Vitamin B12 deficiency
Vitamin B12 deficiency is the medical condition of low blood levels of vitamin B12. A wide variety of signs and symptoms may occur including a decreased ability to think and behavioural and emotional changes such as depression, irritability, and psychosis. Abnormal sensations, changes in reflexes, and poor muscle function can also occur as may inflammation of the tongue, decreased taste, low red blood cells, reduced heart function, and decreased fertility. In young children symptoms include poor growth, poor development, and difficulties with movement. Without early treatment some of the changes may be permanent.
|Vitamin B12 deficiency|
|Symptoms||Decreased ability to think, depression, irritability, abnormal sensations, changes in reflexes|
|Causes||Poor absorption, decreased intake, increased requirements|
|Diagnostic method||Blood levels below 120–180 picomol/L (170–250 pg/mL) in adults|
|Prevention||Supplementation in those at high risk|
|Treatment||Supplementation by mouth or injection|
|Frequency||6% (<60 years old), 20% (>60 years old)|
Common causes include poor absorption from the stomach or intestines, decreased intake, and increased requirements. Decreased absorption may be due to pernicious anemia, surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications, and some genetic disorders. Decreased intake may occur in those who eat a vegan diet or are malnourished. Increased requirements occur in HIV/AIDS and in those with rapid red blood cell breakdown. Diagnosis is typically based on vitamin B12 blood levels below 120–180 picomol/L (170–250 pg/mL) in adults. Elevated methylmalonic acid levels (values >0.4 micromol/L) may also indicate a deficiency. A type of low red blood cells known as megaloblastic anemia is often but not always present.
Supplementation is recommended to prevent deficiency in vegetarians who are pregnant. Once identified it is easily treated with supplementation by mouth or injection. Excess vitamin B12 among those who are otherwise healthy is thought to be safe. Some cases may also be helped by treating the underlying cause. Other cases may require ongoing supplementation as the underlying cause is not curable. Vitamin B12 deficiency is common. It is estimated to occur in about 6% of those under the age of 60 and 20% of those over the age of 60. Rates may be as high as 80% in parts of Africa and Asia.
Signs and symptomsEdit
Vitamin B12 deficiency can lead to anemia and neurologic dysfunction. A mild deficiency may not cause any discernible symptoms, but as the deficiency becomes more significant, symptoms of anemia may result, such as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing and pale color to the skin. It may also cause easy bruising or bleeding, including bleeding gums. GI side effects including sore tongue, stomach upset, weight loss, and diarrhea or constipation. If the deficiency is not corrected, nerve cell damage can result. If this happens, vitamin B12 deficiency may result in tingling or numbness to the fingers and toes, difficulty walking, mood changes, depression, memory loss, disorientation and, in severe cases, dementia.
The main syndrome of vitamin B12 deficiency is pernicious anemia. It is characterized by a triad of symptoms:
- Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
- Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. 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.
- Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures, or even symptoms of dementia and or other psychiatric symptoms may be present. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.
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 necessary cofactor in the production of several 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:
- Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
- Ataxia of dorsal chord type
- Decrease or loss of deep muscle-tendon reflexes
- 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 can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression, ataxia, and personality changes. In infants symptoms include irritability, failure to thrive, apathy, anorexia, and developmental regression.
- 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 and Susabi-nori (Porphyra yezoensis). B12 isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement. Vegans, and also vegetarians but to a lesser degree, may be at risk for B12 deficiency due to inadequate dietary intake of B12, if they do not supplement. However, B12 deficiency can occur even in people who consume meat, poultry, and fish. 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. 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 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.
- Untreated celiac disease may also cause impaired absorption of this vitamin, probably due to damage to the small bowel mucosa. In some people, vitamin B12 deficiency may persist despite treatment with a gluten-free diet and require supplementation.
- 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).
- 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.
- The diabetes medication metformin may interfere with B12 dietary absorption.
- Hereditary causes such as severe MTHFR deficiency, homocystinuria, and transcobalamin deficiency.
- Malnutrition of alcoholism.
- Nitrous oxide abuse.
- Infection with the Diphyllobothrium latum tapeworm
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. However, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables.
Vitamin B12 deficiency causes particular changes to the metabolism of 2 clinically relevant substances in humans:
- Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia may lead to varicose veins
- 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.
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.
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. Abnormalities might be observed in MRI.
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. Some researchers propose that the current standard norms of vitamin B12 levels are too low. One Japanese study states the normal limits as 500–1,300 pg/mL. Range of vitamin B12 levels in humans is considered as normal: >300 pg/mL; moderate deficiency: 201–300 pg/mL; and severe deficiency: <201 pg/mL.
Serum vitamin B12 tests results are in pg/mL (picograms/milliliter) or pmol/L (picomoles/liter). 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. The levels of these substances are high in B12 deficiency and can be helpful if the diagnosis is unclear.
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.
Effect of folic acidEdit
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". Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize. To counter the masking effect of B12 deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults." Most importantly, B12 deficiency needs to be treated with B12 repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B12 deficiency.
B12 can be supplemented by pill or injection and appear to be equally effective in those with low levels due to absorption problems.
When large doses are given by mouth its 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. Even pernicious anemia can be treated entirely by the oral route. These supplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystalline B12 is absorbed along the entire intestine by passive diffusion.
Very high doses of B12 over many years has been linked to an increase in lung cancer risk in male smokers.
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.
Ruminants, such as cows and sheep, absorb B12 produced by bacteria in their guts. For gut bacteria of ruminants to produce B12 the animal must consume sufficient amounts of cobalt in order for B12 to be synthesized. In the early 20th century during the development for farming of the North Island Volcanic Plateau of New Zealand, cattle suffered from what was termed "bush sickness". It was discovered that the volcanic soils lacked the cobalt salts essential for the cattle food chain. The "coast disease" of sheep in the Ninety Mile Desert of the Southeast of South Australia in the 1930s was found to originate in nutritional deficiencies of the trace elements, cobalt and copper. The cobalt deficiency was overcome by the development of "cobalt bullets", dense pellets of cobalt oxide mixed with clay given orally for lodging in the animal's rumen.
- Beriberi (caused by Vitamin B1 deficiency)
- Hunt, A; Harrington, D; Robinson, S (4 September 2014). "Vitamin B12 deficiency" (PDF). BMJ. 349: g5226. doi:10.1136/bmj.g5226. PMID 25189324. Archived (PDF) from the original on 12 March 2017.
- "Dietary Supplement Fact Sheet: Vitamin B12 — Health Professional Fact Sheet". National Institutes of Health: Office of Dietary Supplements. 2016-02-11. Archived from the original on 2016-07-27. Retrieved 2016-07-15.
- Vidal-Alaball, J; Butler, CC; Cannings-John, R; Goringe, A; Hood, K; McCaddon, A; McDowell, I; Papaioannou, A (20 July 2005). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency". Cochrane Database of Systematic Reviews (3): CD004655. doi:10.1002/14651858.CD004655.pub2. PMC . PMID 16034940.
- Herrmann, Wolfgang (2011). Vitamins in the prevention of human diseases. Berlin: Walter de Gruyter. p. 245. ISBN 9783110214482. Archived from the original on 2016-03-05.
- Lachner, C; Steinle, NI; Regenold, WT (2012). "The neuropsychiatry of vitamin B12 deficiency in elderly patients". The Journal of Neuropsychiatry and Clinical Neurosciences. 24 (1): 5–15. doi:10.1176/appi.neuropsych.11020052. PMID 22450609.
- Hankey, Graeme J.; Wardlaw, Joanna M. (2008). Clinical neurology. London: Manson. p. 466. ISBN 9781840765182. Archived from the original on 2017-08-30.
- Schwartz, William (2012). The 5-minute pediatric consult (6th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 535. ISBN 9781451116564. Archived from the original on 2017-08-30.
- Reynolds, E.H. (2014). "The neurology of folic acid deficiency". In Biller, José; Ferro, José M. Neurologic aspects of systemic disease. Handbook of Clinical Neurology. 120. pp. 927–43. doi:10.1016/B978-0-7020-4087-0.00061-9. PMID 24365361.
- Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, Adami F (2013). "Cobalamin Deficiency: Clinical Picture and Radiological Findings". Nutrients. 5 (11): 4521–4539. doi:10.3390/nu5114521. ISSN 2072-6643. PMC . PMID 24248213.
- DN Amarapurka MD, ND Patel MD (September 2004). "Gastric Antral Vascular Ectasia (GAVE) Syndrome" (PDF). Journal of The Association of Physcians of India. 52: 757.
- Matsumoto A, Shiga Y, Shimizu H, Kimura I, Hisanaga K (Apr 2009). "[Encephalomyelopathy due to vitamin B12 deficiency with seizures as a predominant symptom]". Rinsho Shinkeigaku. 49 (4): 179–85. doi:10.5692/clinicalneurol.49.179. PMID 19462816.
- Kumar S (Mar 2004). "Recurrent seizures: an unusual manifestation of vitamin B12 deficiency". Neurology India. Neurologyindia.com. 52 (1): 122–123. PMID 15069260. Archived from the original on 2011-01-23.
- Mustafa TAŞKESEN; Ahmet YARAMIŞ; Selahattin KATAR; Ayfer GÖZÜ PİRİNÇÇİOĞLU; Murat SÖKER. "Neurological presentations of nutritional vitamin B12 deficiency in 42 breastfed infants in Southeast Turkey" (PDF). Turkish Journal of Medical Sciences. 41 (6): 1091–1096. Archived (PDF) from the original on 2013-12-14. Retrieved 2013-12-29.
- Yavuz H (Sep 2008). "'Vitamin B12 deficiency and seizures'". Developmental Medicine & Child Neurology (Open access). 50 (9): 720. doi:10.1111/j.1469-8749.2008.03083.x. PMID 18754925. Archived from the original on 2013-12-30.
- Kumar S, Narasimha A, Holla B, Viswanath B, Narayanaswamy JC, Math SB, Chandrashekar CR (2013). "Reversible dementia in young persons due to cobalamin deficiency". The Journal of Neuropsychiatry and Clinical Neurosciences. 25: E62–E63. doi:10.1176/appi.neuropsych.12040083.
- Kliegman, Robert M.; Stanton, Bonita M.D.; Geme, Joseph St.; Schor, Nina F (eds.). Nelson Textbook of Pediatrics (20th ed.). pp. 2319–2326. ISBN 978-1-4557-7566-8.
- Stover, editors, Janos Zempleni, John W. Suttie, Jesse F. Gregory, III, Patrick J. (2014). Handbook of vitamins (Fifth ed.). Hoboken: CRC Press. p. 477. ISBN 9781466515574. Archived from the original on 2016-08-17.
- Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I (Sep 2001). "Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency". The Israel Medical Association Journal. 3 (9): 701–703. PMID 11574992. Archived from the original on 2014-12-04.
- "Pernicious anemia: MedlinePlus Medical Encyclopedia". National Institutes of Health: National Library of Medicine. Archived from the original on 2016-03-11. Retrieved 2013-12-29.
- Dror DK, Allen LH (May 2008). "Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms". Nutrition Reviews. 66 (5): 250–5. doi:10.1111/j.1753-4887.2008.00031.x. PMID 18454811. Archived from the original on 2008-11-18.
- Black MM (Jun 2008). "Effects of vitamin B12 and folate deficiency on brain development in children". Food and Nutrition Bulletin. 29 (2 Suppl): S126–31. PMC . PMID 18709887.
- Kittaka-Katsura H, Fujita T, Watanabe F, Nakano Y (Aug 2002). "Purification and characterization of a corrinoid compound from Chlorella tablets as an algal health food". Journal of Agricultural and Food Chemistry. 50 (17): 4994–7. doi:10.1021/jf020345w. PMID 12166996.
- Watanabe F, Takenaka S, Kittaka-Katsura H, Ebara S, Miyamoto E (Oct 2002). "Characterization and bioavailability of vitamin B12-compounds from edible algae". Journal of Nutritional Science and Vitaminology. 48 (5): 325–31. doi:10.3177/jnsv.48.325. PMID 12656203.
- Nakano S, Takekoshi H, Nakano M (Mar 2010). "Chlorella pyrenoidosa supplementation reduces the risk of anemia, proteinuria and edema in pregnant women". Plant Foods for Human Nutrition. 65 (1): 25–30. doi:10.1007/s11130-009-0145-9. PMID 20013055.
- Watanabe F, Takenaka S, Katsura H, Miyamoto E, Abe K, Tamura Y, Nakatsuka T, Nakano Y (Dec 2000). "Characterization of a vitamin B12 compound in the edible purple laver, Porphyra yezoensis". Bioscience, Biotechnology, and Biochemistry. 64 (12): 2712–5. doi:10.1271/bbb.64.2712. PMID 11210144.
- Croft MT, Lawrence AD, Raux-Deery E, Warren MJ, Smith AG (Nov 2005). "Algae acquire vitamin B12 through a symbiotic relationship with bacteria". Nature. 438 (7064): 90–3. doi:10.1038/nature04056. PMID 16267554.
- Martens JH, Barg H, Warren MJ, Jahn D (Mar 2002). "Microbial production of vitamin B12". Applied Microbiology and Biotechnology. 58 (3): 275–85. doi:10.1007/s00253-001-0902-7. PMID 11935176.
- McBride, Judy (2 August 2000). "B12 Deficiency May Be More Widespread Than Thought". Agricultural Research Service. United States Department of Agriculture. Archived from the original on 20 June 2012. Retrieved 2 July 2012.
- Lam JR, Schneider JL, Zhao W, Corley DA (Dec 2013). "Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency". JAMA: The Journal of the American Medical Association. 310 (22): 2435–2442. doi:10.1001/jama.2013.280490. PMID 24327038.
- Baik, H.W.; Russell, R.M. (1999). "Vitamin B12 deficiency in the elderly". Annual Review of Nutrition. 19: 357–377. doi:10.1146/annurev.nutr.19.1.357. PMID 10448529.
- Yeomans ND, Hanson RG, Smallwood RA, Mihaly GW, Louis WJ (1982). "Effect of chronic ranitidine treatment on secretion of intrinsic factor". British Medical Journal (Clinical research ed.). 285 (6337): 264. doi:10.1136/bmj.285.6337.264. PMC . PMID 6124297.
- Caruso R, Pallone F, Stasi E, Romeo S, Monteleone G (2013). "Appropriate nutrient supplementation in celiac disease". Annals of Medicine (Review). 45 (8): 522–31. doi:10.3109/07853890.2013.849383. PMID 24195595.
- Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM (Oct 2006). "Risk factors of vitamin B(12) deficiency in patients receiving metformin". Archives of Internal Medicine. 166 (18): 1975–9. doi:10.1001/archinte.166.18.1975. PMID 17030830.
- Kondo H, Osborne ML, Kolhouse JF, Binder MJ, Podell ER, Utley CS, Abrams RS, Allen RH (May 1981). "Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats". Journal of Clinical Investigation. The American Society For Clinical Investigation. 67 (5): 1270–1283. doi:10.1172/JCI110155. PMC . PMID 6112240.
- Voet, Donald, Voet, Judith G. (2010). Biochemistry. New York: J. Wiley & Sons. p. 957. ISBN 978-0470-57095-1.
- Yamada K (2013). "Chapter 9. Cobalt: Its Role in Health and Disease". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. 13. Springer. pp. 295–320. doi:10.1007/978-94-007-7500-8_9.
- Shane B, Stokstad EL (1985). "Vitamin B12-folate interrelationships". Annual Review of Nutrition. 5: 115–41. doi:10.1146/annurev.nu.05.070185.000555. PMID 3927946.
- "Vitamin B12 / Pathophysiology Text". LifeSave.org. p. 215. Archived from the original on 2013-02-06. Retrieved 2013-12-31.
- Guez S, Chiarelli G, Menni F, Salera S, Principi N, Esposito S (2012). "Severe vitamin B12 deficiency in an exclusively breastfed 5-month-old Italian infant born to a mother receiving multivitamin supplementation during pregnancy". BMC Pediatrics (Full text). Biomedcentral.com. 12: 85. doi:10.1186/1471-2431-12-85. PMC . PMID 22726312. Archived from the original on 2014-01-01.
- Hamilton MS, Blackmore S, Lee A (Sep 2006). "Possible cause of false normal B-12 assays". BMJ. 333 (7569): 654–5. doi:10.1136/bmj.333.7569.654-c. PMC . PMID 16990334.
- Goodman M, Chen XH, Darwish D (Oct 1996). "Are U.S. lower normal B12 limits too low?". Journal of the American Geriatrics Society. 44 (10): 1274–5. doi:10.1111/j.1532-5415.1996.tb01389.x. PMID 8856015.
- Mitsuyama Y, Kogoh H (Mar 1988). "Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study". The Japanese Journal of Psychiatry and Neurology. 42 (1): 65–71. doi:10.1111/j.1440-1819.1988.tb01957.x. PMID 3398357.
- Solomon LR (2015). "Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing". Blood. 105 (3): 978–85. doi:10.1182/blood-2004-04-1641. PMID 15466926.
- "Test used to diagnose B12 deficiency may be inadequate". news-medical.net. October 28, 2004. Archived from the original on September 29, 2007. Retrieved 2007-12-04.
- Donaldson MS (2000). "Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements". Annals of Nutrition & Metabolism. 44 (5–6): 229–34. doi:10.1159/000046689. PMID 11146329. Archived from the original on 2011-06-15.
- Devalia V (Aug 2006). "Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay". BMJ. 333 (7564): 385–6. doi:10.1136/bmj.333.7564.385. PMC . PMID 16916826.
- Melinda Beck (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal. Archived from the original on September 8, 2017.
- Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J (Aug 1998). "Effective treatment of cobalamin deficiency with oral cobalamin". Blood. 92 (4): 1191–1198. PMID 9694707. Archived from the original on 2009-01-07.
- Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T (2003). "Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study". Clinical Therapeutics. 25 (12): 3124–34. doi:10.1016/S0149-2918(03)90096-8. PMID 14749150.
- Lane LA, Rojas-Fernandez C; Rojas-Fernandez (2002). "Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy". Annals of Pharmacotherapy. 36 (7–8): 1268–72. doi:10.1345/aph.1A122. PMID 12086562.
- Butler, C. C.; Vidal-Alaball, J; Cannings-John, R; McCaddon, A; Hood, K; Papaioannou, A; McDowell, I; Goringe, A (2006). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: A systematic review of randomized controlled trials". Family Practice. 23 (3): 279–285. doi:10.1093/fampra/cml008. PMID 16585128.
- "Long-Term, High-Dose Vitamin B6/B12 Use Associated With Increased Lung Cancer Risk Among Men". 2017-08-22. Archived from the original on 2017-09-08. Retrieved 2017-08-22.
- Baik HW, Russell RM (1999). "Vitamin B12 deficiency in the elderly". Annual Review of Nutrition. 19: 357–77. doi:10.1146/annurev.nutr.19.1.357. PMID 10448529.
- Gille, D; Schmid, A (February 2015). "Vitamin B12 in meat and dairy products". Nutrition Reviews. 73 (2): 106–15. doi:10.1093/nutrit/nuu011. PMID 26024497.
- McDowell, Lee Russell (2008). Vitamins in Animal and Human Nutrition (2nd ed.). Hoboken: John Wiley & Sons. p. 525. ISBN 9780470376683. Archived from the original on 2017-09-08.
- "Soils". Waikato University. Archived from the original on 2012-01-25. Retrieved 2012-01-16.
- Australian Academy of Science > Deceased Fellows > Hedley Ralph Marston 1900–1965 Archived 2006-12-06 at the Wayback Machine. Accessed 12 May 2013.