Vitamin B12 deficiency

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Vitamin B12 deficiency
Classification and external resources

ICD-10 E53.8
ICD-9 266.2
DiseasesDB 13905

Vitamin B12 deficiency or hypocobalaminemia is typically considered in the presence of a low blood level of vitamin B12 however functional B12 deficiency can occur at any serum level.[1] with or without anaemia and/or macrocytosis.[2] The deficiency is common to all age groups and is sometimes diagnosed late due to the lack of a gold standard assay and its complex aetiology. Neuropsychiatric symptoms can precede hematologic signs and are often the presenting manifestation of B12 deficiency.[2][3][4][5] B12 deficiency can cause permanent damage to nervous tissue if left untreated longer than 6 months.[6] B12 assays may be vulnerable to interference resulting in normal values despite severe B12 deficiency.[7] The standard CBLA B12 test Vitamin B12 itself was discovered through investigation of pernicious anemia, which is an autoimmune disease that destroys parietal cells in the stomach that secrete intrinsic factor. Pernicious anemia and b12 deficiency, if left untreated, can be fatal.[8] Once identified, however, the blood level can be raised very easily but the nerve deterioration can continue if the medication is not of the requisite dosage. It cannot be cured and ongoing treatment is required. Humans obtain almost all of their vitamin B12 from dietary means. Pernicious anemia is usually the result of insufficient secretion of intrinsic factor within the stomach.[9] Other more subtle types of vitamin B12 deficiency have been elucidated, including the biochemical effects, over the course of time in significant numbers.

The results of the Framingham Offspring Study indicate that B12 deficiency may be more common than was previously believed. Deficiency is most significantly linked to improper absorption rather than low consumption, as many who consume high amounts of B12 may still experience deficiency.[10]

Storage and levels

The total amount of vitamin B12 stored in the body is between two and five milligrams in adults. Approximately 50% is stored in the liver, but approximately 0.1% is lost each day, due to secretions into the gut — not all of the vitamin in the gut is reabsorbed. While bile is the main vehicle for B12 excretion, most of the B12 secreted in bile is recycled via enterohepatic circulation. Due to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B12 under normal conditions and functioning.[9] However, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables:

Symptoms and pathomorphology

Vitamin B12 deficiency has the following pathomorphology, signs, and symptoms:[11]

Metabolic

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 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, and the replenishment of tetrahydrofolate stops.[12]

Because B12 and folate are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Methylmalonic acid is used as a more specific test of B12 deficiency.

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.[13]

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. Abnormalities might be observed in MRI.[14]

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 synthesis inhibiting 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. There is an association with GAVE syndrome (commonly called watermelon stomach) and pernicious anemia.[15]
  3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures,[16][17][18][19] or even symptoms of dementia and or other psychiatric symptoms may be present. 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, 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 precursor to multiple neurotransmitters.

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, loss of sense of touch, very annoying and persistent paresthesias
  2. Ataxia of dorsal chord type
  3. Decrease or loss of deep muscle-tendon reflexes
  4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

Vitamin B12 deficiency can 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.

Vitamin B12 deficiency symptoms also include shortness of breath and increased pallor.

Psychological symptoms and mental disorders

Vitamin B12 deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression and personality changes.[20][21][20][22][21][23] In infants symptoms include irritability, failure to thrive, apathy, anorexia, and developmental regression.[24][25]

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.

B12 status may be associated with the onset and cause of Alzheimer's disease. Some studies have found no relationship,[26] while several recent studies[27][28][29] 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.[30] 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.

A relationship between clinical depression levels and deficient B12 blood levels in elderly people is documented in the literature.[31][32]

Causes

  • Inadequate dietary intake of vitamin B12. Vitamin B12 occurs in animal products (eggs, meat, milk) and recent research indicates it may also occur in some algae, such as Chlorella[33][34][35] and Susabi-nori (Porphyra yezoensis).[36][37][38] B12 isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement [39] Vegans, and also vegetarians but to a lesser degree, may be at risk for B12 deficiency due to inadequate dietary intake of B12, since they may not be aware of the few non-animal dietary sources of vitamin B12. However, B12 deficiency can occur even in people who consume meat, poultry, and fish intake.[10] 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.
  • Selective impaired absorption of vitamin B12 due to intrinsic factor deficiency. This may be caused by the 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 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.[40] 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.[citation needed]
  • 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 absorb vitamin B12. This can be treated with regular injections of vitamin B12.
  • Long-term use of ranitidine hydrochloride may contribute to deficiency of vitamin B12.[41]
  • Coeliac disease may also cause impaired absorption of this vitamin, though this is due not to loss of intrinsic factor, but rather damage to the small bowel.[citation needed]
  • 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).[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.[citation needed]
  • The diabetes medication metformin may interfere with B12 dietary absorption.[42]
  • Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.[citation needed]
  • Some studies have shown that giardiasis, or similar parasitic infections may be a cause of vitamin B12 deficiency.[43]
  • Malnutrition of alcoholism.
  • Nitrous oxide abuse.[44]

Diagnosis

Serum B12 levels are often low in B12 deficiency, but if other features of B12 deficiency are present with normal B12 then further investigation is warranted. One possible explanation for normal B12 levels in B12 deficiency is antibody interference in people with high titres of intrinsic factor antibody.[45] Some researchers propose that the current standard norms of vitamin B12 levels are too low.[46] 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).[47]

Serum vitamin B12 tests results are in pg/mL (picograms/millilitre) or pmol/L (picomoles/litre). The laboratory reference ranges for these 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.[48] 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/ml 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.[49]

If nervous system damage is suspected, B12 analysis in cerebrospinal fluid is possible, though such an invasive test should be considered only if blood testing is inconclusive.[50]

The Schilling test has been largely supplanted by tests for antiparietal cell and intrinsic factor antibodies.

Treatment

Hydroxocobalamin injection USP (1000 mcg/mL) is a clear red liquid solution of hydoxocobalamin which is available in a 30 mL brown glass multidose vial packaged in a paper box. Shown is 500 mcg B-12 (as 1/2 cc) drawn up in a 1/2 cc U-100 27 gauge x 1/2" insulin syringe, as prepared for subcutaneous injection.

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.[51]

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.[52] By contrast, the typical Western diet contains 5–7 µg of B12 (Food and Drug Administration (FDA) Daily Value[53]). 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.[54][55]

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 hematopoietic cells, depleting circulating stores of the mineral.

Research has established the effectiveness of other routes of B12 administration, primarily intranasal and sublingual dosing, but neither has been proven to be superior to oral dosing; recommendations are based on a consumers individual circumstances.[56] The sublingual route, in which B12 is absorbed under the tongue, is manufactured in a variety of forms, such as lozenges, pills, and lollipops. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin,[57] 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).

Naturally Occurring Sources

Vitamin B12 can be found in large quantities in animal products, including meat, poultry, fish, seafood, eggs, and dairy products; and the consumption of these products is the most longstanding method by which human beings have taken vitamin B12 into their systems. Bioavailability of B12 in eggs is low (<9%) compared to other animal food sources.[58] B12 vitamin levels in different dietary sources are listed by the recommended dietary allowance per 100g serving of a particular food source.[59] Some animal foods that have high vitamin B12 content per 100g serving (% in RDA) are as follows:[60] Mussels 1267% Mackerel 317%, Herring 312%, Salmon 302%, Liverwurst Sausage 224%, Crab 192%, Tuna 181%, Goose Liver 157%, Emu Steak 156%, Bluefish 104%, Beef (lean fat part) 103%, New England Clam Chowder 80%, Lobster 67%, Lamb (shoulder part) 62%, Swiss Cheese 56%, Manhattan Clam Chowder 55%, Chicken eggs 33%.

Fermented foods and unconventional bacterial sources

Since B12 is produced by bacteria, it is possible that it can be obtained in some bacterially fermented foods such as traditional Korean foods. However, this has not yet be rigorously proven.[61][62]

Certain makers of kombucha cultured tea, such as GT's Kombucha, list vitamin B12 as naturally present in their product. One brand purports to contain 20 percent of the Daily Value of B12 in a single bottle,[63] making kombucha a potential "high" food source of B12. Because kombucha is produced by a symbiosis between yeast and bacteria, the possibility that kombucha contains B12 does not contradict current knowledge. But no scientific studies have yet been published confirming the fact, nor whether the B12 in kombucha is the biologically active B12.

A Japanese fermented black tea known as Batabata-cha has been found to contain biologically active B12.[64] Unlike kombucha which is made by fermenting already prepared tea, Batabata-cha is fermented while still in the tea leaf state.

Unconventional natural sources of B12 also exist, but their utility as food sources of B12 are doubtful. For example, plants pulled from the ground and not washed scrupulously may contain remnants of B12 from the bacteria present in the surrounding soil.[65] B12 is also found in lakes if the water has not been sanitized.[66] Certain insects such as termites contain B12 produced by their gut bacteria, in a way analogous to ruminant animals.[67] The human intestinal tract itself may contain B12 producing bacteria in the small intestine,[68] but it is unclear whether sufficient amounts of the vitamin could be produced to meet nutritional needs.

Fortified sources

Foods fortified with B12 are also sources of the vitamin12. The vitamin is added in supplement form, from commercial bacterial production sources, such as cyanocobalamin. Examples of B12-fortified foods include fortified breakfast cereals, fortified soy products, fortified energy bars, and fortified nutritional yeast. The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, deny that non-animal food sources of vitamin B12 are reliable and recommend that every vegan who is not supplementing consume B12-fortified foods.[69][70][71] Not all of these may contain labeled amounts of vitamin activity. Supplemental B12 added to beverages in one study was found to degrade to contain varying levels of pseudovitamin-B12. One report has found B12 analogues present in varying amounts in some multivitamins.[72][73]

Pseudovitamin sources

So-called pseudovitamin-B12 refers to B12-like analogues that are biologically inactive in humans and yet found to be present alongside B12 in humans,[74][75] many food sources (including animals[76]), and possibly supplements and fortified foods.[72][73] In most cyanobacterium, including Spirulina, and some algae, such as dried Asakusa-nori (Porphyra tenera), pseudovitamin-B12 is found to predominate.[77][78]

Controversial sources in algae with some evidence

The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat B12-fortified foods or take a daily or weekly B12 supplement to meet the recommended intake.[70][71][79]

It is important for vegans, who possess limited food sources of B12, and anyone else wishing to obtain B12 from food sources other than animals, to consume foods that contain little or no pseudovitamin-B12 and are high in biologically active B12. However, there have been no significant human trials of sufficient size to demonstrate enzymatic activity of B12 from nonbacterial sources, such as Chlorella and edible sea algae (seaweeds, such as lavers), although chemically some of these sources have been reported to contain B12 that seems chemically identical to active vitamin.[33][34] However, among these sources, only fresh sea algea such as Susabi-nori (Porphyra yezoensis)[36][37] have been reported to demonstrated vitamin B12 activity in B12 deficient rats. This has yet to be demonstrated for Chlorella, and no study in rats of any algal B12 source has yet to be confirmed by a second independent study. The possibility of algae-derived active forms of B12 presently remains an active topic of research, with no results that have yet reached consensus in the nutritional community.

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.[10] This Tufts University study used the B12 concentration 258 pmol/l (= 350 pg/mL) as a criterion of "low level". However, a recent research[80] has found that B12 deficiency may occur at a much higher B12 concentration (500–600 pg/mL). On this basis Mitsuyama and Kogoh[47] proposed 550 pg/mL, and Tiggelen et al.[81] 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 theorized to be due to low intakes of animal products, particularly among the poor.[82]

B12 deficiency is more common in the elderly.[82] This is because B12 absorption decreases greatly in the presence of atrophic gastritis, which is common in the elderly.

A 1982 American study found that among 83 volunteer subjects, 92% of the vegans, 64% of the lactovegetarians, 47% of the lacto-ovovegetarians, and 20% of the semivegetarians had serum B12 levels less than 200 pg/ml. "However," the researchers said, "their complete blood count values did not deviate greatly from those found for nonvegetarians, even though some had been vegans or lactovegetarians for over 10 years. Macrocytosis among the vegetarians was minimal; none had a mean corpuscular volume greater than 103 fl."[83]

The 2000 Tufts University study found no correlation between eating meat and differences in B12 serum levels.[10]

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".[84] 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.[85] 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."[84] 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.[citation needed]

Patient Forums

The Patient Forum of registered UK Charity 1147839, The Pernicious Anaemia Society:[86]

A link mentioned by UK NHS Choices to Health Unlocked "Pernicious Anaemia Forum"[87] (Right-hand column)

See also

References

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  33. ↑ 33.0 33.1 Kittaka-Katsura H, et al. (2002) "Purification and characterization of a corrinoid compound from Chlorella tablets as an algal health food." J Agric Food Chem. 50 (17): 4994-7. PMID 12166996
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Further reading

  • Pacholok, Sally M.; Stuart, Jeffrey J. (2011). Could It Be B12?: An Epidemic of Misdiagnoses. Fresno, CA: Linden Publishing. ISBN 978-1-61035-065-5. 
  • Hooper, M. (2012). Pernicious Anaemia: The Forgotten Disease - the causes and consequences of Vitamin B12 Deficiency. London: Hammersmith Press. ISBN 978-1-78161-004-6. 

External links

Nutrition disorders (E40–E68, 260–269)
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