vitamin b12 cannot be produced by the human body, and must be obtained from the diet. the body normally gets enough vitamin b12 from the consumption of foods with animal sources. inadequate dietary intake of animal products such as eggs, meat, milk, fish, fowl (and some type of edible algae) can result in a deficiency state. 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 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. 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 gut – not 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 further information: vitamin b12 § coenzyme function 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 more specific test of b12 deficiency. 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. deficiency is often suspected first, as diagnosis usually requires several tests. 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. the presence of antibodies to gastric parietal cells and intrinsic factor may indicate pernicious anemia. deficiency can develop without anemia or within normal vitamin b12 levels, leading to a methylmalonic acid or homocysteine assay. in some cases, a peripheral blood smear may be used; which may allow to show macrocytes and hypersegmented polymorphonuclear leukocytes. neuropsychiatric symptoms can precede hematologic signs and are often the presenting manifestation of b12 deficiency. 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 further information: reference ranges for blood tests § vitamins a blood test shows vitamin b12 levels in the blood. vitamin b12 deficiency can be determined, but not always. this 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. vitamin b12 deficiency can be found within normal levels, so clinical symptoms should be taken into account when a diagnosis is made. normal blood levels are considered to be above 250 pg/ml in adults. some researchers have suggested that current standards for vitamin b12 levels are too low. treatment hydroxocobalamin injection is a clear red liquid solution. treatment should take into account the cause and severity of the condition. treatment is done 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. more serious vitamin b12 deficiency requires injections initially. when supplements given orally in high doses (1 or 2 mg), absorption is not dependent on intrinsic factor or intact ileum; instead, 1% to 5% may be absorbed along the entire intestine by passive diffusion. measuring vitamin b12 values during or after treatment, in order to measure the effectiveness of treatment, is useless. if vitamin b12 deficiency exists with folate deficiency, vitamin b12 should be replaced first to prevent subacute combined degeneration of the spinal cord which, if left untreated, can cause lasting serious side effects that affect the nervous system and brain. 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. according to the world health organization (who), vitamin b12 deficiency may be considered a global public health problem affecting millions of individuals. 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 < 148 pmol/l was present in < 1% of children and adolescents. in adults aged 20–39 years, concentrations were below this cut-off in ≤ 3% of individuals. in the elderly (70 years and older), ≈ 6% of persons had a vitamin b12 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). in the 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. six percent of men (n = 632) and 10% of women (n = 667) had low serum vitamin b12 concentrations, defined as < 150 pmol/l. in a subgroup of women of reproductive age (19 to 49 years), 11% had low serum b12 concentrations < 150 pmol/l (n = 476). the prevalence of vitamin b12 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 < 150 pmol/l. in 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. in germany, a national survey in 1998 was conducted in 1,266 women of childbearing age. approximately, 14.7% of these women had mean serum vitamin b12 concentrations of < 148 pmol/l. few studies have reported vitamin b12 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%) and in the elderly population (> 65 years) in new zealand (12%). 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 (< 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. furthermore, in kenya a local district survey in embu (n = 512) revealed that 40% of school-aged children in kenya had vitamin b12 deficiency. table showing worldwide prevalence of vitamin b12 deficiency (serum/plasma b12 < 148 or 150 pmol/l) group number of studies number of participants vitamin b12 deficiency (%) children (< 1y – 18 years) 14 22,331 12.5 pregnant women 11 11,381 27.5 non-pregnant women 16 18,520 16 all adults (under 60 years) 18 81.438 6 elderly (60+ years) 25 30,449 19 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. in 1934, george whipple shared the 1934 nobel prize in physiology or medicine with william p. murphy and george minot for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount