamin B12 concentrations.\nThe data from the [National Health and Nutrition Examination Survey](https://bliptext.com/articles/national-health-and-nutrition-examination-survey) (NHANES) reported the prevalence of serum vitamin B12 concentrations in the United States population between 1999 and 2002.\nSerum vitamin B12 concentrations of < 148 pmol/L was present in < 1% of children and adolescents.\nIn adults aged 20–39 years, concentrations were below this cut-off in ≤ 3% of individuals.\nIn the elderly (70 years and older), ≈ 6% of persons had a vitamin B12 concentration below the cut-off.\nFurthermore, ≈ 14–16% of adults and > 20% of elderly individuals showed evidence of marginal vitamin B12 depletion (serum vitamin B12: 148–221 pmol/L).\nIn the [United Kingdom](https://bliptext.com/articles/united-kingdom), a National Diet and Nutrition Survey (NDNS) was conducted in adults aged between 19 and 64 years in 2000–2001 and in elderly individuals (≥ 65 years) in 1994–95.\nSix percent of men (n = 632) and 10% of women (n = 667) had low serum vitamin B12 concentrations, defined as < 150 pmol/L.\nIn a subgroup of women of reproductive age (19 to 49 years), 11% had low serum B12 concentrations < 150 pmol/L (n = 476).\nThe prevalence of vitamin B12 deficiency increased substantially in the elderly, where 31% of the elderly had vitamin B12 levels below 130 pmol/L.\nIn the most recent NDNS survey conducted between 2008 and 2011, serum vitamin B12 was measured in 549 adults.\nThe mean serum vitamin B12 concentration for men (19–64 years) was 308 pmol/L, of which 0.9% of men had low serum B12 concentrations < 150 pmol/L.\nIn women aged between 19 and 64 years, the mean serum vitamin B12 concentration was slightly lower than men (298 pmol/L), with 3.3% having low vitamin B12 concentrations < 150 pmol/L.\nIn Germany, a national survey in 1998 was conducted in 1,266 women of childbearing age.\nApproximately, 14.7% of these women had mean serum vitamin B12 concentrations of < 148 pmol/L.\nFew studies have reported vitamin B12 status on a national level in non-Western countries.\nOf these reported studies, vitamin B12 deficiency was prevalent among school-aged children in Venezuela (11.4%), children aged 1–6 years in Mexico (7.7%), women of reproductive age in Vietnam (11.7%), pregnant women in Venezuela (61.34%) and in the elderly population (> 65 years) in New Zealand (12%).\nCurrently, there are no nationally representative surveys for any African or South Asian countries.\nHowever, the very few surveys which have investigated vitamin B12 deficiency in these countries have been based on local or district level data.\nThese surveys have reported a high prevalence of vitamin B12 deficiency (< 150 pmol/L), among 36% of breastfed and 9% of non-breastfed children (n = 2482) in New Delhi and 47% of adults (n = 204) in Pune, Maharashtra, India.\nFurthermore, in Kenya a local district survey in Embu (n = 512) revealed that 40% of school-aged children in Kenya had vitamin B12 deficiency.\nDerived from Table 2 available on\n\n# History\nBetween 1849 and 1887, [Thomas Addison](https://bliptext.com/articles/thomas-addison) described a case of [pernicious anemia](https://bliptext.com/articles/pernicious-anemia), [William Osler](https://bliptext.com/articles/william-osler) and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called \"giant blood corpuscles\" (now called [macrocytes](https://bliptext.com/articles/macrocyte)), [Paul Ehrlich](https://bliptext.com/articles/paul-ehrlich) identified [megaloblasts](https://bliptext.com/articles/megaloblasts) in the bone marrow, and [Ludwig Lichtheim](https://bliptext.com/articles/ludwig-lichtheim) described a case of [myelopathy](https://bliptext.com/articles/myelopathy).\nDuring the 1920s, [George Whipple](https://bliptext.com/articles/george-whipple) discovered that ingesting large amounts of [liver](https://bliptext.com/articles/liver) seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating [liver](https://bliptext.com/articles/liver) might treat pernicious anemia.\n[Edwin Cohn](https://bliptext.com/articles/edwin-cohn) prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products.\n[William Castle](https://bliptext.com/articles/william-bosworth-castle) demonstrated that gastric juice contained an \"intrinsic factor\" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.\nIn 1934, George Whipple shared the 1934 [Nobel Prize in Physiology or Medicine](https://bliptext.com/articles/nobel-prize-in-physiology-or-medicine) with [William P. Murphy](https://bliptext.com/articles/william-p-murphy) and [George Minot](https://bliptext.com/articles/george-minot) for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.\n\n# Other animals\n[Ruminants](https://bliptext.com/articles/ruminants), such as cattle and sheep, absorb B12 synthesized by their [gut bacteria](https://bliptext.com/articles/gut-bacteria).\nSufficient amounts of [cobalt](https://bliptext.com/articles/cobalt) and [copper](https://bliptext.com/articles/copper) need to be consumed for this B12 synthesis to occur.\nIn the early 20th century, during the development for farming of the [North Island Volcanic Plateau](https://bliptext.com/articles/north-island-volcanic-plateau) of New Zealand, cattle had what was termed \"bush sickness\".\nIt was discovered in 1934 that the volcanic soils lacked the cobalt salts essential for synthesis of vitamin B12 by their gut bacteria.\nThe \"[coast disease](https://bliptext.com/articles/coast-disease)\" of sheep in the [coastal sand dunes](https://bliptext.com/articles/limestone-coast) of [South Australia](https://bliptext.com/articles/south-australia) in the 1930s was found to originate in nutritional deficiencies of the [trace elements](https://bliptext.com/articles/trace-element), cobalt and copper.\nThe cobalt deficiency was overcome by the development of \"cobalt bullets\", dense pellets of cobalt oxide mixed with clay given orally, which then was retained in the animal's [rumen](https://bliptext.com/articles/rumen).","current_revision":null,"created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-26T09:55:50.736Z","updated_at":"2025-01-26T09:55:50.736Z","search_vector":"'b12':2 'defici':3 'vitamin':1","search_content":" \n \n**Name:** Vitamin B12 deficiency \n**Synonyms:** Hypocobalaminemia, cobalamin deficiency \n**Field:** [Neurology](https://bliptext.com/articles/neurology), [hematology](https://bliptext.com/articles/hematology) \n**Symptoms:** Decreased ability to think, [feeling tired](https://bliptext.com/articles/fatigue), [depression](https://bliptext.com/articles/depression-mood), irritability, [abnormal sensations](https://bliptext.com/articles/paresthesia), changes in reflexes \n**Complications:** [Megaloblastic anemia](https://bliptext.com/articles/megaloblastic-anemia), irreversible damage to the [brain](https://bliptext.com/articles/brain) and [nervous system](https://bliptext.com/articles/nervous-system) \n**Causes:** Poor absorption, decreased intake, increased requirements \n**Diagnosis:** Blood levels below 148–185 pmol/L (200–250 pg/mL) in adults \n**Prevention:** Supplementation in those at high risk \n**Treatment:** Supplementation by mouth or injection \n**Frequency:** 6% ( 60 years old) \n \n\n# \n**Vitamin B12 deficiency**, also known as **cobalamin deficiency**, is the medical condition in which the blood and tissue have a lower than normal level of [vitamin B12](https://bliptext.com/articles/vitamin-b12).\nSymptoms can vary from none to severe.\nMild deficiency may have few or absent symptoms.\nIn moderate deficiency, [feeling tired](https://bliptext.com/articles/fatigue), [headaches](https://bliptext.com/articles/headache), [soreness of the tongue](https://bliptext.com/articles/glossitis), [mouth ulcers](https://bliptext.com/articles/aphthous-stomatitis), breathlessness, [feeling faint](https://bliptext.com/articles/presyncope), [rapid heartbeat](https://bliptext.com/articles/tachycardia), [low blood pressure](https://bliptext.com/articles/low-blood-pressure), pallor, hair loss, decreased ability to think and severe [joint pain](https://bliptext.com/articles/arthralgia) and the beginning of [neurological](https://bliptext.com/articles/neurological) symptoms, including [abnormal sensations](https://bliptext.com/articles/paresthesia) such as pins and needles, numbness and tinnitus may occur.\nSevere deficiency may include symptoms of [reduced heart function](https://bliptext.com/articles/cardiomyopathy) as well as more severe neurological symptoms, including changes in [reflexes](https://bliptext.com/articles/reflex), poor muscle function, memory problems, [blurred vision](https://bliptext.com/articles/blurred-vision), irritability, [ataxia](https://bliptext.com/articles/ataxia), decreased [smell](https://bliptext.com/articles/anosmia) and [taste](https://bliptext.com/articles/hypogeusia), [decreased level of consciousness](https://bliptext.com/articles/stupor), depression, anxiety, guilt and [psychosis](https://bliptext.com/articles/psychosis).\nIf left untreated, some of these changes can become permanent.\nTemporary [infertility](https://bliptext.com/articles/infertility), reversible with treatment, may occur.\nA late finding type of anemia known as [megaloblastic anemia](https://bliptext.com/articles/megaloblastic-anemia) is often but not always present.\nIn exclusively breastfed infants of [vegan](https://bliptext.com/articles/vegan) mothers, undetected and untreated deficiency can lead to [poor growth](https://bliptext.com/articles/failure-to-thrive), poor development, and [difficulties with movement](https://bliptext.com/articles/movement-disorder).\nCauses are usually related to conditions that give rise to [malabsorption](https://bliptext.com/articles/malabsorption) of vitamin B12 particularly [autoimmune gastritis](https://bliptext.com/articles/atrophic-gastritis) in [pernicious anemia](https://bliptext.com/articles/pernicious-anemia).\nOther conditions giving rise to malabsorption include [surgical removal of the stomach](https://bliptext.com/articles/gastrectomy), chronic [inflammation of the pancreas](https://bliptext.com/articles/pancreatitis), [intestinal parasites](https://bliptext.com/articles/intestinal-parasite), certain medications such as long-term use of [proton pump inhibitors](https://bliptext.com/articles/proton-pump-inhibitors), [H2-receptor blockers](https://bliptext.com/articles/h2-receptor-blocker), and [metformin](https://bliptext.com/articles/metformin), and some [genetic disorders](https://bliptext.com/articles/genetic-disorder).\nDeficiency can also be caused by inadequate dietary intake such as with the diets of [vegetarians](https://bliptext.com/articles/vegetarian), and [vegans](https://bliptext.com/articles/vegan), and in the [malnourished](https://bliptext.com/articles/malnutrition).\nDeficiency may be caused by increased needs of the body for example in those with [HIV/AIDS](https://bliptext.com/articles/hiv-aids), and [shortened red blood cell lifespan](https://bliptext.com/articles/hemolysis).\nDiagnosis is typically based on blood levels of vitamin B12 below 148–185 [pmol/L](https://bliptext.com/articles/orders-of-magnitude-mass) (200 to 250 pg/mL) in adults.\nDiagnosis is not always straightforward as [serum](https://bliptext.com/articles/serum-vitamin-b12) levels can be falsely high or normal.\nElevated [methylmalonic acid](https://bliptext.com/articles/methylmalonic-acid) levels may also indicate a deficiency.\nIndividuals with low or marginal values of vitamin B12 in the range of 148–221 pmol/L (200–300 pg/mL) may not have classic neurological or hematological signs or symptoms.\nTreatment is by vitamin B12 supplementation, either by mouth or by injection.\nInitially in high daily doses, followed by less frequent lower doses, as the condition improves.\nIf a reversible cause is found, that cause should be corrected if possible.\nIf no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin B12 administration is usually recommended.\nA nasal spray is also available.\nVitamin B12 deficiency is preventable with supplements, which are recommended for pregnant vegetarians and vegans, and not harmful in others.\nRisk of toxicity due to vitamin B12 is low.\nVitamin B12 deficiency in the [US](https://bliptext.com/articles/united-states) and the [UK](https://bliptext.com/articles/united-kingdom) is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60.\nIn [Latin America](https://bliptext.com/articles/latin-america), about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of [Africa](https://bliptext.com/articles/africa) and [Asia](https://bliptext.com/articles/asia).\nMarginal deficiency is much more common and may occur in up to 40% of Western populations.\n\n# Signs, symptoms and complications\nVitamin B12 deficiency appears slowly and worsens over time, and can often be confused with other conditions.\nIt may often go unrecognized, as the body becomes used to feeling unwell.\nVitamin B12 deficiency can lead to anemia, neurologic, and digestive dysfunctions.\nA mild deficiency may not cause any discernible symptoms, but at levels moderately lower than normal, a range of symptoms such as [feeling tired](https://bliptext.com/articles/fatigue), weak, lightheadedness, headaches, dizziness, rapid breathing, rapid heartbeat, cold hands and feet, low-grade [fevers](https://bliptext.com/articles/fever), tremor, [cold intolerance](https://bliptext.com/articles/cold-sensitivity), easy bruising and bleeding, [pale skin](https://bliptext.com/articles/pallor), low blood pressure, [sore tongue](https://bliptext.com/articles/glossitis), [upset stomach](https://bliptext.com/articles/dyspepsia), loss of appetite, weight loss, [constipation](https://bliptext.com/articles/constipation), [diarrhea](https://bliptext.com/articles/diarrhea), severe [joint pain](https://bliptext.com/articles/arthralgia), [feeling abnormal sensations](https://bliptext.com/articles/paresthesia) including numbness or tingling (pins and needles) to the fingers and toes, and tinnitus, may be experienced.\nA wide range of associated symptoms may include [angular cheilitis](https://bliptext.com/articles/angular-cheilitis), mouth ulcers, bleeding gums, hair loss and thinning, premature greying, a look of exhaustion and [dark circles around the eyes](https://bliptext.com/articles/periorbital-dark-circles), as well as brittle nails.\nSevere vitamin B12 deficiency can damage nerve cells.\nIf this happens, vitamin B12 deficiency may result in sense loss, loss of sensation in the feet, [difficulty walking](https://bliptext.com/articles/ataxia), poor balance, blurred vision, changes in reflexes, [muscle weakness](https://bliptext.com/articles/muscle-weakness), decreased smell and taste, [decreased level of consciousness](https://bliptext.com/articles/stupor), mood changes, memory loss, depression, irritability, anxiety, clumsiness, disorientation, psychosis and, in severe cases, dementia.\nTissue deficiencies may negatively affect [nerve cells](https://bliptext.com/articles/nerve-cell), [bone marrow](https://bliptext.com/articles/bone-marrow), and the skin.\nA further complication of severe deficiency is the neurological complex known as [subacute combined degeneration of spinal cord](https://bliptext.com/articles/subacute-combined-degeneration-of-spinal-cord).\nalso myelosis funicularis, or funicular myelosis.\nThis complex consists of the following symptoms:\nThe presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B12 deficiency instead of folate deficiency.\nMethylmalonic acid, if not properly handled by B12, remains in the [myelin sheath](https://bliptext.com/articles/myelin-sheath), causing fragility.\nDementia and depression have been associated with this deficiency as well, possibly from the under-production of [methionine](https://bliptext.com/articles/methionine) because of the inability to convert homocysteine into this product.\nMethionine is a necessary cofactor in the production of several [neurotransmitters](https://bliptext.com/articles/neurotransmitters).\nEach of those symptoms can occur either alone or with others.\nVitamin B12 is essential for the development of the brain.\nIts deficiency can cause neurodevelopmental problems which can be partly reversible with early treatment.\nOnly a small subset of dementia cases have been found to be reversible with vitamin B12 therapy.\n[Tinnitus](https://bliptext.com/articles/tinnitus) may be associated with vitamin B12 deficiency.\nVitamin B12 deficiency may accompany certain eating disorders or restrictive diets.\n\n## Pernicious anemia\n[Pernicious anemia](https://bliptext.com/articles/pernicious-anemia) is a disease caused by an [autoimmune response](https://bliptext.com/articles/autoimmune-disease) that produces [antibodies](https://bliptext.com/articles/antibodies) that attack the [parietal cells](https://bliptext.com/articles/parietal-cell) in the [stomach lining](https://bliptext.com/articles/gastric-mucosa), preventing them from creating [intrinsic factor](https://bliptext.com/articles/intrinsic-factor) needed for the absorption of vitamin B12.\nIt is the main and most common cause of vitamin B12 deficiency anemia in developed countries, and is characterized by a [triad of symptoms](https://bliptext.com/articles/list-of-medical-triads-and-pentads):\nIn babies, neurological symptoms can occur from malnutrition or pernicious anemia in the mother.\nThese include poor growth, apathy, having no desire for food, and developmental regression.\nWhile most symptoms resolve with supplementation, some developmental and cognitive problems may persist.\n\n## Metabolic risk in offspring\nVitamin B12 is a critical micronutrient essential for supporting the increasing metabolic demands of the [foetus](https://bliptext.com/articles/fetus) during pregnancy.\nB12 deficiency in pregnant women is increasingly common and has been shown to be associated with major maternal health implications, including increased obesity, higher body mass index (BMI), insulin resistance, gestational diabetes, and type 2 diabetes (T2D) in later life.\nA study in a pregnant white non-diabetic population in England, found that for every 1% increase in BMI, there was 0.6% decrease in circulating B12.\nFurthermore, an animal study in ewes demonstrated that a B12, folate and methionine restricted diet around conception, resulted in offspring with higher adiposity, blood pressure and insulin resistance which could be accounted for by altered DNA methylation patterns.\nBoth vitamin B12 and folate are involved in the one-carbon metabolism cycle.\nIn this cycle, vitamin B12 is a necessary cofactor for methionine synthase, an enzyme involved in the methylation of homocysteine to methionine.\nDNA methylation is involved in the functioning of genes and is an essential epigenetic control mechanism in mammals.\nThis methylation is dependent on methyl donors such as vitamin B12 from the diet.\nVitamin B12 deficiency has the potential to influence methylation patterns in DNA, besides other epigenetic modulators such as micro (RNAs), leading to the altered expression of genes.\nConsequently, an altered gene expression can possibly mediate impaired foetal growth and the programming of non-communicable diseases.\nVitamin B12 and folate status during pregnancy is associated with the increasing risk of low birth weight, preterm birth, insulin resistance and obesity in the offspring.\nIn addition it has been associated with adverse foetal and neonatal outcomes including [neural tube defects](https://bliptext.com/articles/neural-tube-defect) (NTDs) and delayed myelination or demyelination.\nThe mother's B12 status can be important in determining the later health of the child, as shown in the Pune maternal Nutrition Study, conducted in India.\nIn this study, children born to mothers with high folate concentrations and low vitamin B12 concentrations were found to have higher adiposity and insulin resistance at age 6.\nIn the same study, over 60% of pregnant women were deficient in vitamin B12, which was considered to increase the risk of gestational and later diabetes in the mothers.\nIncreased longitudinal cohort studies or randomised controlled trials are required to understand the mechanisms between vitamin B12 and metabolic outcomes, and to potentially offer interventions to improve maternal and offspring health.\n\n## Cardiometabolic disease outcomes\nMultiple studies have explored the association between vitamin B12 and metabolic disease outcomes, such as [obesity](https://bliptext.com/articles/obesity), [insulin resistance](https://bliptext.com/articles/insulin-resistance) and the development of [cardiovascular disease](https://bliptext.com/articles/cardiovascular-disease).\nA long-term study where vitamin B12 was supplemented across a period of 10 years, led to lower levels of weight gain in overweight or obese individuals (p 20% of elderly individuals showed evidence of marginal vitamin B12 depletion (serum vitamin B12: 148–221 pmol/L).\nIn the [United Kingdom](https://bliptext.com/articles/united-kingdom), a National Diet and Nutrition Survey (NDNS) was conducted in adults aged between 19 and 64 years in 2000–2001 and in elderly individuals (≥ 65 years) in 1994–95.\nSix percent of men (n = 632) and 10% of women (n = 667) had low serum vitamin B12 concentrations, defined as 65 years) in New Zealand (12%).\nCurrently, there are no nationally representative surveys for any African or South Asian countries.\nHowever, the very few surveys which have investigated vitamin B12 deficiency in these countries have been based on local or district level data.\nThese surveys have reported a high prevalence of vitamin B12 deficiency (< 150 pmol/L), among 36% of breastfed and 9% of non-breastfed children (n = 2482) in New Delhi and 47% of adults (n = 204) in Pune, Maharashtra, India.\nFurthermore, in Kenya a local district survey in Embu (n = 512) revealed that 40% of school-aged children in Kenya had vitamin B12 deficiency.\nDerived from Table 2 available on\n\n# History\nBetween 1849 and 1887, [Thomas Addison](https://bliptext.com/articles/thomas-addison) described a case of [pernicious anemia](https://bliptext.com/articles/pernicious-anemia), [William Osler](https://bliptext.com/articles/william-osler) and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called \"giant blood corpuscles\" (now called [macrocytes](https://bliptext.com/articles/macrocyte)), [Paul Ehrlich](https://bliptext.com/articles/paul-ehrlich) identified [megaloblasts](https://bliptext.com/articles/megaloblasts) in the bone marrow, and [Ludwig Lichtheim](https://bliptext.com/articles/ludwig-lichtheim) described a case of [myelopathy](https://bliptext.com/articles/myelopathy).\nDuring the 1920s, [George Whipple](https://bliptext.com/articles/george-whipple) discovered that ingesting large amounts of [liver](https://bliptext.com/articles/liver) seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating [liver](https://bliptext.com/articles/liver) might treat pernicious anemia.\n[Edwin Cohn](https://bliptext.com/articles/edwin-cohn) prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products.\n[William Castle](https://bliptext.com/articles/william-bosworth-castle) demonstrated that gastric juice contained an \"intrinsic factor\" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.\nIn 1934, George Whipple shared the 1934 [Nobel Prize in Physiology or Medicine](https://bliptext.com/articles/nobel-prize-in-physiology-or-medicine) with [William P. Murphy](https://bliptext.com/articles/william-p-murphy) and [George Minot](https://bliptext.com/articles/george-minot) for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.\n\n# Other animals\n[Ruminants](https://bliptext.com/articles/ruminants), such as cattle and sheep, absorb B12 synthesized by their [gut bacteria](https://bliptext.com/articles/gut-bacteria).\nSufficient amounts of [cobalt](https://bliptext.com/articles/cobalt) and [copper](https://bliptext.com/articles/copper) need to be consumed for this B12 synthesis to occur.\nIn the early 20th century, during the development for farming of the [North Island Volcanic Plateau](https://bliptext.com/articles/north-island-volcanic-plateau) of New Zealand, cattle had what was termed \"bush sickness\".\nIt was discovered in 1934 that the volcanic soils lacked the cobalt salts essential for synthesis of vitamin B12 by their gut bacteria.\nThe \"[coast disease](https://bliptext.com/articles/coast-disease)\" of sheep in the [coastal sand dunes](https://bliptext.com/articles/limestone-coast) of [South Australia](https://bliptext.com/articles/south-australia) in the 1930s was found to originate in nutritional deficiencies of the [trace elements](https://bliptext.com/articles/trace-element), cobalt and copper.\nThe cobalt deficiency was overcome by the development of \"cobalt bullets\", dense pellets of cobalt oxide mixed with clay given orally, which then was retained in the animal's [rumen](https://bliptext.com/articles/rumen).","revisionCount":0},"hasMore":false,"nextCursor":null}