Vitamin B12 deficiency

Vitamin B12 deficiency
Classification and external resources
Cyanocobalamin
ICD-10	E53.8
ICD-9	266.2
DiseasesDB	13905

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 cells 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.^[1] 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:^[2]

Biochemistry: Vitamin B₁₂ deficiency causes particular changes to the metabolism of 2 clinically relevant substances in humans:

1. Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia;
2. 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.^[3] This is why it is important to know the underlying cause of the megaloblastic anemia, because administration of folate would not improve the anemia in a case of B₁₂ deficiency.

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 astrocytes, 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:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
2. 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.
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, 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 cord 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:

1. Impaired perception of deep touch, pressure and vibration, abolishment of sense of touch, very annoying and persistent paresthesias
2. Ataxia of dorsal cord type
3. Decrease or abolishment of deep muscle-tendon reflexes
4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

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, and poor memory may be experienced.^[4] 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.^{[5][6][5][7][6][8]}

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. Some studies have found no relationship,^[9] while several recent studies^[10][11][12] 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.^[13] 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.^[14][15]

Bipolar disorder appears to genetically co-segregate with the hereditary B₁₂-deficiency disorder pernicious anemia.^[16][17]

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."^[18] There is also evidence correlating brain shrinkage with a lack of vitamin B12 in the diets of elderly people.^[19][20][21]

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.^[22][23] 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 factor deficiency. This may depend on loss of gastric parietal cells in chronic atrophic gastritis (in which case, the resulting megaloblastic anemia takes the name of "pernicious anemia"), 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 malabsorption or maldigestion syndrome. This includes any form of structural damage or wide surgical resection of the terminal ileum (the principal site of vitamin B₁₂ absorption).

• Forms of achlorhydria (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 factor. 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 disease) such that the patient presents with short bowel syndrome and is unable to produce vitamin B₁₂. This can be treated with regular injections of vitamin B₁₂.

• Long-term use of Rantidine Hydrochloride may contribute to deficiency of vitamin B₁₂ ^[24]

• Coeliac disease 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 procedures, especially those that involve removal of part of the stomach, such as Roux-en-Y gastric bypass surgery. (Procedures such as the adjustable gastric band 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 Scandinavia and parts of Eastern Europe (for example, in preparers of gefilte fish, who would acquire the tapeworm by nibbling bits of fish before it was cooked while making the Eastern European delicacy).^{[citation needed]}

• Bacterial overgrowth in parts of the small bowel are thought to be able to absorb B₁₂. An example occurs in so-called blind loop syndrome. 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 metformin may interfere with B₁₂ dietary absorption.^[25]

• Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.

• Some studies have shown that giardiasis, 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.^[26]

• Chronic alcohol abuse. However the mild macrocytosis 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 oxide abuse^[27]

Diagnosis

Serum 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.^[28] Some researchers propose that the current standard norms of vitamin B₁₂ levels are too low.^[29] 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).^[30]

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.^{[citation needed]} 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.^[31] 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.^{[citation needed]}

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.^[32]

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.^[33]

The Schilling test can play a role in the diagnosis.

Treatment

B₁₂ can be supplemented in healthy subjects by oral pill; sublingual 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.^[34]

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 [1]. By contrast, the typical Western diet contains 5–7 µg of B₁₂ (Food and Drug Administration (FDA) Daily Value ^[35]). 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.^[36][37]

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,^[38] 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,^[39] 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.^[40] 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.^{[citation needed]}

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.^[41] 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^{[citation needed]} has found that B₁₂ deficiency may occur at a much higher B₁₂ concentration (500–600 pg/mL). On this basis Mitsuyama and Kogoh ^[30] proposed 550 pg/mL, and Tiggelen et al.^[42] 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.^[43] 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.^[43] 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.^[44] 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.^[41]

Masking effect of folic acid

The National Institutes of Health 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".^[45] 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.^[46] 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."^[45] 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 anemia
• Pernicious anemia
• Vitamin B12
• Cyanocobalamin
• Hydroxocobalamin
• 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

References

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