Vitamin B12 deficiency
|Vitamin B12 deficiency|
|Classification and external resources|
|Patient UK||Vitamin B12 deficiency|
Vitamin B12 deficiency, also known as hypocobalaminemia, refers to low blood levels of vitamin B12. A wide variety of signs and symptoms may occur including a decreased ability to think and changes in personality 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.
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 have malnutrition. 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 indicated 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. There are no concerns from excess vitamin B12 among those who are otherwise healthy. 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 symptoms
Vitamin B12 deficiency can lead to vitamin B12 deficiency 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.[specify] 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. 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 symptoms also include shortness of breath and increased pallor.
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 intake. 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.
- Celiac disease may also cause impaired absorption of this vitamin, though this is due not to loss of intrinsic factor, but rather damage to the small bowel.
- 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.
- One anecdotal study has shown that giardiasis may be a cause of vitamin B12 deficiency, but larger studies have shown no correlation.
- Malnutrition of alcoholism.
- Nitrous oxide abuse.
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.
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.
The Schilling test has been largely supplanted by tests for antiparietal cell and intrinsic factor antibodies.
Effect of folic acid
The National Institutes of Health has found that "Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency". 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.
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.
A study in the year 2000 indicates that B12 deficiency is far more widespread than formerly believed. The study found that 39 percent of studied group of 3,000 had low values. This Tufts University study used the B12 concentration 258 pmol/l (= 350 pg/mL) as a criterion of "low level". However, recent research has found that B12 deficiency may occur at a much higher B12 concentration (500–600 pg/mL). Against this background, there are reasons to believe that B12 deficiency is present in a far greater proportion of the population than 39% as reported by Tufts University.
In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is theorized to be due to low intakes of animal products, particularly among the poor.
- Beri beri (caused by Vitamin B1 deficiency)
- Herrmann, Wolfgang (2011). Vitamins in the prevention of human diseases. Berlin: Walter de Gruyter. p. 245. ISBN 9783110214482.
- Hunt, A; Harrington, D; Robinson, S (4 September 2014). "Vitamin B12 deficiency.". BMJ (Clinical research ed.) 349: g5226. PMID 25189324.
- "Vitamin B12 Dietary Supplement Fact Sheet". June 24, 2011. Retrieved 21 April 2015.
- 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. PMID 22450609.
- 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.". The Cochrane database of systematic reviews (3): CD004655. PMID 16034940.
- Wardlaw, Graeme J. Hankey, Joanna M. (2008). Clinical neurology. London: Manson. p. 466. ISBN 9781840765182.
- Schwartz, William (2012). The 5-minute pediatric consult (6th ed. ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 535. ISBN 9781451116564.
- DN Amarapurka MD, ND Patel MD (September 2004). "Gastric Antral Vascular Ectasia Syndrome". 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]". Rinshō Shinkeigaku = Clinical Neurology 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.
- 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). Turk J Med Sci 41 (6): 1091–1096. Retrieved 2013-12-29.
- Yavuz H (Sep 2008). "'Vitamin B12 deficiency and seizures'". Developmental Medicine and Child Neurology (Open access) 50 (9): 720. doi:10.1111/j.1469-8749.2008.03083.x. PMID 18754925.
- Reversible dementia in young persons due to cobalamin deficiency. Kumar S, Narasimha A, Holla B, Viswanath B, Narayanaswamy JC, Math SB, Chandrashekar CR. The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:E62-E63. doi:10.1176/appi.neuropsych.12040083 http://journals.psychiatryonline.org/article.aspx?articleid=1660553
- Sethi NK, Robilotti E, Sadan Y (2005). "Neurological Manifestations Of Vitamin B-12 Deficiency". The Internet Journal of Nutrition and Wellness 2 (1).
- 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.
- "Pernicious anemia: MedlinePlus Medical Encyclopedia". Nlm.nih.gov. 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.
- 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 3137939. 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). 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). 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). doi:10.1007/s11130-009-0145-9. PMID 20013055.
- Watanabe F, Takenaka S, Katsura H, Miyamoto E, Abe K, Tamura Y et al. (Dec 2000). "Characterization of a vitamin B12 compound in the edible purple laver, Porphyra yezoensis". Bioscience, Biotechnology, and Biochemistry 64 (12). 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). 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). 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. 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 310 (22): 2435–2442. doi:10.1001/jama.2013.280490. PMID 24327038.
- Yeomans ND, Hanson RG, Smallwood RA, Mihaly GW, Louis WJ (1982). "Effect of chronic ranitidine treatment on secretion of intrinsic factor". Br Med J (Clin Res Ed) 285 (6337): 264. doi:10.1136/bmj.285.6337.264. PMC 1499627. PMID 6124297.
- 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.
- Cordingley FT, Crawford GP (Feb 1986). "Giardia infection causes vitamin B12 deficiency". Australian and New Zealand Journal of Medicine 16 (1): 78–9. doi:10.1111/j.1445-5994.1986.tb01127.x. PMID 3458451.
- 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 Investigation (The American Society For Clinical Investigation) 67 (5): 1270–1283. doi:10.1172/JCI110155. PMC 370693. 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. 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. PMID 22726312.
- 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 1570871. 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. 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.
- "Test used to diagnose B12 deficiency may be inadequate". news-medical.net. October 28, 2004. 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.
- 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 1550477. PMID 16916826.
- "Dietary Supplement Fact Sheet:Vitamin B12". National Institutes of Health.
- Melinda Beck (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal.
- 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.
- Thomas, Donald (2011-06-22). New Jump Swing Healthy Aging and Athletic Nutrition Program. Xlibris. p. 41. ISBN 978-1-4628-8427-8.
- 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.
- Pacholok SM, Stuart JJ (2011). Could It Be B12?: An Epidemic of Misdiagnoses. Fresno, CA: Linden Publishing. ISBN 978-1-61035-065-5.
- Hooper M (2012). Pernicious Anaemia: The Forgotten Disease - the causes and consequences of Vitamin B12 Deficiency. London: Hammersmith Press. ISBN 978-1-78161-004-6.
- http://www.webmd.com/a-to-z-guides/vitamin-b12-deficiency-anemia-topic-overview WebMD overview
- Vitamin B12 and Folate at Lab Tests Online