vitamin b12 deficiency vitamin b12 deficiency 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. symptoms can vary from none to severe. mild deficiency may have few or absent symptoms. in moderate deficiency, feeling tired, anemia, soreness of the tongue, mouth ulcers, breathlessness, feeling faint, rapid heartbeat, low blood pressure, pallor, hair loss, decreased ability to think and severe joint pain and the beginning of neurological symptoms, including abnormal sensations such as pins and needles, numbness and tinnitus may occur. severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, blurred vision, irritability, ataxia, decreased smell and taste, decreased level of consciousness, depression, anxiety, guilt and psychosis. if left untreated, some of these changes can become permanent. temporary infertility reversible with treatment, may occur. in exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement. vitamin b12 deficiencyother nameshypocobalaminemia, cobalamin deficiencyimage 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.specialtyneurology, hematologysymptomsdecreased ability to think, feeling tired, anemia, abnormal sensations, depression, irritability, changes in reflexescomplicationsmegaloblastic anemia, irreversible damage to the brain and nervous systemcausespoor absorption, decreased intake, increased requirementsrisk factorspernicious anemia, genetic disorders, age, vegan diet, atrophic gastritis and some other chronic gastrointestinal diseasesdiagnostic methodblood levels below 148–185 pmol/l (200–250 pg/ml) in adultspreventionsupplementation in those at high risktreatmentsupplementation by mouth or injectionfrequency6% (< 60 years old), 20% (> 60 years old) causes are usually related to conditions that give rise to malabsorption of vitamin b12 particularly autoimmune gastritis in pernicious anemia. other conditions giving rise to malabsorption include surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications such as long-term use of proton pump inhibitors, h2-receptor blockers, and metformin, and some genetic disorders. deficiency can also be caused by inadequate dietary intake such as with the diets of vegetarians, and vegans, and in the malnourished. deficiency may be caused by increased needs of the body for example in those with hiv/aids, and shortened red blood cell lifespan. diagnosis is typically based on blood levels of vitamin b12 below 148–185 pmol/l (200 to 250 pg/ml) in adults. serum may give a false normal or even false high results. elevated methylmalonic acid levels may also indicate a deficiency. a type of anemia known as megaloblastic anemia is often but not always present. individuals 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. treatment is by vitamin b12 supplementation, either by mouth or by injection. initially in high daily doses, followed by less frequent lower doses, as the condition improves. if a reversible cause is found, that cause should be corrected if possible. if no reversible cause is found, or when found it cannot be eliminated, lifelong vitamin b12 administration is usually recommended. a nasal spray is also available. vitamin b12 deficiency is preventable with supplements, which are recommended for pregnant vegetarians and vegans, and not harmful in others. risk of toxicity due to vitamin b12 is low. vitamin b12 deficiency in the us and the uk 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. in latin america, about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of africa and asia. marginal deficiency is much more common and may occur in up to 40% of western populations. signs, symptoms and complications possible oral manifestation of b12 deficiency: erythema and depapillation of the tongue in a patient. from kim et al., 2016. vitamin b12 deficiency appears slowly and worsens over time, and can often be confused with other conditions. it may often go unrecognized, as the body becomes used to feeling unwell. vitamin b12 deficiency can lead to anemia, neurological and digestive disorders. a mild deficiency may not cause any discernible symptoms, but at levels moderately lower than normal, a range of symptoms such as feeling tired, weak, lightheadedness, headaches, dizziness, rapid breathing, rapid heartbeat, cold hands and feet, low-grade fevers, tremor, cold intolerance, easy bruising and bleeding, pale skin, low blood pressure, sore tongue, upset stomach, loss of appetite, weight loss, constipation, diarrhea, severe joint pain, feeling abnormal sensations including numbness or tingling (pins and needles) to the fingers and toes, and tinnitus, may be experienced. a wide range of associated symptoms may include angular cheilitis, mouth ulcers, bleeding gums, hair loss and thinning, premature greying, a look of exhaustion and dark circles around the eyes, as well as brittle nails. severe vitamin b12 deficiency can damage nerve cells. if this happens, vitamin b12 deficiency may result in sense loss, loss of sensation in the feet, difficulty walking, poor balance, blurred vision, changes in reflexes, muscle weakness, decreased smell and taste, decreased level of consciousness, mood changes, memory loss, depression, irritability, anxiety, clumsiness, confusion, psychosis and, in severe cases, dementia. tissue deficiencies may negatively affect nerve cells, bone marrow, and the skin. a further complication of severe deficiency is the neurological complex known as subacute combined degeneration of spinal cord. also myelosis funicularis, or funicular myelosis. this complex consists of the following symptoms: impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias ataxia of dorsal column type decrease or loss of deep muscle-tendon reflexes pathological reflexes – babinski, rossolimo and others, also severe paresis. the 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. methylmalonic acid, if not properly handled by b12, remains in the myelin sheath, causing fragility. dementia and depression have been associated with this deficiency as well, possibly from the under-production of methionine because of the inability to convert homocysteine into this product. methionine is a necessary cofactor in the production of several neurotransmitters. each of those symptoms can occur either alone or with others. vitamin b12 is essential for the development of the brain. its deficiency can cause neurodevelopmental problems which can be partly reversible with early treatment. only a small subset of dementia cases have been found to be reversible with vitamin b12 therapy. tinnitus may be associated with vitamin b12 deficiency. vitamin b12 deficiency may accompany certain eating disorders or restrictive diets. pernicious anemia pernicious anemia is a disease caused by an autoimmune response that produces antibodies that attack the parietal cells in the stomach lining, preventing them from creating intrinsic factor needed for the absorption of vitamin b12. it is the main and most common cause of vitamin b12 deficiency anemia in developed countries, and 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 may be due to defective dna synthesis inhibiting replication in a site with a high turnover of cells. this may also result from the autoimmune attack on parietal cells of the stomach. there is an association with "watermelon stomach" (gave) and pernicious anemia. neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, or seizures. deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements, and hypotonia. in babies, neurological symptoms can occur from malnutrition or pernicious anemia in the mother. these include poor growth, apathy, having no desire for food, and developmental regression. while most symptoms resolve with supplementation, some developmental and cognitive problems may persist. metabolic risk in offspring vitamin b12 is a critical micronutrient essential for supporting the increasing metabolic demands of the foetus during pregnancy. b12 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. a 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. furthermore, 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. both vitamin b12 and folate are involved in the one-carbon metabolism cycle. in this cycle, vitamin b12 is a necessary cofactor for methionine synthase, an enzyme involved in the methylation of homocysteine to methionine. dna methylation is involved in the functioning of genes and is an essential epigenetic control mechanism in mammals. this methylation is dependent on methyl donors such as vitamin b12 from the diet. vitamin 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. consequently, an altered gene expression can possibly mediate impaired foetal growth and the programming of non-communicable diseases. vitamin 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. in addition it has been associated with adverse foetal and neonatal outcomes including neural tube defects (ntds) and delayed myelination or demyelination. the 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. in 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. in 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. increased 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. cardiometabolic disease outcomes multiple studies have explored the association between vitamin b12 and metabolic disease outcomes, such as obesity, insulin resistance and the development of cardiovascular disease. a 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). there are several mechanisms which may explain the relationship between obesity and decreased vitamin b12 status. vitamin b12 is a major dietary methyl donor, involved in the one-carbon cycle of 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. vitamin b12 is also a co-enzyme which converts methylmalonyl- coa to succinyl-coa in the one carbon cycle. if this reaction cannot occur, methylmalonyl- coa levels elevate, inhibiting the rate-limiting enzyme of fatty acid oxidation (cpt1 – carnitine palmitoyl transferase), leading to lipogenesis and insulin resistance. further 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. it 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 density. finally, vitamin b12 is involved in the production of red blood cells, and vitamin b12 deficiency can result in anemia, which causes fatigue and the lack of motivation to exercise. the 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. deficiency of vitamin b12 can impair the remethylation of homocysteine