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[[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]].
[[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 are 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 or helpful, 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&nbsp;µg (micrograms) of cobalamin.<ref>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.</ref> Sublingual methods of replacement are 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).
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 are 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&nbsp;µg (micrograms) of cobalamin<ref>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.</ref>, 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===
===Natural food sources of B12===

Revision as of 02:56, 25 April 2010

Vitamin B12 deficiency
SpecialtyEndocrinology Edit this on Wikidata

Vitamin B12 deficiency is a reduction in vitamin B12 from inadequate dietary intake or impaired absorption. The condition is commonly asymptomatic, but can also present as anemia characterized by enlarged blood corpuscles with characteristic changes in neutrophils, known as megaloblastic anemia.

In serious cases deficiency can potentially cause severe and irreversible damage to the nervous system, including subacute combined degeneration of spinal cord.

The anemia is thought to be due to problems in DNA synthesis, specifically in the synthesis of thymine, which is dependent on products of the MTR reaction. Other blood cell types such as white blood cells and platelets are often also low. Bone marrow examination may show megaloblastic hemopoiesis. The anemia responds completely to vitamin B12; the neurological symptoms (if any) respond partly or completely, depending on prior severity and duration.

Presentation

Early and even fairly pronounced deficiency does not always cause distinct or specific symptoms. Common early symptoms are tiredness, a decreased mental work capacity, weakened concentration and memory, and irritability and depression.

Sleep disturbances may occur, because B12 may be involved in the regulation of the sleep wake cycle by the pineal gland (through melatonin).[1]

Neurological signs of B12 deficiency, which can occur with or without anemia, include sensory disturbances (due to damage to peripheral nerves caused by demyelination) and irreversible nerve cell death. Symptoms include numbness and/or tingling of the extremities, altered proprioception, impaired sense of smell, loss of appetite (anorexia), disturbed coordination and, if not treated in time, an ataxic gait especially in the dark when there is less visual reference[2]. In extreme cases, B12 deficiency can lead to a syndrome known as subacute combined degeneration of spinal cord.

B12 deficiency can also cause symptoms of mania, psychosis, fatigue, memory impairment, irritability, depression and personality changes.[2][3][4][5]

B12 status may be associated with the onset and course of Alzheimer's disease. Some studies have found no relationship,[6] while several recent studies[7][8][9] 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.[10] 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.[11][12]

Bipolar disorder appears to genetically co-segregate with the hereditary B12-deficiency disorder pernicious anemia [13][14].

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."[15][16][17][18]

The following symptoms have been recorded, beginning with those perhaps most likely to be indicative of B12 deficiency.

1. Itchy or tingling tongue. The tongue suddenly itches from time to time without warning. This occurs on the edge of the tongue, along one side or the other or at the tip. Some individuals experience stinging, pain, or tingling instead of itching.

2. White spots in the skin, resulting from melanin becoming absent in the area. These often occur on the outside of the forearm, but may occur in other places. The longer these spots are there, the whiter they get. As time goes by, the spots become very dry and flaky to the extent that small raw spots of skin may be exposed.

3. Sharp stabbing, tingling pain in the palm of one or both hands. This occurs suddenly and for no apparent reason in a spot directly below the ring finger, approximately where the first palm crease is. If B12 deficiency is not treated, a tingling pain may begin to occur along the outside edge of the hand, starting from the wrist. This pain occurs when the wrist is extended.

4. Sores at the corners of the mouth, sometimes extending along the edge of the lip. These are raw spots, not blisters, and they tend to come and go.

5. Nerve shock in the side of the body. It can be felt coming on a few seconds before it hits, and then it hits almost like a mild but deep electric shock and quickly subsides. It can occur at the side of either hip or on either side of the upper body, along the ribs. It can occur consecutively in at least two or three locations, one right after the other.

6. Shortness of breath, but without chest pain. This can occur when walking just a few yards.

7. Hemifacial (one side of the face) spasm usually manifesting in the eye. Can occur in multiple spots on the face such as the lip, nose, eyelids, and eyebrow.

8. Facial pain, usually on only one side of the face at a time. This pain varies so much that it would be difficult to describe all the possibilities. This can present as a dull pain in the cheek bone right underneath an eye, or a sharp shooting pain across the forehead, sometimes coming downward from the scalp to the edge of the nose by the eye.

9. Tingling along the back of one or both thighs, starting at the hips and shooting downward.

10. Memory loss and/or disorientation.

11. Migraine headaches. These may be preceded by a temporary blind spot in the center of the field of vision, usually lasting about ten minutes, and sometimes followed by facial pain under the eyes. After the blind spot vanishes, there may be zigzag streaks through the vision that may last up to hours. Even in the same person, there may be extreme variations in the headaches themselves. They may be quite severe with nausea or they may be virtually nonexistent.

Migraines of most individuals have causes other than B12 deficiency, but migraines of certain individuals diminish or stop completely after they are treated for B12 deficiency.

12. Irritability and/or depression and/or personality changes.

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.[19][20]
  • 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]
  • 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.[22]

Incidence/prevalence

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.[23] This study at Tufts University used the B12 concentration 258 pmol/l (= 350 pg/liter) 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/l). On this basis Mitsuyama and Kogoh [24] proposed 550 pg/l, and Tiggelen et al.[25] proposed 600 pg/l. 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, particular among the poor. [26] 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 [26]. 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 B.[27] 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.

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[citation needed]. 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).[24]

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; 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-guage 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 are 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[36], 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.[37] 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 nutritional yeast, fortified soy milks, and fortified energy bars.

References

  1. ^ Hashimoto S, Kohsaka M, Morita N, Fukuda N, Honma S, Honma K (1996). "Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans". Neurosci. Lett. 220 (2): 129–32. doi:10.1016/S0304-3940(96)13247-X. PMID 8981490.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b [1]
  3. ^ 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)
  4. ^ Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I (2001). "Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency". Isr. Med. Assoc. J. 3 (9): 701–3. PMID 11574992.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ [2]
  6. ^ 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)
  7. ^ Siuda J, Gorzkowska A, Patalong-Ogiewa M; et al. (2009). "From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up". Neurologia I Neurochirurgia Polska. 43 (4): 321–9. PMID 19742390. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ Kivipelto M, Annerbo S, Hultdin J; et al. (2009). "Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study". European Journal of Neurology. 16 (7): 808–13. doi:10.1111/j.1468-1331.2009.02590.x. PMID 19453410. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Kageyama M, Hiraoka M, Kagawa Y (2008). "Relationship between genetic polymorphism, serum folate and homocysteine in Alzheimer's disease" ([dead link‍]). Asia-Pacific Journal of Public Health. 20 Suppl: 111–7. PMID 19533869. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Prodan CI, Cowan LD, Stoner JA, Ross ED (2009). "Cumulative incidence of vitamin B12 deficiency in patients with Alzheimer disease". Journal of the Neurological Sciences. 284 (1–2): 144–8. doi:10.1016/j.jns.2009.05.005. PMID 19464701. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP (2000). "Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study". The American Journal of Psychiatry. 157 (5): 715–21. doi:10.1176/appi.ajp.157.5.715. PMID 10784463. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM (2002). "Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study". The American Journal of Psychiatry. 159 (12): 2099–101. doi:10.1176/appi.ajp.159.12.2099. PMID 12450964. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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.
  14. ^ Reading CM (1975). "Latent pernicious anaemia: a preliminary report". Med. J. Aust. 1 (4): 91–4. PMID 1134417.
  15. ^ sciencedaily.com, B-vitamin Deficiency May Cause Vascular Cognitive Impairment
  16. ^ news.bbc.co.uk, Vitamin linked to brain shrinking
  17. ^ nytimes.com, Aging: Lack of B12 Linked to Brain Shrinkage
  18. ^ webmd.com, Vitamin B12 Boasts Brain Benefits Simple Dietary Changes May Help Ward Off Brain Volume Loss in Old Age
  19. ^ "Pernicious Anaemia Society - What is Pernicious Anaemia?". Archived from the original on 2 July 2007. Retrieved 30 July 2007.
  20. ^ Feldman, Elaine B.; Berdanier, Carolyn D.; Dwyer, Johanna T. (2007). Handbook of Nutrition and Food, Second Edition. Boca Raton: CRC. ISBN 0-8493-9218-7.{{cite book}}: CS1 maint: multiple names: authors list (link)[page needed]
  21. ^ 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)
  22. ^ Cordingley FT, Crawford GP (1986). "Giardia infection causes vitamin B12 deficiency". Aust N Z J Med. 16 (1): 78–9. PMID 3458451.
  23. ^ "B12 Deficiency May Be More Widespread Than Thought / August 2, 2000 / News from the USDA Agricultural Research Service". Retrieved 2007-07-01.
  24. ^ 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.
  25. ^ 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)
  26. ^ 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.
  27. ^ 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.
  28. ^ 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)
  29. ^ "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. ^ 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.
  37. ^ Dietary Supplement Fact Sheet: Vitamin B12
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