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[[Vitamin B12|Vitamin B<sub>12</sub>]] 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]]. Before 1920, pernicious anemia was once fatal if untreated. 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 B<sub>12</sub> in amounts that occur in foods, and thus a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B<sub>12</sub> 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 B<sub>12</sub> deficiency and their biochemical effects have since been elucidated.
[[Vitamin B12|Vitamin B<sub>12</sub>]] 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]]. Before 1920, pernicious anemia was fatal if untreated, but the disease is no longer life threatening nowadays with medical advances. Once identified, 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 B<sub>12</sub> in amounts that occur in foods, and thus a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B<sub>12</sub> 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 B<sub>12</sub> deficiency and their biochemical effects have since been elucidated.


One government study suggests that B<sub>12</sub> deficiency is much more common to the general public than was previously believed.<ref>http://www.ars.usda.gov/is/pr/2000/000802.htm</ref> Vegans, especially, are encouraged to ingest B<sub>12</sub> supplements, which are vegan since all commercial B<sub>12</sub> is produced directly by bacteria.
One government study suggests that B<sub>12</sub> deficiency is much more common to the general public than was previously believed.<ref>http://www.ars.usda.gov/is/pr/2000/000802.htm</ref> Vegans, especially, are encouraged to ingest B<sub>12</sub> supplements, which are vegan since all commercial B<sub>12</sub> is produced directly by bacteria.

Revision as of 00:04, 2 August 2011

Vitamin B12 deficiency
SpecialtyEndocrinology Edit this on Wikidata

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. Before 1920, pernicious anemia was fatal if untreated, but the disease is no longer life threatening nowadays with medical advances. Once identified, 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 poor in the vitamin.

Symptoms and pathomorphology

Vitamin B12 deficiency has the following pathomorphology and symptoms:[2]

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)
  2. Gastrointestinal symptoms
  3. Neurological 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:

  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.[3] 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.[4][5][4][6][5][7]

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,[8] while several recent studies[9][10][11] 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.[12] 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.[13][14]

Bipolar disorder appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia.[15][16]

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."[17][18][19][20]

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.[21][22] Children are at primary risk for dietary deficiency, since they have fewer vitamin stores and a relatively larger vitamin need per calorie of intake.
  • 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.
  • 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.
  • 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.
  • 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.[24]
  • 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.

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.[26] Some researchers propose that the current standard norms of vitamin B12 levels are too low.[27] 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).[28]

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.[29] 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.[30]

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.[31]

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.[32]

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 [3]. By contrast, the typical Western diet contains 5–7 µg of B12 (Food and Drug Administration (FDA) Daily Value [33]). 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.[34][35]

Hypokalemia, an excessive 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,[36] 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,[37] 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.[38] 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

Recent research indicates that B12 deficiency is far more widespread than formerly believed. A large study in the US found that 39 percent of studied group of 3,000 had low values.[39] 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 [28] proposed 550 pg/mL, and Tiggelen et al.[40] 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.[41] 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.[41] This is because B12 absorption decreases greatly in the presence of atrophic gastritis, which is common in the elderly.

B12 deficiency is common among vegetarians and vegans who do not take B12 supplements. In vegans the risk is very high because none of their natural food sources contain B12. 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.[42] 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 soy drinks are often fortified with vitamin B12.

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".[43] 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.[44] 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."[43]

See also

References

  1. ^ http://www.ars.usda.gov/is/pr/2000/000802.htm
  2. ^ Anatol Dowżenko Clinical Neurology ISBN 83-200-1197-3, p. 451
  3. ^ Dietary Supplement Fact Sheet: Vitamin B12
  4. ^ a b Sethi NK, Robilotti E, Sadan Y (2005). "Neurological Manifestations Of Vitamin B-12 Deficiency". The Internet Journal of Nutrition and Wellness. 2 (1).{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "ijnwvitaminb12" was defined multiple times with different content (see the help page).
  5. ^ a b Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I (2001). "Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency". Israeli Medical Association Journal. 3: 701–703.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "imajvitaminb12" was defined multiple times with different content (see the help page).
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  8. ^ Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT (2006). "Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease". Journal of Alzheimer's Disease. 9 (4): 435–43. PMID 16917153. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  15. ^ Reading CM. (1979). "X-linked dominant manic-depressive illness: Linkage with Xg blood-group, red-green color-blindness and vitamin-B12 deficiency". Orthomolecular Psychiatry. 8: 68–77.
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  20. ^ webmd.com, Vitamin B12 Boasts Brain Benefits Simple Dietary Changes May Help Ward Off Brain Volume Loss in Old Age
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  23. ^ Ting R, Szeto C, Chan M, Ma K, Chow K (2006). "Risk factors of vitamin B(12) deficiency in patients receiving metformin". Arch Intern Med. 166 (18): 1975–9. doi:10.1001/archinte.166.18.1975. PMID 17030830.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Cordingley FT, Crawford GP (1986). "Giardia infection causes vitamin B12 deficiency". Aust N Z J Med. 16 (1): 78–9. doi:10.1111/j.1445-5994.1986.tb01127.x. PMID 3458451.
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  26. ^ Hamilton MS, Blackmore S, Lee A (2006). "Possible cause of false normal B-12 assays". BMJ. 333 (7569): 654–5. doi:10.1136/bmj.333.7569.654-c. PMC 1570871. PMID 16990334.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Goodman M, Chen XH, Darwish D (1996). "Are US lower normal B 12 limits too low? [Letter]". J Am Geriatr Soc. 44 (10): 1274–5. PMID 8856015.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ a b Mitsuyama Y, Kogoh H (1988). "Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study". Jpn. J. Psychiatry Neurol. 42 (1): 65–71. doi:10.1111/j.1440-1819.1988.tb01957.x. PMID 3398357.
  29. ^ 12 deficiency may be inadequate">"Test used to diagnose B12 deficiency may be inadequate". Retrieved 2007-12-04.
  30. ^ Donaldson MS (2000). "Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements". Ann. Nutr. Metab. 44 (5–6): 229–34. doi:10.1159/000046689. PMID 11146329.
  31. ^ Devalia V (2006). "Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay". Brit J Med. 333 (7564): 385–6. doi:10.1136/bmj.333.7564.385. PMC 1550477. PMID 16916826.
  32. ^ American Hearing Research Foundation Chicago, Illinois 2008
  33. ^ "Dietary Supplement Fact Sheet: Vitamin B12". National Institutes of Health: Office of Dietary Supplements. Retrieved 2006-06-06.
  34. ^ Antoinette M. Kuzminski; et al. (1998). "Effective Treatment of Cobalamin Deficiency With Oral Cobalamin". Blood. 92 (4): 1191–8. PMID 9694707. {{cite journal}}: Explicit use of et al. in: |author= (help)
  35. ^ Butler CC, Vidal-Alaball J, Cannings-John R; et al. (2006). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials". Fam Pract. 23 (3): 279–85. doi:10.1093/fampra/cml008. PMID 16585128. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  36. ^ "Vitamin B12 Deficiency".
  37. ^ Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8. PMID 14616423.
  38. ^ Dietary Supplement Fact Sheet: Vitamin B12
  39. ^ "B12 Deficiency May Be More Widespread Than Thought / August 2, 2000 / News from the USDA Agricultural Research Service". Retrieved 2007-07-01.
  40. ^ VanTiggelen CJM, Peperkamp JPC, TerToolen JFW. (1983). "Vitamin-B12 levels of cerebrospinal fluid in patients with organic mental disorder". Journal of Orthomolecular Psychiatry (12): 305–11.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  41. ^ a b Baik HW, Russell RM (1999). "Vitamin B12 deficiency in the elderly". Annu. Rev. Nutr. 19: 357–77. doi:10.1146/annurev.nutr.19.1.357. PMID 10448529.
  42. ^ Dong A, Scott SC (1982). "Serum vitamin B12 and blood cell values in vegetarians". Ann. Nutr. Metab. 26 (4): 209–16. doi:10.1159/000176565. PMID 6897159.
  43. ^ a b "Dietary Supplement Fact Sheet:Vitamin B12". National Institutes of Health.
  44. ^ Melinda Beck (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal.
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