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 Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

, soreness of the tongue, mouth ulcers, breathlessness, feeling faint,

rapid heartbeat Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

, pallor, hair loss, decreased ability to think and severe

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

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 Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

, decreased smell and

taste The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...

decreased level of consciousness An altered level of consciousness is any measure of arousal other than normal. Level of consciousness (LOC) is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of conscious ...

, depression, anxiety, guilt and

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

. If left untreated, some of these changes can become permanent. Temporary infertility reversible with treatment, may occur. In exclusively breastfed infants of

vegan Veganism is the practice of abstaining from the use of animal product—particularly in diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is known as a vegan. ...

mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement. Causes are usually related to conditions that give rise to

malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...

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 parasite An intestinal parasite infection is a condition in which a parasite infects the gastro-intestinal tract of humans and other animals. Such parasites can live anywhere in the body, but most prefer the intestinal wall. Routes of exposure and inf ...

s, certain medications such as long-term use of

proton pump inhibitors Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

H2-receptor blocker H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of st ...

s, and

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...

, and some

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s. Deficiency can also be caused by inadequate dietary intake such as with the diets of

vegetarian Vegetarianism is the practice of abstaining from the consumption of meat (red meat, poultry, seafood, insects, and the flesh of any other animal). It may also include abstaining from eating all by-products of animal slaughter. Vegetariani ...

s, and

s, and in the

malnourished Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...

. Deficiency may be caused by increased needs of the body for example in those with

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

, and shortened red blood cell lifespan. Diagnosis is typically based on blood levels of vitamin B₁₂ below 150–180 pmol/L (200 to 250 pg/mL) in adults. A false high or normal assay may be observed. Elevated

methylmalonic acid Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a ''C''-methylated derivative of malonate. The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalon ...

levels may also indicate a deficiency. A type of anemia known as

megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synth ...

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 Latin America or * french: Amérique Latine, link=no * ht, Amerik Latin, link=no * pt, América Latina, link=no, name=a, sometimes referred to as LatAm is a large cultural region in the Americas where Romance languages — languages derived f ...

, about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of

Africa Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 6% of Earth's total surface area ...

and

Asia Asia (, ) is one of the world's most notable geographical regions, which is either considered a continent in its own right or a subcontinent of Eurasia, which shares the continental landmass of Afro-Eurasia with Africa. Asia covers an are ...

. Marginal deficiency is much more common and may occur in up to 40% of Western populations.

Signs, symptoms and complications

Image of the tongue in a B12-deficient patient without a history of gastrectomy

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

, 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

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

s, tremor,

cold intolerance Cold sensitivity or cold intolerance is unusual discomfort felt by some people when in a cool environment. There is much variation in the sensitivity to cold experienced by different people, with some putting on many layers of clothing while other ...

, easy bruising and bleeding,

pale skin Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and may also be visible as pallor of the conjunctivae of the eyes o ...

, low blood pressure, sore tongue,

upset stomach Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

, loss of appetite, weight loss,

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

, severe

, 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 Angular cheilitis (AC) is inflammation of one or both corners of the mouth. Often the corners are red with skin breakdown and crusting. It can also be itchy or painful. The condition can last for days to years. Angular cheilitis is a type of ch ...

, 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,

, mood changes, memory loss, depression, irritability, anxiety, clumsiness, confusion, psychosis and, in severe cases, dementia. Tissue deficiencies may negatively affect

nerve cell A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...

s, 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 Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

dorsal column Dorsal (from Latin ''dorsum'' ‘back’) may refer to: * Dorsal (anatomy), an anatomical term of location referring to the back or upper side of an organism or parts of an organism * Dorsal, positioned on top of an aircraft's fuselage * Dorsal c ...

type # Decrease or loss of deep muscle-tendon reflexes # Pathological reflexes Babinski, Rossolimo and others, also severe

paresis In medicine, paresis () is a condition typified by a weakness of voluntary movement, or by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it can also be used to desc ...

. 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 Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

, 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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neurot ...

. 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 Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

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 cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the s ...

s in the stomach lining, preventing them from creating

intrinsic factor Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption ...

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 Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

with bone marrow promegaloblastosis (

). This is due to the inhibition of

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...

(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 Gastric antral vascular ectasia (GAVE) is an uncommon cause of chronic gastrointestinal bleeding or iron deficiency anemia. The condition is associated with dilated small blood vessels in the pyloric antrum, which is a distal part of the stomach. T ...

" ( 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 Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...

, regression,

irritability Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessi ...

, involuntary movements, and

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

. 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 A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

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 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 defect Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...

s (NTDs)Gaber, K.R., et al., Maternal vitamin B₁₂ and the risk of fetal neural tube defects in Egyptian patients. Clin Lab, 2007. 53(1–2): pp. 69–75. 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 Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, 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 Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

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 The carbon cycle is the biogeochemical cycle by which carbon is exchanged among the biosphere, pedosphere, geosphere, hydrosphere, and atmosphere of the Earth. Carbon is the main component of biological compounds as well as a major componen ...

. 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 cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s, 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 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. Alternatively, low levels of vitamin B₁₂ may increase the levels of proinflammatory proteins which may induce ischaemic stroke. 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. More studies are needed to test for the causality of vitamin B₁₂ and obesity using genetic markers. 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. Previous clinical and population-based studies have indicated that vitamin B₁₂ deficiency is prevalent amongst adults with type 2 diabetes. Kaya et al., conducted a study in women with

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

, 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 OMAindex) 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. A recent literature review conducted over seven studies, found that there was limited evidence to show that low vitamin B₁₂ status increased the risk of cardiovascular disease and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

. However, the review did not identify any associations between vitamin B₁₂ and cardiovascular disease in the remaining four studies. Currently, no data supports vitamin B₁₂ supplementation on reducing the risk of cardiovascular disease. In a dose-response meta-analysis of five prospective cohort studies, it was reported that the risk of

coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

(CHD) did not change substantially with increasing dietary vitamin B₁₂ intake. 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

Vitamin B₁₂ deficiency is one of the main causes of

. In countries where B₁₂ deficiency is common, it is generally assumed that there is a greater risk of developing anemia. However, the overall contribution of vitamin B₁₂ deficiency to the global incidence of anemia may not be significant, except in elderly individuals,

vegetarians Vegetarianism is the practice of abstaining from the consumption of meat (red meat, poultry, seafood, insects, and the flesh of any other animal). It may also include abstaining from eating all by-products of animal slaughter. Vegetarianism ma ...

, cases of malabsorption and some genetic disorders. Anemia is defined as a condition in which there are not enough

s, as the tissues and organs of the body do not get enough oxygen.

Megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synth ...

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. The 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. Adult patients often report to medical attention symptoms related to anemia, such as feeling tired and weak, breathlessness,

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...

, feeling faint, headaches, paleness, dry lips and a disturbance of taste. Pernicious 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

. There are relatively few studies which have assessed the impact of haematological measures in response to B₁₂ supplementation. One 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. In deficient Mexican adult women and pre-schoolers, it was found that vitamin B₁₂ supplementation did not affect any haematologic parameters.

Ageing

In the elderly, vitamin B₁₂ deficiency has been associated with the development of

macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

, 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

(MMA) concentrations 39, 140 Furthermore, another study looking at elderly women (n=326), found that certain genetic variants associated with vitamin B₁₂ status (Transcobalamin 2) may contribute to reduced energy metabolism, consequently contributing to frailty. In contrast, a recent study by Dokuzlar et al., found that there was no association between vitamin B₁₂ levels and frailty in the geriatric population (n=335). Given that there are limited studies, which have assessed 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 A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

of the posterior and lateral columns of the spinal cord. Symptoms include memory and cognitive impairment, sensory loss, motor disturbances, 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. Studies 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.

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 Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 μmol/L. As a consequence of the biochemical reactions in which homocysteine is involved ...

, which is associated with

cerebrovascular disease Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. Th ...

, 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 Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profes ...

, 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.

Osteoporosis

There has been growing interest on the effect of low serum vitamin B₁₂ concentrations on bone health. 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, 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. Randomized intervention trials investigating the association of vitamin B₁₂ supplementation and bone health have yielded mixed results. Two studies conducted in osteoporotic risk patients with hyperhomocysteinemia and individuals who had undergone a stroke, 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. Impaired absorption explains most cases of vitamin B₁₂ deficiency, but it can also result from other factors.

Impaired absorption

* Impaired absorption of vitamin B₁₂ leads to pernicious anemia a type of

. Pernicious anemia comes about from the lack of gastric intrinsic factor produced by

s in the

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

, and needed in the

ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...

for the absorption of vitamin B₁₂. Pernicious anemia is the most common cause of vitamin B₁₂ deficiency. Any disruption that leads to the loss of parietal cells can lead to malabsorption, and includes

atrophic gastritis Atrophic gastritis is a process of chronic inflammation of the gastric mucosa of the stomach, leading to a loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. As a result, the stomach's secretion o ...

, a condition that often affects the elderly, and gastric surgeries that involve the removal of all or part of the stomach, such as Roux-en-Y gastric bypass surgery. Surgical removal of the small bowel such as in Crohn's disease results in

short bowel syndrome Short bowel syndrome (SBS, or simply short gut) is a rare malabsorption disorder caused by a lack of functional small intestine. The primary symptom is diarrhea, which can result in dehydration, malnutrition, and weight loss. Other symptoms may in ...

and the inability to absorb vitamin B₁₂. Impaired absorption can also result from blind loop syndrome where an overpopulation of bacteria in the small intestine absorb the vitamin. Some infections such as giardiasis, and

diphyllobothriasis Diphyllobothriasis is the infection caused by tapeworms of the genus ''Diphyllobothrium'' (commonly '' D. latum'' and ''D. nihonkaiense''). Diphyllobothriasis mostly occurs in regions where raw fish is regularly consumed; those who consume raw fi ...

caused by parasites can also cause malabsorption. * Forms of

achlorhydria Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively. It is associated with various other medical problems. Sig ...

(including that artificially induced by drugs such as

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

. This process does not affect absorption of small amounts of B₁₂ in supplements such as multivitamins, since it is not bound to proteins, as is the B₁₂ in foods. * Long-term use of

ranitidine Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome ...

hydrochloride may contribute to deficiency of vitamin B₁₂. * Untreated

celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...

may also cause impaired absorption of this vitamin, probably due to damage to the small bowel mucosa. In some people, vitamin B₁₂ deficiency may persist despite treatment with a

gluten-free diet A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of proteins found in wheat (and all of its species and hybrids, such as spelt, kamut, and triticale), as well as barley, rye, and oats. The incl ...

and require supplementation. * The

medication

may interfere with B₁₂ dietary absorption. * A

, transcobalamin II deficiency can be a cause. *

Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has ...

exposure, and

recreational use Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...

. * Chronic exposure to toxigenic molds and

mycotoxin A mycotoxin (from the Greek μύκης , "fungus" and τοξίνη , "toxin") is a toxic secondary metabolite produced by organisms of kingdom Fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' ...

s found in water damaged buildings. * B₁₂ deficiency caused by Helicobacter pylori was positively correlated with

CagA ''Helicobacter pylori'' virulence factor CagA (cytotoxin-associated gene A) is a 120–145kDa protein encoded on the 40kb ''cag'' pathogenicity island (PAI). ''H. pylori'' strains can be divided into CagA positive or negative strains. Approximately ...

positivity and gastric inflammatory activity, rather than gastric atrophy.

Inadequate intake

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 Hemolysis or haemolysis (), also known by several other names, is the rupturing ( lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo ...

(the breakdown of red blood cells), which stimulates increased red cell production.

Mechanism

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 The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, 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 Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...

. 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 A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the for ...

released by the

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

in the small intestine. Following its release, most B₁₂ is absorbed in the

, the last part of the small intestine, after binding to a protein known as

Pathophysiology

Vitamin B₁₂ deficiency causes particular changes to the metabolism of two clinically relevant substances in humans: #

Homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...

(homocysteine to methionine, catalysed by methionine synthase) leading to

Methylmalonic acid Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a ''C''-methylated derivative of malonate. The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalon ...

(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

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 Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

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

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s, 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 requires further investigation into its cause. There is no gold standard assay to confirm a vitamin B₁₂ deficiency. Serum levels of B₁₂ are often low in vitamin B₁₂ deficiency, but if there are clinical signs that conflict with normal levels of vitamin B₁₂; additional investigations are justified. Deficiency is often suspected first, as diagnosis usually requires several tests. Diagnosis requires serum levels of vitamin B₁₂ in the blood, levels of

and/or

homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...

, and a complete blood count. Occasionally, the blood may be tested for antibodies against

and the

s of the stomach. Blood tests may show low levels of vitamin B₁₂, elevated levels of methylmalonic acid and/or homocysteine, and a routine complete blood counts may shows

with an elevated mean cell volume. The presence of antibodies to gastric parietal cells and IF may be indicative of pernicious anemia (PA). These antibody tests can distinguish between PA and food-B₁₂ malabsorption. Deficiency can develop without anemia or within normal vitamin B₁₂ levels, methylmalonic acid and/or homocysteine assay is required. Higher levels indicate a deficiency, indicators are usually more reliable. In some cases, a

peripheral blood smear A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the ...

may be used; which may allow to show macrocytes and hypersegmented

polymorphonuclear leukocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...

s. 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 Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to prope ...

. If elevated methylmalonic acid levels are further accompanied by elevated malonic acid levels, this may be indicative of

combined malonic and methylmalonic aciduria Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothe ...

(CMAMMA). If nervous system damage is present and blood testing is inconclusive, a lumbar puncture to measure

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

B-₁₂ levels may be done. On bone marrow aspiration or biopsy,

megaloblasts A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of t ...

are seen. The

Schilling test The Schilling test was a medical investigation used for patients with vitamin B (cobalamin) deficiency. The purpose of the test was to determine how well a patient is able to absorb B12 from their intestinal tract. The test is now considered obs ...

was a radio-isotope method, now outdated, of testing for low vitamin B₁₂.

Serum levels

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. The normal serum levels are considered to be between (200–1000 pg/mL) in adults. Vitamin B₁₂ levels in humans that are 400 pg/mL or higher considered as "normal"; less than 400 pg/mL considered as "marginal deficiency"; 200 pg/ml or less considered as "deficiency". Some researchers have suggested that current standards for vitamin B₁₂ levels are too low. a Japanese study showed that the normal limits should be between (500–1300 pg/mL).

Treatment

Treatment should take into account the cause and severity of the condition. The duration and course of treatment may vary. Depending on the cause, treatment may need to be lifelong. 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. More serious vitamin B₁₂ deficiency requires injections initially. When supplements given orally in high doses (1 or 2 mg), absorption is not dependent on

or intact

; instead, 1% to 5% may be absorbed along the entire intestine by passive diffusion. If vitamin B₁₂ deficiency exists with

folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...

, 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 The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...

(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 The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...

and the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

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

, 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) 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 Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...

identified

in the bone marrow, and

Ludwig Lichtheim Ludwig Lichtheim (7 December 1845 in Breslau – 13 January 1928) was a German physician of Jewish descent. Biography He was educated at the gymnasium in Breslau, and studied medicine at the universities of Berlin, Zurich, and Breslau, gr ...

described a case of

myelopathy Myelopathy describes any neurologic deficit related to the spinal cord. The most common form of myelopathy in humans, ''Spinal cord compression, cervical spondylotic myelopathy (CSM)'', also called ''degenerative cervical myelopathy'', results fro ...

. Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel During the 1920s,

George Whipple George Hoyt Whipple (August 28, 1878 – February 1, 1976) was an American physician, pathologist, biomedical researcher, and medical school educator and administrator. Whipple shared the Nobel Prize in Physiology or Medicine in 1934 with George ...

discovered that ingesting large amounts of

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 William Castle (born William Schloss Jr.; April 24, 1914 – May 31, 1977) was an American film director, producer, screenwriter, and actor. Orphaned at 11, Castle dropped out of high school at 15 to work in the theater. He came to the attenti ...

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 The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...

with William P. Murphy and

George Minot George Richards Minot (December 2, 1885 – February 25, 1950) was an American medical researcher who shared the 1934 Nobel Prize with George Hoyt Whipple and William P. Murphy for their pioneering work on pernicious anemia. Early life George R ...

for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B₁₂.

Other animals

Ruminants Ruminants (suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. The ...

, such as cattle and sheep, absorb B₁₂ synthesized by their gut bacteria. Sufficient amounts of

cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...

and

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...

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 The North Island Volcanic Plateau (often called the Central Plateau and occasionally the Waimarino Plateau) is a volcanic plateau covering much of central North Island of New Zealand with volcanoes, lava plateaus, and crater lakes. It contains ...

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. The " coast disease" of sheep in the coastal sand dunes of

South Australia South Australia (commonly abbreviated as SA) is a state in the southern central part of Australia. It covers some of the most arid parts of the country. With a total land area of , it is the fourth-largest of Australia's states and territories ...

in the 1930s was found to originate in nutritional deficiencies of the trace elements, cobalt and copper. The 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 The rumen, also known as a paunch, is the largest stomach compartment in ruminants and the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. The rumen's microbial favoring environment al ...

References

External links

What Is Vitamin B₁₂ Deficiency Anemia?
WebMD overview * Vitamin B₁₂ and Folate a
Lab Tests Online
{{DEFAULTSORT:Vitamin B12 Deficiency Vitamin deficiencies Biology of bipolar disorder Vitamin B12 Wikipedia medicine articles ready to translate Wikipedia emergency medicine articles ready to translate