Vitamin B12 deficiency

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, neurologic, and digestive dysfunctions. A mild deficiency may not cause any discernible symptoms, but moderate deficiency can cause various symptoms, such as feeling tired, lightheadedness, cold intolerance, pale skin, sore tongue, upset stomach, loss of appetite, numbness or tingling (pins and needles) of the fingers and toes, and vision, cognitive or psychological problems. 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. Only a small subset of dementia cases are 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. • 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. B12 deficiency in pregnant women is increasingly common and has been shown to be associated with major maternal health implications, including increased obesity, insulin resistance, 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. 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. preterm birth, 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. 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 12 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. Deficiency of vitamin B12 can impair the remethylation of homocysteine in the methionine cycle, and result in raised homocysteine levels. There 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. In adults with metabolic syndrome, individuals with low levels of vitamin B12 had higher levels of homocysteine compared to healthy subjects. It is thus possible that vitamin B12 deficiency enhances the risk of developing cardiovascular disease in individuals who are obese. It 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. A few studies have also reported no deficiency of vitamin B12 in obese individuals. Finally, a recent literature review conducted over 19 studies, found no evidence of an inverse association between BMI and circulating vitamin B12. Kaya et al., conducted a study in women with polycystic ovary syndrome, and found that obese women with insulin resistance had lower vitamin B12 concentrations compared to those without insulin resistance. Similarly, in a study conducted in European adolescents, there was an association between high adiposity and higher insulin sensitivity with vitamin B12 concentrations. Individuals with a higher fat mass index and higher insulin sensitivity (high Homeostatic Model Assessment [HOMA] index) had lower plasma vitamin B12 concentrations. Furthermore, 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. However, B12 levels of middle aged-women with and without metabolic syndrome showed no difference in vitamin B12 levels between those with insulin resistance (IR) and those without. It 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). Furthermore, 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. However, the review did not identify any associations between vitamin B12 and cardiovascular disease in the remaining four studies. Of 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). Anemia is defined as a condition in which there are not enough red blood cells, as the tissues and organs of the body do not get enough oxygen. Megaloblastic anemia caused by vitamin B12 deficiency is characterized by red blood cells that are larger than normal and are unable to deliver oxygen to the body's organs. Aging In the elderly, vitamin B12 deficiency has been associated with the development of macular degeneration, and the risk of frailty. Macular degeneration is the leading cause of severe, irreversible vision loss in older adults. Several risk factors have been linked to macular degeneration, including family history, genetics, hypercholesterolemia, hypertension, sunlight exposure and lifestyle (smoking and diet). It 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). However, 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. Frailty 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. Frailty is associated with an increased vulnerability to fractures, falls from heights, reduced cognitive function and more frequent hospitalisation. The 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. Poor vitamin B status has been shown to be associated with an increased risk of frailty. Two 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 (MMA) concentrations. Furthermore, another study of elderly women, found that certain genetic variants associated with vitamin B12 status (transcobalamin II) may contribute to reduced energy metabolism, consequently contributing to frailty. Given that there are limited studies assessing the relationship between vitamin B12 and frailty status, more longitudinal studies are needed to clarify the relationship. Neurological decline Severe vitamin B12 deficiency is associated with subacute combined degeneration of the spinal cord, which involves demyelination of the posterior and lateral columns of the spinal cord. Symptoms include memory and cognitive impairment, sensory loss, motor disturbances, personality changes, disorientation, irritability, dementia, loss of posterior column functions and disturbances in proprioception. In 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. Cognitive decline Elderly individuals are currently assessed on vitamin B12 status during the screening process for dementia. Studies investigating the association between vitamin B12 concentrations and cognitive status have produced inconclusive results. It has been shown that elevated MMA concentrations are associated with decreased cognitive decline and Alzheimer's disease. In addition, low vitamin B12 and folate intakes have shown associations with hyperhomocysteinemia, which is associated with cerebrovascular disease, cognitive decline and an increased risk of dementia in prospective studies. There are limited intervention studies which have investigated the effect of supplementation of vitamin B12 and cognitive function. A Cochrane review, analysing two studies, found no effect of vitamin B12 supplementation on the cognitive scores of older adults. A 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 and MMA levels. More intervention studies are needed to determine the modifiable effects of vitamin B12 supplementation on cognition on people who are not deficient. Studies have found a connection between elevated plasma and an increased risk of bone fractures, but is unknown whether this is related to the increased levels of or to vitamin B12 levels (which are involved in homocysteine metabolism). Results from the third NHANES conducted in the United States, found that individuals had significantly lower bone mass density (BMD) and higher osteoporosis rates with each higher quartile of serum MMA (n= 737 men and 813 women). Given that poor bone mineralization has been found in individuals with pernicious anemia, it is possible that vitamin B12 deficiency is causally related to poor bone health. Randomized intervention trials investigating the association of vitamin B12 supplementation and bone health have yielded mixed results. One study conducted on osteoporotic risk patients with hyperhomocysteinemia found positive effects between supplementation of B vitamins on BMD. However, no improvement in BMD was observed in a group of healthy older people. Further, controlled trials are needed to confirm the impact and mechanisms vitamin B12 deficiency has on bone mineralization. ==Causes==

Vitamin B12 deficiency can be caused by impaired absorption, inadequate dietary intake, or increased requirements. PA may be considered as an end stage of autoimmune atrophic gastritis, a disease characterised by stomach atrophy and the presence of antibodies to parietal cells and intrinsic factor. It can also occur following the surgical removal of all or part of the stomach or small intestine; from an inherited disorder or illnesses that damage the stomach lining. Gastric surgeries that involve the removal of all or part of the stomach, such as Roux-en-Y gastric bypass or surgical removal of the small bowel results in short bowel syndrome. • Digestive conditions: conditions that can give rise to impaired absorption of vitamin B12 may include achlorhydria, Crohn's disease, coeliac disease, chronic pancreatitis, and some intestinal parasites. Forms of achlorhydria (including that artificially induced by drugs such as proton pump inhibitors and histamine 2 receptor antagonists) can cause B12 malabsorption from foods, since acid is needed to split B12 from food proteins and salivary binding proteins. This process is thought to be the most common cause of low B12 in the elderly, who often have some degree of achlorhydria without being formally low in intrinsic factor. and diphyllobothriasis caused by parasites can also cause malabsorption. Impaired absorption can also result from blind loop syndrome where an overpopulation of bacteria in the small intestine absorb the vitamin. • Medications: long-term use of certain medications can result in poor absorption of dietary vitamin B12. • A genetic disorder, transcobalamin II deficiency, or Imerslund–Gräsbeck syndrome can be a cause. • Nitrous oxide exposure, and recreational use. Inadequate intake Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. Vegans, 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. Children 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. Increased need Increased needs by the body can occur due to AIDS and hemolysis (the breakdown of red blood cells), which stimulates increased red cell production. ==Mechanism==

": note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology. Physiology The total amount of vitamin B12 stored in the body is between two and five milligrams in adults. Approximately 50% is stored in the liver, but approximately 0.1% is lost each day, due to secretions into the gutnot all of the vitamin in the gut is reabsorbed. While bile is the main vehicle for B12 excretion, most of this is recycled via enterohepatic circulation. Due to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B12 under normal conditions and functioning. However, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables. The human physiology of active vitamin B12 absorption from food is complex. When foods containing B12 are eaten, the vitamin is usually bound to protein and is released by proteases released by the pancreas in the small intestine. Following its release, most B12 is absorbed in the ileum, the last part of the small intestine, after binding to a protein known as intrinsic factor. Pathophysiology Vitamin B12 deficiency causes particular changes to the metabolism of two clinically relevant substances in humans: • Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia • Methylmalonic acid (methylmalonyl-CoA to succinyl-CoA, of which methylmalonyl-CoA is made from methylmalonic acid in a preceding reaction) Methionine is activated to S-adenosyl methionine, which aids in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production and DNA methylation. 5-methyl tetrahydrofolate provides a methyl group, which is released to the reaction with homocysteine, resulting in methionine. This reaction requires cobalamin as a cofactor. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. If B12 is absent, the forward reaction of homocysteine to methionine does not occur, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops. Because B12 and folate are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Methylmalonic acid is used as a test of B12 deficiency, but has a low specificity. Nervous system Early changes include a spongiform state of neural tissue, along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those 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. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, and also round hemorrhages with a torus of glial cells. MRI of the brain may show periventricular white matter abnormalities. MRI 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. ==Diagnosis==

A diagnosis of vitamin B12 deficiency is determined by blood levels lower than 200 or 250 picograms per ml (148 or 185 picomoles per liter). Measurement of blood methylmalonic acid (MMA), a vitamin B12-associated metabolite, is a commonly used biomarker. There is no gold standard assay to confirm a vitamin B12 deficiency. Blood tests may show low levels of vitamin B12, elevated levels of methylmalonic acid or homocysteine, and a routine complete blood counts may shows anemia with an elevated mean cell volume. In some cases, a peripheral blood smear may be used; which may allow to show macrocytes and hypersegmented polymorphonuclear leukocytes. Anemia can be prevented or masked by folic acid in which activate tetrahydrofolate (THF) needed for DNA synthesis. However, elevated methylmalonic acid levels may also be related to metabolic disorders such as methylmalonic acidemia. If elevated methylmalonic acid levels are further accompanied by elevated malonic acid levels, this may be indicative of combined malonic and methylmalonic aciduria (CMAMMA). If nervous system damage is present and blood testing is inconclusive, a lumbar puncture to measure cerebrospinal fluid B-12 levels may be done. On bone marrow aspiration or biopsy, megaloblasts are seen. The Schilling test was a radio-isotope method, now outdated, of testing for low vitamin B12. Serum levels An isolated serum vitamin B12 level has poor sensitivity and specificity for reliably detecting the deficiency; it can be falsely low in some individuals, and falsely normal or high in deficient individuals. Vitamin B12 deficiency can be determined, but not always. The deficiency can develop within normal levels, so clinical symptoms should be taken into account when a diagnosis is made. ==Treatment==

Treatment should take into account the cause and severity of the condition. There 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. Measuring vitamin B12 values during or after treatment, in order to measure the effectiveness of treatment, is useless. ==Epidemiology==

Vitamin B12 deficiency is common and occurs worldwide. In 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. In 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. However, the incidence and prevalence of vitamin B12 deficiency worldwide is unknown due to the limited population-based data available (see table below). Developed countries such as the United States, Germany and the United Kingdom have relatively constant mean vitamin B12 concentrations. The data from the National Health and Nutrition Examination Survey (NHANES) reported the prevalence of serum vitamin B12 concentrations in the United States population between 1999 and 2002. Serum vitamin B12 concentrations of 12 concentration below the cut-off. Furthermore, ≈ 14–16% of adults and > 20% of elderly individuals showed evidence of marginal vitamin B12 depletion (serum vitamin B12: 148–221 pmol/L). and in elderly individuals (≥ 65 years) in 1994–95. Six percent of men (n = 632) and 10% of women (n = 667) had low serum vitamin B12 concentrations, defined as 12 concentrations 12 deficiency increased substantially in the elderly, where 31% of the elderly had vitamin B12 levels below 130 pmol/L. In the most recent NDNS survey conducted between 2008 and 2011, serum vitamin B12 was measured in 549 adults. The 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 12 concentration was slightly lower than men (298 pmol/L), with 3.3% having low vitamin B12 concentrations 12 status on a national level in non-Western countries. Of 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%) Currently, there are no nationally representative surveys for any African or South Asian countries. However, the very few surveys which have investigated vitamin B12 deficiency in these countries have been based on local or district level data. These surveys have reported a high prevalence of vitamin B12 deficiency (12 deficiency. Derived from Table 2 available on ==History==

Between 1849 and 1887, Thomas Addison described a case of pernicious anemia, 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), Paul Ehrlich identified megaloblasts in the bone marrow, and Ludwig Lichtheim described a case of myelopathy. During the 1920s, George Whipple discovered that ingesting large amounts of liver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia. Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products. William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition. ==Other animals==

Ruminants, such as cattle and sheep, absorb B12 synthesized by their gut bacteria. Sufficient amounts of cobalt and copper need to be consumed for this B12 synthesis to occur. In the early 20th century, during the development for farming of the North Island Volcanic Plateau of New Zealand, cattle had what was termed "bush sickness". It was discovered in 1934 that the volcanic soils lacked the cobalt salts essential for synthesis of vitamin B12 by their gut bacteria. == References ==