Vitamin B12 deficiency
Encyclopedia
Vitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12
was discovered from its relationship to the disease pernicious anemia
, which is an autoimmune disease
that destroys parietal cell
s in the stomach that secrete intrinsic factor
. Pernicious anemia, untreated, is usually fatal within three years. Once identified, however, it can be treated successfully and with relative ease (although it cannot be cured and continued treatment is required). Intrinsic factor is crucial for the normal absorption of B12 in amounts that occur in foods, and thus a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B12 deficiency. Pernicious anemia can cause permanent damage to nervous tissue if it has been symptomatic and has gone without treatment for sufficient time. Many other subtler kinds of vitamin B12 deficiency and their biochemical effects have since been elucidated.
One government study suggests that B12 deficiency is much more common to the general public than was previously believed. Vegans, especially, are encouraged to ingest B12 supplements, which are vegan since all commercial B12 is produced directly by bacteria.
The total amount of vitamin B12 stored in the body is about 2–5 mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed. Bile is the main form of B12 excretion; however, most of the B12 secreted in the bile is recycled via enterohepatic circulation. Due to the extremely efficient enterohepatic circulation of B12, the liver can store several years’ worth of vitamin B12. How quickly B12 levels may change when dietary intake is low, depends on the balance between how much B12 is obtained from the diet, how much is secreted, and how much is absorbed. B12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable, or may not appear for decades. In infants and children, B12 deficiency appears much more quickly when the diet becomes vitamin-poor.
Biochemistry: Vitamin B12 deficiency causes particular changes to the metabolism of 2 clinically relevant substances in humans:
Methionine is important when it is activated to S-adenosylmethionine to aid in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production as well as DNA methylation. Folate along with B12 is involved in the first reaction by providing a methyl group to the reaction. 5-methyl tetrahydrofolate is used in the reaction homocysteine to methionine. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. Therefore, if there is no B12 to enable the forward reaction of homocysteine to methionine, the replenishment of tetrahydrofolate cannot occur and the homocysteine to methionine reaction can no longer move forward.
Because B12 and folate (as well as other genetic problems) are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Therefore, the levels of methylmalonic acid are used as a specific test for B12 deficiency.
Pathomorphology: 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 apply to dorsal parts of the spinal cord and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord
.
In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocyte
s, usually subcortically located, and also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.
Clinical symptoms: The main syndrome of vitamin B12 deficiency is Biermer's disease (pernicious anemia
). It is characterized by a triad of symptoms:
Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.
At levels only slightly lower than normal, a range of symptoms such as fatigue, depression
, and poor memory
may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B12 deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression and personality changes.
In general psychiatric symptoms referable to deficiency of B12 are thought to be reversible when vitamin B12 has been repleted. However, mental symptoms which do not reverse may be attributed to other causes, and are difficult to prove were as a direct result of vitamin deficiency.
B12 status may be associated with the onset and cause of Alzheimer's disease
. Some studies have found no relationship, while several recent studies indicate a relationship between B12, homocysteine
, and Alzheimer's. B12 status is routinely measured at the time of Alzheimer's diagnosis, and there is some indication that ongoing measurements may be useful to detect the development of a severe deficiency. In addition to checking serum B12, checking the levels of other compounds (particularly methylmalonic acid
) may be necessary to accurately detect a deficiency state, because serum levels do not necessarily correlate with efficient utilization of B12.
Studies showing a relationship between clinical depression
levels and deficient B12 blood levels in elderly people are documented in the clinical literature.
Bipolar disorder
appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia
.
Science Daily
reported that "a deficiency of B-vitamins may cause vascular
cognitive impairment, according to a new study by the Jean Mayer
USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University
." Aron Troen, PhD, said that: "The vascular changes occurred in the absence of neurotoxic or degenerative changes. Metabolic impairments induced by a diet deficient in three B-vitamins — folate, B12 and B6 — caused cognitive dysfunction and reductions in brain capillary length and density in our mouse model." There is also evidence correlating brain shrinkage with a lack of vitamin B12 in the diets of elderly people.
B12 levels are often low in B12 deficiency, but if other features of B12 deficiency are present with normal B12 then the diagnosis must not be discounted. One possible explanation for normal B12 levels in B12 deficiency is antibody interference in people with high titres of intrinsic factor antibody.
Some researchers propose that the current standard norms of vitamin B12 levels are too low.
In Japan, the lowest acceptable level for vitamin B12 in blood has been raised from about 200 pg/ml (145 pM) to 550 pg/ml (400 pM).
There is confusion in units of B12 deficiency when given by various labs in various countries. Where units are presented as pg/liter, or pg/L, they are likely in error. Where they are presented as pg/mL or pmol/L, they are likely correct. The ranges for these two units are similar, since the molecular weight of B12 is approximately 1000, the difference between mL and L. Thus: 550 pg/mL = 400 pmol/L.
Serum Homocysteine and Methylmalonic acid levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood, see for example research at the St. Louis University. The levels of these substances are high in B12 deficiency and can be helpful if the diagnosis is unclear. Approximately 10% of patients with vitamin B12 levels between 200–400pg/l will have a vitamin B12 deficiency on the basis of elevated levels of homocysteine
and methylmalonic acid
.
Routine monitoring of methylmalonic acid
levels in urine is an option for people who may not be getting enough dietary B12, as a rise in methylmalonic acid
levels may be an early indication of deficiency.
If nervous system damage is suspected, B12 analysis in cerebrospinal fluid
can also be helpful, though such an invasive test would be applicable only after unrevealing blood testing.
The Schilling test
can play a role in the diagnosis.
pill, liquid, or strip; intranasal spray; transdermal
patch or by injection. B12 is available singly or in combination with other supplements. B12 supplements are available in forms including cyanocobalamin
, hydroxocobalamin
, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide"). Oral treatments involve giving 250 µg to 1 mg of B12 daily.
Vitamin B12 can be given as intramuscular or subcutaneous injections of hydroxycobalamin, methylcobalamin, or cyanocobalamin
. Body stores (in the liver) are partly repleted with half a dozen injections in the first couple of weeks (full repletion of liver stores requires about 20 injections) and then maintenance with monthly injections throughout the life of the patient
. Vitamin B12 can also be easily self-administered by injection by the patient, using the same fine-gauge needles and syringes used for self-administration of insulin
.
B12 has traditionally been given parenterally (by injection) to ensure absorption. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B12 are absorbed when large doses are given. This absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose http://www.bloodjournal.org/cgi/content/full/92/4/1191. By contrast, the typical Western diet contains 5–7 µg of B12 (Food and Drug Administration (FDA) Daily Value ). It has been appreciated since the 1960s that B12 deficiency in adults resulting from malabsorption (including loss of intrinsic factor) can be treated with oral B12 supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B12 can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. In two studies, oral treatment with 2 mg per day was as effective as monthly 1 mg injections.
Hypokalemia
, an excessively low potassium
level in the blood
, is anecdotally reported as a complication of vitamin B12 repletion after deficiency. Excessive quantities of potassium
are used by newly growing and dividing hematopoeitic cells, depleting circulating stores of the mineral
.
Recently, claims have been made that other routes of B12 administration, such as intranasal and sublingual routes of administration, are superior to the simple swallowed pill. Although the intranasal route is effective at increasing B12 levels, there have been no direct comparisons to show that they are any more effective than simple swallowed megadose tablets (1 to 2 mg). In particular, the sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary, though there are a number of lozenges, pills, and even a lollipop designed for sublingual absorption. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin, although the study measured only serum levels as opposed to tissue levels, which is more reflective of B12 levels. Sublingual methods of replacement may be effective only because of the typically high doses (500 micrograms), which are swallowed, not because of placement of the tablet. As noted below, such very high doses of oral B12 may be effective as treatments, even if gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).
In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is due to low intakes of animal products, particularly among the poor. The increased bacterial load due to poor sanitation, unprocessed/unsterilized food, or other sources of dietary contamination could also lead to pathogen-related malabsorption issues.
B12 deficiency is even more common in the elderly. This is because B12 absorption decreases greatly in the presence of atrophic gastritis
, which is common in the elderly.
One American study found blood levels below normal in 92 % of vegans, 64 % of lactovegetarians, 47 % of lacto-ovo vegetarians who did not supplement their diet with B12. The study applied the old normal values, so in reality a considerably greater proportion may have been deficient. On the other hand, one must take into account that the study was conducted in 1982 with a group taking no vitamin supplements: today many non-dairy milk, sport, and energy drinks are fortified with vitamin B12. Further the 2000 study did not find a correlation between eating meat and differences in B12 deficiency.
has found that "Large amounts of folic acid
can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency". Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize. To counter the masking effect of B12 deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults." Most importantly, B12 deficiency needs to be treated with B12 repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B12 deficiency.
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
was discovered from its relationship to the disease pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
, which is an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
that destroys parietal cell
Parietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s in the stomach that secrete intrinsic factor
Intrinsic factor
Intrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
. Pernicious anemia, untreated, is usually fatal within three years. Once identified, however, it can be treated successfully and with relative ease (although it cannot be cured and continued treatment is required). Intrinsic factor is crucial for the normal absorption of B12 in amounts that occur in foods, and thus a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B12 deficiency. Pernicious anemia can cause permanent damage to nervous tissue if it has been symptomatic and has gone without treatment for sufficient time. Many other subtler kinds of vitamin B12 deficiency and their biochemical effects have since been elucidated.
One government study suggests that B12 deficiency is much more common to the general public than was previously believed. Vegans, especially, are encouraged to ingest B12 supplements, which are vegan since all commercial B12 is produced directly by bacteria.
The total amount of vitamin B12 stored in the body is about 2–5 mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed. Bile is the main form of B12 excretion; however, most of the B12 secreted in the bile is recycled via enterohepatic circulation. Due to the extremely efficient enterohepatic circulation of B12, the liver can store several years’ worth of vitamin B12. How quickly B12 levels may change when dietary intake is low, depends on the balance between how much B12 is obtained from the diet, how much is secreted, and how much is absorbed. B12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable, or may not appear for decades. In infants and children, B12 deficiency appears much more quickly when the diet becomes vitamin-poor.
Symptoms and Pathomorphology
Vitamin B12 deficiency has the following pathomorphology and symptoms:Biochemistry: Vitamin B12 deficiency causes particular changes to the metabolism of 2 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 preceeding reaction)
Methionine is important when it is activated to S-adenosylmethionine to aid in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production as well as DNA methylation. Folate along with B12 is involved in the first reaction by providing a methyl group to the reaction. 5-methyl tetrahydrofolate is used in the reaction homocysteine to methionine. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. Therefore, if there is no B12 to enable the forward reaction of homocysteine to methionine, the replenishment of tetrahydrofolate cannot occur and the homocysteine to methionine reaction can no longer move forward.
Because B12 and folate (as well as other genetic problems) are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Therefore, the levels of methylmalonic acid are used as a specific test for B12 deficiency.
Pathomorphology: A spongiform state of neural tissue along with edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
of fibers and deficiency of tissue. The myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
decays, along with axial fiber. In later phases, fibric sclerosis
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord
Subacute combined degeneration of spinal cord
Subacute combined degeneration of spinal cord, also known as Lichtheim's disease, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency , vitamin E deficiency or Friedrich's ataxia...
.
In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s, usually subcortically located, and also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.
Clinical symptoms: The main syndrome of vitamin B12 deficiency is Biermer's disease (pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
). It is characterized by a triad of symptoms:
- AnemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
with bone marrow promegaloblastosis (megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
). This is due to the inhibition of DNA synthesis (specifically purines and thymidine) - Gastrointestinal symptoms: These are thought to be due to defective DNA sythesis inhibting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia.
- Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cordSubacute combined degeneration of spinal cordSubacute combined degeneration of spinal cord, also known as Lichtheim's disease, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency , vitamin E deficiency or Friedrich's ataxia...
, or even symptoms of dementia and or other psychiatric symptoms may be present. The presence of peripheral sensorymotor symptoms or subacute combined degeneration of spinal cordSubacute combined degeneration of spinal cordSubacute combined degeneration of spinal cord, also known as Lichtheim's disease, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency , vitamin E deficiency or Friedrich's ataxia...
strongly suggests the presence of a B12 deficiency instead of folate deficiency.
Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:
- Impaired perception of deep touch, pressure and vibration, abolishment of sense of touch, very annoying and persistent paresthesiaParesthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
s - AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
of dorsal cord type - Decrease or abolishment of deep muscle-tendon reflexes
- Pathological reflexes — Babinski, RossolimoRossolimo's signRossolimo's sign is a clinical sign in which percussion of the tips of the toes causes an exaggerated flexion of the toes. It is found in patients with pyramidal tract lesions, and is one of a number of Babinski-like responses....
and others, also severe paresisParesisParesis is a condition typified by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it also can be used to describe the muscles of the eyes , the stomach , and also the vocal cords...
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.
Psychological symptoms and mental disorders
During the course of disease, mental disorders can occur. These include irritability, focus/concentration problems and depressive state with suicidal tendencies.At levels only slightly lower than normal, a range of symptoms such as fatigue, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, and poor memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B12 deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression and personality changes.
In general psychiatric symptoms referable to deficiency of B12 are thought to be reversible when vitamin B12 has been repleted. However, mental symptoms which do not reverse may be attributed to other causes, and are difficult to prove were as a direct result of vitamin deficiency.
Association of low B12 with diseases not classically due to vitamin deficiency
A number of diseases not classically thought to be caused by B12 deficiency are epidemiologically associated with it, raising questions of whether B12 status is an independent risk-factor, or a partial causal agent in these states. None of these causal connections have been proved, and all are under active investigation. These diseases are listed not as symptoms of B12 deficiency, but as investigational candidates where B12 deficiency has been investigated as having a role.B12 status may be associated with the onset and cause of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. Some studies have found no relationship, while several recent studies indicate a relationship between B12, homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
, and Alzheimer's. B12 status is routinely measured at the time of Alzheimer's diagnosis, and there is some indication that ongoing measurements may be useful to detect the development of a severe deficiency. In addition to checking serum B12, checking the levels of other compounds (particularly methylmalonic acid
Methylmalonic acid
Methylmalonic acid 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 methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
) may be necessary to accurately detect a deficiency state, because serum levels do not necessarily correlate with efficient utilization of B12.
Studies showing a relationship between clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
levels and deficient B12 blood levels in elderly people are documented in the clinical literature.
Bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
.
Science Daily
Science Daily
Science Daily is a news website for topical science articles. It features articles on a wide variety of science topics including: astronomy, exoplanets, computer science, nanotechnology, medicine, psychology, sociology, anthropology, biology, geology, climate, space, physics, mathematics,...
reported that "a deficiency of B-vitamins may cause vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
cognitive impairment, according to a new study by the Jean Mayer
Jean Mayer
Jean Mayer was a renowned French-American nutritionist and the tenth president of Tufts University from 1976 to 1992...
USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University
Tufts University
Tufts University is a private research university located in Medford/Somerville, near Boston, Massachusetts. It is organized into ten schools, including two undergraduate programs and eight graduate divisions, on four campuses in Massachusetts and on the eastern border of France...
." Aron Troen, PhD, said that: "The vascular changes occurred in the absence of neurotoxic or degenerative changes. Metabolic impairments induced by a diet deficient in three B-vitamins — folate, B12 and B6 — caused cognitive dysfunction and reductions in brain capillary length and density in our mouse model." There is also evidence correlating brain shrinkage with a lack of vitamin B12 in the diets of elderly people.
Causes
- Inadequate dietary intake of vitamin B12. As the vitamin B12 occurs naturally only in animal products (eggs, meat, milk); a vegan diet can produce a deficiency unless one uses supplements or eats enriched food. Children are at primary risk for dietary deficiency, since they have fewer vitamin stores and a relatively larger vitamin need per calorie of intake.
- Selective impaired absorption of vitamin B12 due to intrinsic factorIntrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
deficiency. This may depend on loss of gastricStomachThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
parietal cells in chronic atrophic gastritisAtrophic gastritisAtrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
(in which case, the resulting megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
takes the name of "pernicious anemiaPernicious anemiaPernicious anemia is one of many types of the larger family of megaloblastic anemias...
"), or may result from wide surgical resection of stomach (for any reason), or from rare hereditary causes of impaired synthesis of intrinsic factor.
- Impaired absorption of vitamin B12 in the setting of a more generalized malabsorptionMalabsorptionMalabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
or maldigestion syndrome. This includes any form of structural damage or wide surgical resection of the terminal ileumIleumThe 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 may be used instead of ileum.The ileum follows the duodenum...
(the principal site of vitamin B12 absorption).
- Forms of achlorhydriaAchlorhydriaAchlorhydria or hypochlorhydria refers to states where the production of gastric acid in the stomach is absent or low, respectively. It is associated with various other medical problems.-Signs and symptoms:...
(including that artificially induced by drugs such as proton pump inhibitors) 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 factorIntrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
. 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.
- Surgical removal of the small bowel (for example in Crohn's diseaseCrohn's diseaseCrohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
) such that the patient presents with short bowel syndromeShort bowel syndromeShort bowel syndrome is a malabsorption disorder caused by the surgical removal of the small intestine, or rarely due to the complete dysfunction of a large segment of bowel. Most cases are acquired, although some children are born with a congenital short bowel...
and is unable to produce vitamin B12. This can be treated with regular injections of vitamin B12.
- Long-term use of RanitidineRanitidineRanitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...
Hydrochloride may contribute to deficiency of vitamin B12
- Coeliac diseaseCoeliac diseaseCoeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
may also cause impaired absorption of this vitamin, but this is due not to loss of intrinsic factor, but damage to the small bowel so that it cannot be absorbed.
- Some bariatric surgical proceduresBariatric surgeryBariatric surgery includes a variety of procedures performed on people who are obese. Weight loss is achieved by reducing the size of the stomach with an implanted medical device or through removal of a portion of the stomach or by resecting and re-routing the small intestines...
, especially those that involve removal of part of the stomach, such as Roux-en-YRoux-en-YRoux-en-Y may refer to:*A type of gastric bypass operation*Roux-en-Y anastomosis...
gastric bypass surgery. (Procedures such as the adjustable gastric bandAdjustable gastric bandA laparoscopic adjustable gastric band, commonly referred to as a lap band, is an inflatable silicone device that is placed around the top portion of the stomach, via laparoscopic surgery, in order to treat obesity...
type do not appear to affect B12 metabolism significantly).
- Chronic intestinal infestation by the fish tapeworm Diphyllobothrium, that competes for vitamin B12, seizing it for its own use and therefore leaving insufficient amount for the host organism. This is mostly confined to ScandinaviaScandinaviaScandinavia is a cultural, historical and ethno-linguistic region in northern Europe that includes the three kingdoms of Denmark, Norway and Sweden, characterized by their common ethno-cultural heritage and language. Modern Norway and Sweden proper are situated on the Scandinavian Peninsula,...
and parts of Eastern EuropeEastern EuropeEastern Europe is the eastern part of Europe. The term has widely disparate geopolitical, geographical, cultural and socioeconomic readings, which makes it highly context-dependent and even volatile, and there are "almost as many definitions of Eastern Europe as there are scholars of the region"...
(for example, in preparers of gefilte fishGefilte fishGefilte fish is a poached fish mince stuffed into the fish skin.More common since the Second World War are the Polish patties similar to quenelles or fish balls made from a mixture of ground deboned fish, mostly carp or pike...
, who would acquire the tapeworm by nibbling bits of fish before it was cooked while making the Eastern European delicacy).
- Bacterial overgrowth in parts of the small bowel are thought to be able to absorb B12. An example occurs in so-called blind loop syndromeBlind loop syndromeBlind loop syndrome, also known as Stagnant loop syndrome, is a medical condition that occurs when the intestine is obstructed, slowing or stopping the progress of digested food, and thus facilitating the growth of bacteria to the point that problems in nutrient absorption occur.-Physiology:The...
. This absorption by a different organism in the bowel before the body can absorb the vitamin somewhat resembles that from fish tapeworm disease.
- The diabetes medication metforminMetforminMetformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
may interfere with B12 dietary absorption.
- Hereditary causes such as severe MTHFR deficiency, homocystinuriaHomocystinuriaHomocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase...
, and transcobalaminTranscobalaminTranscobalamins are carrier proteins which bind cobalamin ....
deficiency.
- Some studies have shown that giardiasisGiardiasisGiardiasis or beaver fever in humans is a diarrheal infection of the small intestine by a single-celled organism Giardia lamblia. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. In the U.S., 20,000 cases are reported to the CDC annually, but the true annual...
, or similar parasite should be considered as a cause of Vitamin B12 deficiency, this a result of the problems caused within the intestinal absorption system.
- Chronic alcohol abuse. However the mild macrocytosisMacrocytosisMacrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume of greater than 100 femtolitres .- Causes :...
of chronic alcoholism is usually not due to vitamin deficiency, but is due to a direct toxic effect of alcohol on red cell formation.
- Nitrous oxideNitrous oxideNitrous oxide, commonly known as laughing gas or sweet air, is a chemical compound with the formula . It is an oxide of nitrogen. At room temperature, it is a colorless non-flammable gas, with a slightly sweet odor and taste. It is used in surgery and dentistry for its anesthetic and analgesic...
abuse
Diagnosis
SerumBlood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
B12 levels are often low in B12 deficiency, but if other features of B12 deficiency are present with normal B12 then the diagnosis must not be discounted. One possible explanation for normal B12 levels in B12 deficiency is antibody interference in people with high titres of intrinsic factor antibody.
Some researchers propose that the current standard norms of vitamin B12 levels are too low.
In Japan, the lowest acceptable level for vitamin B12 in blood has been raised from about 200 pg/ml (145 pM) to 550 pg/ml (400 pM).
There is confusion in units of B12 deficiency when given by various labs in various countries. Where units are presented as pg/liter, or pg/L, they are likely in error. Where they are presented as pg/mL or pmol/L, they are likely correct. The ranges for these two units are similar, since the molecular weight of B12 is approximately 1000, the difference between mL and L. Thus: 550 pg/mL = 400 pmol/L.
Serum Homocysteine and Methylmalonic acid levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood, see for example research at the St. Louis University. The levels of these substances are high in B12 deficiency and can be helpful if the diagnosis is unclear. Approximately 10% of patients with vitamin B12 levels between 200–400pg/l will have a vitamin B12 deficiency on the basis of elevated levels of homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
and methylmalonic acid
Methylmalonic acid
Methylmalonic acid 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 methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
.
Routine monitoring of methylmalonic acid
Methylmalonic acid
Methylmalonic acid 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 methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
levels in urine is an option for people who may not be getting enough dietary B12, as a rise in methylmalonic acid
Methylmalonic acid
Methylmalonic acid 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 methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
levels may be an early indication of deficiency.
If nervous system damage is suspected, B12 analysis in cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
can also be helpful, though such an invasive test would be applicable only after unrevealing blood testing.
The Schilling test
Schilling test
The Schilling test is a medical investigation used for patients with vitamin B deficiency. The purpose of the test is to determine whether the patient has pernicious anemia.It is named for Robert F. Schilling.-Process:The Schilling test has multiple stages...
can play a role in the diagnosis.
Treatment
B12 can be supplemented in healthy subjects by oral pill; sublingualSublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
pill, liquid, or strip; intranasal spray; transdermal
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
patch or by injection. B12 is available singly or in combination with other supplements. B12 supplements are available in forms including cyanocobalamin
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
, hydroxocobalamin
Hydroxocobalamin
Hydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
, methylcobalamin, and adenosylcobalamin (sometimes called "cobamamide" or "dibencozide"). Oral treatments involve giving 250 µg to 1 mg of B12 daily.
Vitamin B12 can be given as intramuscular or subcutaneous injections of hydroxycobalamin, methylcobalamin, or cyanocobalamin
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
. Body stores (in the liver) are partly repleted with half a dozen injections in the first couple of weeks (full repletion of liver stores requires about 20 injections) and then maintenance with monthly injections throughout the life of the patient
Patient
A patient is any recipient of healthcare services. The patient is most often ill or injured and in need of treatment by a physician, advanced practice registered nurse, veterinarian, or other health care provider....
. Vitamin B12 can also be easily self-administered by injection by the patient, using the same fine-gauge needles and syringes used for self-administration of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
.
B12 has traditionally been given parenterally (by injection) to ensure absorption. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B12 are absorbed when large doses are given. This absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose http://www.bloodjournal.org/cgi/content/full/92/4/1191. By contrast, the typical Western diet contains 5–7 µg of B12 (Food and Drug Administration (FDA) Daily Value ). It has been appreciated since the 1960s that B12 deficiency in adults resulting from malabsorption (including loss of intrinsic factor) can be treated with oral B12 supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B12 can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. In two studies, oral treatment with 2 mg per day was as effective as monthly 1 mg injections.
Hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
, an excessively low potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
level in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, is anecdotally reported as a complication of vitamin B12 repletion after deficiency. Excessive quantities of potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
are used by newly growing and dividing hematopoeitic cells, depleting circulating stores of the mineral
Mineral
A mineral is a naturally occurring solid chemical substance formed through biogeochemical processes, having characteristic chemical composition, highly ordered atomic structure, and specific physical properties. By comparison, a rock is an aggregate of minerals and/or mineraloids and does not...
.
Recently, claims have been made that other routes of B12 administration, such as intranasal and sublingual routes of administration, are superior to the simple swallowed pill. Although the intranasal route is effective at increasing B12 levels, there have been no direct comparisons to show that they are any more effective than simple swallowed megadose tablets (1 to 2 mg). In particular, the sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary, though there are a number of lozenges, pills, and even a lollipop designed for sublingual absorption. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin, although the study measured only serum levels as opposed to tissue levels, which is more reflective of B12 levels. Sublingual methods of replacement may be effective only because of the typically high doses (500 micrograms), which are swallowed, not because of placement of the tablet. As noted below, such very high doses of oral B12 may be effective as treatments, even if gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).
Natural food sources of B12
Vitamin B12 can be found in animal products, including fish, meat, poultry, eggs, milk, and milk products and fortified breakfast cereals. However, B12 is first made by yeasts and microorganisms and thus, animal products are not the only reliable source. One half chicken breast, provides some 0.3 µg per serving or 6% of your daily value (DV), 3 ounces of beef, 2.4 µg, or 40% of your DV, one slice of liver 47.9 µg or 780% of your DV, and 3 ounces of molluscs 84.1 µg, or 1,400% of your DV, while one egg provides 0.6 µg or 10% of your DV. Other sources include fortified nutritional yeast, fortified soy milks, and fortified energy bars.Epidemiology
A study in the year 2000 indicates that B12 deficiency is far more widespread than formerly believed. The study found that 39 percent of studied group of 3,000 had low values. This study at Tufts University used the B12 concentration 258 pmol/l (= 350 pg/mL) as a criterion of "low level". However, a recent research has found that B12 deficiency may occur at a much higher B12 concentration (500–600 pg/mL). On this basis Mitsuyama and Kogoh proposed 550 pg/mL, and Tiggelen et al. proposed 600 pg/mL. Against this background, there are reasons to believe that B12 deficiency is present in a far greater proportion of the population than 39% as reported by Tufts University.In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is due to low intakes of animal products, particularly among the poor. The increased bacterial load due to poor sanitation, unprocessed/unsterilized food, or other sources of dietary contamination could also lead to pathogen-related malabsorption issues.
B12 deficiency is even more common in the elderly. This is because B12 absorption decreases greatly in the presence of atrophic gastritis
Atrophic gastritis
Atrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
, which is common in the elderly.
One American study found blood levels below normal in 92 % of vegans, 64 % of lactovegetarians, 47 % of lacto-ovo vegetarians who did not supplement their diet with B12. The study applied the old normal values, so in reality a considerably greater proportion may have been deficient. On the other hand, one must take into account that the study was conducted in 1982 with a group taking no vitamin supplements: today many non-dairy milk, sport, and energy drinks are fortified with vitamin B12. Further the 2000 study did not find a correlation between eating meat and differences in B12 deficiency.
Masking effect of folic acid
The National Institutes of HealthNational Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
has found that "Large amounts of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency". Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize. To counter the masking effect of B12 deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults." Most importantly, B12 deficiency needs to be treated with B12 repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B12 deficiency.
See also
- Megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
- Pernicious anemiaPernicious anemiaPernicious anemia is one of many types of the larger family of megaloblastic anemias...
- Vitamin B12Vitamin B12Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
- CyanocobalaminCyanocobalaminCyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
- HydroxocobalaminHydroxocobalaminHydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
- Methylcobalamin
- Adenosylcobalamin
- List of hematologic conditions
External links
- http://www.webmd.com/a-to-z-guides/vitamin-b12-deficiency-anemia-topic-overview WebMD overview
- http://www.b12deficiency.org b12 deficiency