Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition of low blood and tissue levels of vitamin B12.[4] In mild deficiency, a person may feel tired and have a reduced number of red blood cells (anemia).[1] In moderate deficiency, soreness of the tongueapthous ulcers, breathlessness, jaundice, hair fall and severe joint pain (arthralgia) may occur, and the beginning of neurological symptoms, including abnormal sensations such as pins and needles, numbness and tinnitus.[1] Severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, irritability, ataxiadecreased tastedecrease level of consciousness, depression, anxiety, guilt and psychosis.[1] Infertility may occur.[1][5] In young children, symptoms include poor growthpoor development, and difficulties with movement.[2] Without early treatment, some of the changes may be permanent.[6]

Causes are categorized as decreased absorption of vitamin B12 from the stomach or intestines, deficient intake, or increased requirements.[1] Decreased absorption may be due to pernicious anemiasurgical removal of the stomach, chronic inflammation of the pancreasintestinal parasites, certain medications, and some genetic disorders.[1] Medications that may decrease absorption include proton pump inhibitorsH2-receptor blockers, and metformin.[7] Decreased intake may occur in vegetarians, vegans and the malnourished.[1][8] Increased requirements occur in people with HIV/AIDS, and in those with shortened red blood cell lifespan.[1] Diagnosis is typically based on blood levels of vitamin B12 below 120–180 pmol/L (170 to 250 pg/mL) in adults.[2] Elevated methylmalonic acid levels may also indicate a deficiency.[2] A type of anemia known as megaloblastic anemia is often but not always present.[2]

Treatment consists of using vitamin B12 by mouth or by injection; initially in high daily doses, followed by less frequent lower doses as the condition improves.[3] If a reversible cause is found, that cause should be corrected if possible.[9] If no reversible cause is found—or when found it cannot be eliminated—lifelong vitamin B12 administration is usually recommended.[10] Vitamin B12 deficiency is preventable with supplements containing the vitamin: this is recommended in pregnant vegetarians and vegans, and not harmful in others.[2] Risk of toxicity due to vitamin B12 is low.[2]

Vitamin B12 deficiency in the US and the UK is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60.[1] In Latin America, about 40 percent are estimated to be affected, and this may be as high as 80 percent in parts of Africa and Asia.[1]

Contents

Signs and symptoms[edit]

Vitamin B12 deficiency can lead to anemia and neurological disorders.[11] 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, gastrointestinal 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. Tissue deficiency resulting in negative effects in nerve cellsbone marrow, and the skin.[4]

The main type of vitamin B 12 deficiency anemia is 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: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control.[12] 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.[13]
  3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, or seizures.[14][15] Deficiency symptoms in children include developmental delayregressionirritabilityinvoluntary movements and hypotonia.[16]

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:

  1. Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
  2. Ataxia of dorsal column type
  3. Decrease or loss of deep muscle-tendon reflexes
  4. Pathological reflexes â€“ BabinskiRossolimo 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 blood abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. Elderly people are at an even higher risk of this type of damage.[17] In babies a number of neurological symptoms can be evident due to malnutrition or pernicious anemia in the mother. These include poor growth, apathy, having no desire for food, and developmental regression. While most symptoms resolve with supplementation some developmental and cognitive problems may persist.[18][19]

Vitamin B12 deficiency may accompany certain eating disorders or restrictive diets.[20] In 2020, such a case made headlines when it emerged that a teenager from BristolEngland, had gone blind (via atrophy of the optic nerves) and sustained severe pernicious anemia after eating a highly restricted diet consisting of white breadpotato crisps and chips with virtually no meat.[21] The patient reported that they ate these types of food because they disliked the texture of other food, and thus ate their restricted diet obsessively.[22][23] In this instance, the hypocobalaminemia was accompanied by other consequences of the malnutrition, including zinc and selenium deficiencyhypovitaminosis Dhypocupremia and reduced bone density.[24]

Only a small subset of dementia cases have been found to be reversible with vitamin B12 therapy.[25] Tinnitus may be associated with vitamin B12 deficiency.[26]

Effect of folic acid[edit]

Large amounts of folic acid can correct the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological abnormalities, and could also worsen the anemia and the cognitive symptoms associated with vitamin B12 deficiency.[2] 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 folate than they realize.[27] To avoid this potential problem, the U.S. Food and Drug Administration recommends that folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults.[2][28] The European Food Safety Authority reviewed the safety question and agreed with the US that the tolerable upper intake levels (UL) be set at 1,000 μg.[29] The Japan National Institute of Health and Nutrition set the adult UL at 1,300 or 1,400 μg depending on age.[30]

Causes[edit]

Inadequate intake[edit]

Inadequate dietary intake of animal products such as eggs, meat, milk, fish, fowl (and some type of edible algae) can result in a deficiency state.[31] Vegans, and to a lesser degree vegetarians, are at risk for B12 deficiency if they do not consume either a dietary supplement or vitamin-fortified foods. 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.[32]

Impaired absorption[edit]

Increased need[edit]

Increased needs by the body can occur due to AIDS and hemolysis (the breakdown of red blood cells), which stimulates increased red cell production.[1]

Mechanism[edit]

MRI image of the brain in vitamin B12 deficiency, axial view showing the “precontrast FLAIR image“: note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology.MRI image of the cervical spinal cord in vitamin B12 deficiency showing subacute combined degeneration. (A) The midsagittal T2 weighted image shows linear hyperintensity in the posterior portion of the cervical tract of the spinal cord (black arrows). (B) Axial T2 weighted images reveal the selective involvement of the posterior columns.

Physiology[edit]

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 this 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.[44] However, the rate at which B12 levels may change when dietary intake is low depends on the balance between several variables.[45]

Pathophysiology[edit]

Vitamin B12 deficiency causes particular changes to the metabolism of two 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, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops.[46] 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.

Nervous system[edit]

Early changes include 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 occur in dorsal parts of the spinal cord and to pyramidal tracts in lateral cords and is called subacute combined degeneration of spinal cord.[47] Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.

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.

MRI of the brain may show periventricular white matter abnormalities. MRI of the spinal cord may show linear hyperintensity in the posterior portion of the cervical tract of the spinal cord, with selective involvement of the posterior columns.

Diagnosis[edit]

The diagnosis is frequently first suspected when a routine complete blood count shows anemia with an elevated MCV. In addition, on the peripheral blood smearmacrocytes and hypersegmented polymorphonuclear leukocytes may be seen.

Diagnosis is typically confirmed based on vitamin B12 blood levels below 120–180 pmol/L (170–250 pg/mL) in adults.[2] Elevated serum homocysteine (over 12 μmol/L) and methylmalonic acid (over 0.4 micromol/L) levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood.[2][48] If nervous system damage is present and blood testing is inconclusive, a lumbar puncture to measure cerebrospinal fluid B-12 levels may be done.[49] On bone marrow aspiration or biopsy, megaloblasts are seen.[citation needed]

The Schilling test was a radio-isotope method, now outdated, of testing for low vitamin B12.[50]

Treatment[edit]

Hydroxocobalamin injection is a clear red liquid solution.

B12 can be supplemented by pill or injection and appears to be equally effective in those with low levels due to deficient absorption of B12. When large doses are given by mouth its absorption does not rely on the presence of intrinsic factor or an intact ileum. Instead, these large-dose supplements result in 1% to 5% absorption along the entire intestine by passive diffusion. Generally 1 to 2 mg daily is required as a large dose. Even pernicious anemia can be treated entirely by the oral route.[3][51][52]

Epidemiology[edit]

Vitamin B12 deficiency is common and occurs worldwide. In the US and UK, around 6 percent of the general population have the deficiency; in those over the age of sixty, around 20 percent are deficient. In under-developed countries, the rates are even higher: across Latin America 40 percent are deficient; in some parts of Africa, 70 percent; and in some parts of India, 70 to 80 percent.[1]

According to the World Health Organization (WHO), vitamin B12 deficiency may be considered a global public health problem affecting millions of individuals.[53] However, the incidence and prevalence of vitamin B12 deficiency worldwide is unknown due to the limited population-based data available (see table below).

Developed countries such as the United StatesGermany and the United Kingdom have relatively constant mean vitamin B12 concentrations.[54] The data from the National Health and Nutrition Examination Survey (NHANES) reported the prevalence of serum vitamin B12 concentrations in the United States population between 1999 to 2002.[55][56] Serum vitamin B12 concentrations of <148 pmol/L was present in < 1% of children and adolescents. In adults aged 20-39 years, concentrations were below this cut-off in ≤3% of individuals. In the elderly (70 years and older), ≈ 6% of persons had a vitamin B12 concentration below the cut-off.

Furthermore, ≈ 14-16% of adults and >20% of elderly individuals showed evidence of marginal vitamin B12 depletion (serum vitamin B12: 148-221 pmol/L).[55][56] In the United Kingdom, a National Diet and Nutrition Survey (NDNS) was conducted in adults aged between 19 to 64 years in 2000–2001[57] and in elderly individuals (≥ 65 years) in 1994–95.[58] Six percent of men (n = 632) and 10% of women (n = 667) had low serum vitamin B12 concentrations, defined as <150 pmol/L. In a subgroup of women of reproductive age (19 to 49 years), 11% had low serum B12 concentrations <150 pmol/L (n=476). The prevalence of vitamin B12 deficiency increased substantially in the elderly, where 31% of the elderly had vitamin B12 levels below 130 pmol/L. In the most recent NDNS survey conducted between 2008-2011, serum vitamin B12 was measured in 549 adults.[59] The mean serum vitamin B12 concentration for men (19-64 years) was 308 pmol/L, of which 0.9% of men had low serum B12 concentrations <150 pmol/L. In women aged between 19-64 years, the mean serum vitamin B12 concentration was slightly lower than men (298 pmol/L), with 3.3% having low vitamin B12 concentrations <150 pmol/L.[59] In Germany, a national survey in 1998 was conducted in 1,266 women of childbearing age. Approximately, 14.7% of these women had mean serum vitamin B12 concentrations of <148 pmol/L.[60]

Few studies have reported vitamin B12 status on a national level in non-Western countries.[61] Of these reported studies, vitamin B12 deficiency was prevalent among school- aged children in Venezuela (11.4% ),[62] children aged 1-6 years in Mexico (7.7%),[63] women of reproductive age in Vietnam (11.7%),[64] pregnant women in Venezuela (61.34%)[62] and in the elderly population (>65 years) in New Zealand (12%)[65]. Currently, there are no nationally representative surveys for any African or South Asian countries. However, the very few surveys which have investigated vitamin B12 deficiency in these countries have been based on local or district level data. These surveys have reported a high prevalence of vitamin B12 deficiency (<150 pmol/L), among 36% of breastfed and 9% of non-breastfed children (n=2482) in New Delhi[66] and 47% of adults (n=204)[67] in Pune, Maharashtra, India. Furthermore, in Kenya a local district survey in Embu (n=512) revealed that 40% of school- aged children in Kenya had vitamin B12 deficiency.[68]

Table showing worldwide prevalence of vitamin B12 deficiency (serum/plasma B12 < 148 or 150 pmol/L)

GroupNumber of studiesNumber ofparticipantsVitamin B12 deficiency (%)
Children (< 1y – 18 years)1422,33112.5
Pregnant women1111,38127.5
Non-pregnant women1618,52016
All adults (Under 60 years)1881.4386
Elderly (60+ years)2530,44919

Derived from Table 2 available on[69]

History[edit]

Between 1849 and 1887, Thomas Addison described a case of pernicious anemiaWilliam Osler and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called “giant blood corpuscles” (now called macrocytes), Paul Ehrlich identified megaloblasts in the bone marrow, and Ludwig Lichtheim described a case of myelopathy.[70] During the 1920s, George Whipple discovered that ingesting large amounts of liver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.[71] Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products. William Castle demonstrated that gastric juice contained an “intrinsic factor” which when combined with meat ingestion resulted in absorption of the vitamin in this condition.[70] In 1934, George Whipple shared the 1934 Nobel Prize in Physiology or Medicine with William P. Murphy and George Minot for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.[70][72]

Other animals[edit]

Ruminants, such as cows and sheep, absorb B12 synthesized by their gut bacteria.[73] Sufficient amounts of cobalt and copper need to be consumed for this B12 synthesis to occur.[74]

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 in 1934 that the volcanic soils lacked the cobalt salts essential for synthesis of vitamin B12 by their gut bacteria.[75][74] The “coast disease” of sheep in the coastal sand dunes 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, which then was retained in the animal’s rumen.[74][76]

References[edit]

  1. Jump up to:a b c d e f g h i j k l m n o Hunt A, Harrington D, Robinson S (September 2014). “Vitamin B12 deficiency” (PDF). BMJ349: g5226. doi:10.1136/bmj.g5226PMID 25189324. Archived from the original (PDF) on 12 March 2017.
  2. Jump up to:a b c d e f g h i j k l m “Dietary Supplement Fact Sheet: Vitamin B12 – Health Professional Fact Sheet”National Institutes of Health: Office of Dietary Supplements. 2016-02-11. Archivedfrom the original on 2016-07-27. Retrieved 2016-07-15.
  3. Jump up to:a b c Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH (March 2018). “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency”The Cochrane Database of Systematic Reviews3: CD004655. doi:10.1002/14651858.CD004655.pub3PMC 5112015PMID 29543316.
  4. Jump up to:a b Herrmann W (2011). Vitamins in the prevention of human diseases. Berlin: Walter de Gruyter. p. 245. ISBN 978-3110214482.
  5. ^ “Complications”nhs.uk. 2017-10-20.
  6. ^ Lachner C, Steinle NI, Regenold WT (2012). “The neuropsychiatry of vitamin B12 deficiency in elderly patients”. The Journal of Neuropsychiatry and Clinical Neurosciences24(1): 5–15. doi:10.1176/appi.neuropsych.11020052PMID 22450609.
  7. ^ Miller JW (July 2018). “Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications”Advances in Nutrition9 (4): 511S–518S. doi:10.1093/advances/nmy023PMC 6054240PMID 30032223.
  8. ^ Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D (February 2013). “How prevalent is vitamin B(12) deficiency among vegetarians?”. Nutrition Reviews71 (2): 110–7. doi:10.1111/nure.12001PMID 23356638.
  9. ^ Hankey GJ, Wardlaw JM (2008). Clinical neurology. London: Manson. p. 466. ISBN 978-1840765182.
  10. ^ Schwartz W (2012). The 5-minute pediatric consult (6th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 535. ISBN 9781451116564.
  11. ^ Reynolds EH (2014). “The neurology of folic acid deficiency”. In Biller J, Ferro JM (eds.). Neurologic aspects of systemic disease. Handbook of Clinical Neurology. 120. pp. 927–43. doi:10.1016/B978-0-7020-4087-0.00061-9ISBN 9780702040870PMID 24365361.
  12. ^ Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, Adami F (November 2013). “Cobalamin deficiency: clinical picture and radiological findings”Nutrients5 (11): 4521–39. doi:10.3390/nu5114521PMC 3847746PMID 24248213.
  13. ^ Amarapurka DN, Patel ND (September 2004). “Gastric Antral Vascular Ectasia (GAVE) Syndrome” (PDF). Journal of the Association of Physicians of India52: 757. Archived (PDF)from the original on 2016-03-04.
  14. ^ Matsumoto A, Shiga Y, Shimizu H, Kimura I, Hisanaga K (April 2009). “[Encephalomyelopathy due to vitamin B12 deficiency with seizures as a predominant symptom]”Rinsho Shinkeigaku = Clinical Neurology49 (4): 179–85. doi:10.5692/clinicalneurol.49.179PMID 19462816.
  15. ^ Kumar S (March 2004). “Recurrent seizures: an unusual manifestation of vitamin B12 deficiency”Neurology India52(1): 122–3. PMID 15069260Archived from the original on 2011-01-23.
  16. ^ Kliegman RM, Stanton B, St Geme J, Schor NF, eds. (2016). Nelson Textbook of Pediatrics (20th ed.). pp. 2319–26. ISBN 978-1-4557-7566-8.
  17. ^ Stabler SP, Lindenbaum J, Allen RH (October 1997). “Vitamin B-12 deficiency in the elderly: current dilemmas”The American Journal of Clinical Nutrition66 (4): 741–9. doi:10.1093/ajcn/66.4.741PMID 9322547.
  18. ^ Dror DK, Allen LH (May 2008). “Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms”. Nutrition Reviews66 (5): 250–5. doi:10.1111/j.1753-4887.2008.00031.xPMID 18454811.
  19. ^ Black MM (June 2008). “Effects of vitamin B12 and folate deficiency on brain development in children”Food and Nutrition Bulletin29 (2 Suppl): S126-31. doi:10.1177/15648265080292S117PMC 3137939PMID 18709887.
  20. ^ O’Gorman P, Holmes D, Ramanan AV, Bose-Haider B, Lewis MJ, Will A (June 2002). “Dietary vitamin B12 deficiency in an adolescent white boy”Journal of Clinical Pathology55 (6): 475–6. doi:10.1136/jcp.55.6.475PMC 1769668PMID 12037034.
  21. ^ “August: diet-study | News and features”. University of Bristol. Retrieved 2021-02-06.
  22. ^ “Teenager ‘blind’ from living off crisps and chips”BBC News. 2019-09-03. Retrieved 2021-02-06.
  23. ^ “Teenager goes blind after living on diet of chips and sausages”ITV News. 2019-09-02. Retrieved 2021-02-06.
  24. ^ “Teenage boy goes blind after existing on Pringles, white bread and French fries”WXMI. 2019-09-03. Retrieved 2021-02-06.
  25. ^ Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D (April 2012). “Cognitive impairment and vitamin B12: a review”. International Psychogeriatrics24 (4): 541–56. doi:10.1017/S1041610211002511PMID 22221769.
  26. ^ Zempleni J, Suttie JW, Gregory III JF, Stover PJ, eds. (2014). Handbook of vitamins (Fifth ed.). Hoboken: CRC Press. p. 477. ISBN 9781466515574Archived from the original on 2016-08-17.
  27. ^ Beck M (January 18, 2011). “Sluggish? Confused? Vitamin B12 May Be Low”. Wall Street Journal. Archived from the original on September 8, 2017.
  28. ^ Institute of Medicine (1998). “Folate”Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. pp. 196–305. ISBN 978-0-309-06554-2. Retrieved 25 September 2019.
  29. ^ “Tolerable Upper Intake Levels For Vitamins And Minerals”(PDF). European Food Safety Authority. 2006.
  30. ^ Shibata K, Fukuwatari T, Imai E, Hayakawa T, Watanabe F, Takimoto H, Watanabe T, Umegaki K (2013). “Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins”Journal of Nutritional Science and Vitaminology2013 (59): S67–S82.
  31. ^ Croft MT, Lawrence AD, Raux-Deery E, Warren MJ, Smith AG (November 2005). “Algae acquire vitamin B12 through a symbiotic relationship with bacteria”. Nature438 (7064): 90–3. Bibcode:2005Natur.438…90Cdoi:10.1038/nature04056PMID 16267554S2CID 4328049.
  32. ^ Rasmussen SA, Fernhoff PM, Scanlon KS (January 2001). “Vitamin B12 deficiency in children and adolescents”. The Journal of Pediatrics138 (1): 10–7. doi:10.1067/mpd.2001.112160PMID 11148506.
  33. Jump up to:a b Baik HW, Russell RM (1999). “Vitamin B12 deficiency in the elderly”. Annual Review of Nutrition19: 357–77. doi:10.1146/annurev.nutr.19.1.357PMID 10448529.
  34. ^ Lam JR, Schneider JL, Zhao W, Corley DA (December 2013). “Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency”Jama310 (22): 2435–42. doi:10.1001/jama.2013.280490PMID 24327038.
  35. ^ Yeomans ND, Hanson RG, Smallwood RA, Mihaly GW, Louis WJ (July 1982). “Effect of chronic ranitidine treatment on secretion of intrinsic factor”British Medical Journal285(6337): 264. doi:10.1136/bmj.285.6337.264PMC 1499627PMID 6124297.
  36. ^ Caruso R, Pallone F, Stasi E, Romeo S, Monteleone G (December 2013). “Appropriate nutrient supplementation in celiac disease”. Annals of Medicine (Review). 45 (8): 522–31. doi:10.3109/07853890.2013.849383PMID 24195595S2CID 11093737.
  37. ^ “Blind loop syndrome – Diagnosis and treatment – Mayo Clinic”www.mayoclinic.orgArchived from the original on 2018-05-09.
  38. ^ Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM (October 2006). “Risk factors of vitamin B(12) deficiency in patients receiving metformin”Archives of Internal Medicine166 (18): 1975–9. doi:10.1001/archinte.166.18.1975PMID 17030830.
  39. Jump up to:a b Nagao T, Hirokawa M (October 2017). “Diagnosis and treatment of macrocytic anemias in adults”Journal of General and Family Medicine18 (5): 200–204. doi:10.1002/jgf2.31PMC 5689413PMID 29264027.
  40. ^ Kondo H, Osborne ML, Kolhouse JF, Binder MJ, Podell ER, Utley CS, et al. (May 1981). “Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats”The Journal of Clinical Investigation67 (5): 1270–83. doi:10.1172/JCI110155PMC 370693PMID 6112240.
  41. ^ Anyanwu EC, Morad M, Campbell AW (August 2004). “Metabolism of mycotoxins, intracellular functions of vitamin B12, and neurological manifestations in patients with chronic toxigenic mold exposures. A review”TheScientificWorldJournal4: 736–45. doi:10.1100/tsw.2004.133PMC 5956359PMID 15349513.
  42. ^ Anyanwu EC, Kanu I (October 2007). “Biochemical impedance on intracellular functions of vitamin B12 in chronic toxigenic mold exposures”TheScientificWorldJournal7: 1649–57. doi:10.1100/tsw.2007.113PMC 5900526PMID 17982599.
  43. ^ Ulasoglu C, Temiz HE, SaÄŸlam ZA. The Relation of Cytotoxin-Associated Gene-A Seropositivity with Vitamin B12 Deficiency in Helicobacter pylori-Positive Patients. Biomed Res Int. 2019;2019:1450536. Published 2019 Dec 9. doi:10.1155/2019/1450536
  44. ^ Voet D, Voet JG (2010). Biochemistry. New York: J. Wiley & Sons. p. 957ISBN 978-0470-57095-1.
  45. ^ Kazuhiro Y (2013). “Chapter 9. Cobalt: Its Role in Health and Disease”. In Sigel A, Sigel H, Sigel RK (eds.). 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_9ISBN 978-94-007-7499-5PMID 24470095.
  46. ^ Shane B, Stokstad EL (1985). “Vitamin B12-folate interrelationships”. Annual Review of Nutrition5: 115–41. doi:10.1146/annurev.nu.05.070185.000555PMID 3927946.
  47. ^ “Vitamin B12 / Pathophysiology Text”. LifeSave.org. p. 215. Archived from the original on 2013-02-06. Retrieved 2013-12-31.
  48. ^ “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.
  49. ^ Devalia V (August 2006). “Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay”BMJ333 (7564): 385–6. doi:10.1136/bmj.333.7564.385PMC 1550477PMID 16916826.
  50. ^ Nickoloff E (1988). “Schilling test: physiologic basis for and use as a diagnostic test”. Critical Reviews in Clinical Laboratory Sciences26 (4): 263–76. doi:10.3109/10408368809105892PMID 3077032.
  51. ^ Lane LA, Rojas-Fernandez C (2002). “Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy”. The Annals of Pharmacotherapy36 (7–8): 1268–72. doi:10.1345/aph.1A122PMID 12086562S2CID 919401.
  52. ^ Butler CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou A, et al. (June 2006). “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials”Family Practice23 (3): 279–85. doi:10.1093/fampra/cml008PMID 16585128.
  53. ^ de Benoist B (June 2008). “Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies”Food and Nutrition Bulletin29 (2 Suppl): S238-44. doi:10.1177/15648265080292S129PMID 18709899.
  54. ^ Stabler SP, Allen RH (2004-07-14). “Vitamin B12 deficiency as a worldwide problem”Annual Review of Nutrition24 (1): 299–326. doi:10.1146/annurev.nutr.24.012003.132440PMID 15189123.
  55. Jump up to:a b Pfeiffer CM, Johnson CL, Jain RB, Yetley EA, Picciano MF, Rader JI, et al. (September 2007). “Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004”The American Journal of Clinical Nutrition86 (3): 718–27. doi:10.1093/ajcn/86.3.718PMID 17823438.
  56. Jump up to:a b Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ (August 2005). “Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000”The American Journal of Clinical Nutrition82 (2): 442–50. doi:10.1093/ajcn/82.2.442PMID 16087991.
  57. ^ Ruston D, Henderson L, Gregory J, Bates CJ, Prentice A, Birch M, Swan G, Farron M (2004). “National Diet and Nutrition Survey: Adults Aged 19 to 64 Years”. Nutritional Status (Anthropometry and Blood Analytes), Blood Pressure and Physical Activity. The Stationery Office. 4.
  58. ^ Smithers G, Finch S, Doyle W, Lowe C, Bates CJ, Prentice A, Clarke PC (June 1998). “The National Diet and Nutrition Survey: people aged 65 years and over”. Nutrition & Food Science98(3): 133–134. doi:10.1108/00346659810209791.
  59. Jump up to:a b Bates B, Prentice A, Bates C, Swan G (2011). National Diet and Nutrition Survey: Headline Results from Years 1, 2 and 3 (combined) of the Rolling Programme 2008/09 – 2010/11 (Report).
  60. ^ Thamm M, Mensink GB, Thierfelder W (December 1999). “[Folic acid intake of women in childbearing age]”. Gesundheitswesen (Bundesverband Der Arzte Des Offentlichen Gesundheitsdienstes (Germany)) (in German). 61 Spec No: S207–12. PMID 10726422.
  61. ^ McLean E, de Benoist B, Allen LH (June 2008). “Review of the magnitude of folate and vitamin B12 deficiencies worldwide”. Food and Nutrition Bulletin29 (2 Suppl): S38-51. doi:10.1177/15648265080292S107PMID 18709880.
  62. Jump up to:a b García-Casal MN, Osorio C, Landaeta M, Leets I, Matus P, Fazzino F, Marcos E (September 2005). “High prevalence of folic acid and vitamin B12 deficiencies in infants, children, adolescents and pregnant women in Venezuela”European Journal of Clinical Nutrition59 (9): 1064–70. doi:10.1038/sj.ejcn.1602212PMID 16015269.
  63. ^ Cuevas-Nasu L, Mundo-Rosas V, Shamah-Levy T, Méndez-Gómez Humaran I, Avila-Arcos MA, Rebollar-Campos M, Villalpando S (April 2012). “Prevalence of folate and vitamin B12 deficiency in Mexican children aged 1 to 6 years in a population-based survey”Salud Publica De Mexico54 (2): 116–24. doi:10.1590/S0036-36342012000200007PMID 22535170.
  64. ^ Laillou A, Pham TV, Tran NT, Le HT, Wieringa F, Rohner F, et al. (2012-04-17). Smith B (ed.). “Micronutrient deficits are still public health issues among women and young children in Vietnam”PloS One7 (4): e34906. doi:10.1371/journal.pone.0034906PMC 3328495PMID 22529954.
  65. ^ Green TJ, Venn BJ, Skeaff CM, Williams SM (February 2005). “Serum vitamin B12 concentrations and atrophic gastritis in older New Zealanders”European Journal of Clinical Nutrition59(2): 205–10. doi:10.1038/sj.ejcn.1602059PMID 15483636.
  66. ^ Taneja S, Bhandari N, Strand TA, Sommerfelt H, Refsum H, Ueland PM, et al. (November 2007). “Cobalamin and folate status in infants and young children in a low-to-middle income community in India”. The American Journal of Clinical Nutrition86 (5): 1302–9. doi:10.1093/ajcn/86.5.1302PMID 17991639.
  67. ^ Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, et al. (August 2001). “Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians”The American Journal of Clinical Nutrition74 (2): 233–41. doi:10.1093/ajcn/74.2.233PMID 11470726.
  68. ^ Siekmann JH, Allen LH, Bwibo NO, Demment MW, Murphy SP, Neumann CG (November 2003). “Kenyan school children have multiple micronutrient deficiencies, but increased plasma vitamin B-12 is the only detectable micronutrient response to meat or milk supplementation”The Journal of Nutrition133 (11 Suppl 2): 3972S–3980S. doi:10.1093/jn/133.11.3972SPMID 14672298.
  69. ^ Smith AD, Warren MJ, Refsum H (2018). “Chapter Six – Vitamin B12”. In Eskin NA (ed.). Advances in Food and Nutrition Research. Academic Press. pp. 215–279. doi:10.1016/bs.afnr.2017.11.005.
  70. Jump up to:a b c Greer JP (2014). Wintrobe’s Clinical Hematology Thirteenth Edition. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-1-4511-7268-3. Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel
  71. ^ “George H. Whipple – Biographical”www.nobelprize.org. Retrieved 2017-10-10.
  72. ^ The Nobel Prize in Physiology or Medicine 1934Nobelprize.org, Nobel Media AB 2014. Retrieved December 2, 2015.
  73. ^ Gille D, Schmid A (February 2015). “Vitamin B12 in meat and dairy products”. Nutrition Reviews73 (2): 106–15. doi:10.1093/nutrit/nuu011PMID 26024497.
  74. Jump up to:a b c McDowell LR (2008). Vitamins in Animal and Human Nutrition (2nd ed.). Hoboken: John Wiley & Sons. p. 525. ISBN 9780470376683Archived from the original on 2017-09-08.
  75. ^ “Soils”. Waikato University. Archived from the original on 2012-01-25. Retrieved 2012-01-16.
  76. ^ “Hedley Ralph Marston 1900–1965”Biographical Memoirs of Deceased Fellows. Australian Academy of Science. Archived from the original on 2006-12-06. Retrieved 12 May2013.