Vitamin B12

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Cobalamin is a cobalt containing co-factor in metabolism. It is present in meat, fish, eggs, milk, butter (foods of animal origin). The daily requirement of an adult is approximately 1 µg (normal intake 10-15 µg). It is stored in the liver and body stores may last for 2-4 years. Deficiency causes megaloblastic anaemia (Pernicious anaemia, Addison's anaemia, Biermer's disease).

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  • B12 deficiency is not that rare in secondary care but uncommon in community practice
  • It does not have to be associated with macrocytic anaemia to produce neurological symptoms
  • Symptomatic B12 deficiency is best initially treated parenterally with hydroxocobalamin. Regimes in some neurological presentations are more intense initially.
  • Asymptomatic B12 deficiency associated with metformin therapy will not need parental therapy[1] but always check for neuropathy as this is associated with B12 deficiency in those on metformin[2]

Contents

Functions

Role of B12.gif

Uptake

Deficiency

Clinical Features

Laboratory findings

Info bulb.pngA B12 level may still be valid even after transfusion as the amount of vitamin B12 carried inside the cells is modest. Still the failure to order the test before transfusion, or the resorting to transfusion when the anaemic patient has a high MCV that might be due to B12 deficiency is unlikely to impress a junior doctor's seniors
Info bulb.pngB12 is the most complex vitamin molecule. Lester Smith first isolated the pure compound in 1948. Dorothy Hodkin took 8 years to deduce its structure by X-ray crystallography for which she received the Nobel Prize for Chemistry in 1964. Robert Burns Woodward then lead with Albert Eschenmoser the international collaboration that in 1972 synthesised this molecule with 9 chiral centres, four different corrin rings and an adenosine loop from one of these corrin rings to the cobalt atom

Causes of deficiency

Treatment

Severe deficiency of vitamin B12 can be corrected rapidly with parental hydroxocobalamin. There is now considerable evidence that oral cyanocobalamin can be effective at doses such as 1-2mg per day even in most malabsorbtion syndromes. (Doses as high as this seem to bypass the intrinsic factor transport system.)[11]

There is no evidence that the treatment of borderline B12 levels as often found in Alzheimer's disease is of benefit [12] or to prevent vascular disease[13]. Combined treatment with folate has been reported to be associated with a higher incidence of malignancy[14] so prophylactic use may have some risk.

Physiology

This can start for simplicity at the beginning of the G/I tract with the vitamin B12 binding R-proteins (such as haptocorrins and cobalaphilin) produced in the salivary glands. However their action to protect vitamin B12 freed from ingested food by pepsin from being broken down by the acid in the stomach takes place in the stomach. The physiological decrease in parietal cell numbers with age will increase the risk of B12 deficiency therefore. Indeed the normal 30–60% excretion in faeces of dietary oral B12 rises to above 80% in the elderly.

The parietal cells also secrete the next binding protein intrinsic factor (IF), in response to histamine, gastrin and pentagastrin, or food. In the duodenum, proteases digest R-proteins releasing vitamin B12, which then binds to IF. The IF/B12 complex stops small bowel bacteria catabolising B12 and is then recognised by receptors on the enterocytes in the terminal ileum and absorbed actively.

The IF/B12 complex is transported into the portal circulation and processed with the vitamin transferred to transcobalamin II (TC-II/B12), which serves as the plasma transporter. Genetic defects in transcobalamins and their receptors may cause infantile megaloblastic anaemia. The TC-II/B12 complex binds to cell receptors, is endocytosed, and degraded in lysosomes. The free B12 is then modified to active coenzyme, by certain cellular enzymes (see above).

Normal maximum absorption is about 1.5 microgram a day, whatever dose of B12 is given orally (sometimes in mg amounts). Total amount of vitamin B12 stored in body is about 2–5 mg in adults, mostly in the liver. Gut loss, say in the bile, is minimised by recycling via enterohepatic circulation. Excess parental B12 beyond the blood's binding capacity is usually excreted in urine. This means that a healthy adult has 2 to 3 year reserves, although this is less in infants. Symptomatic B12 deficiency may therefore take years to manifest and the different causes of B12 deficiency mean that blood levels do not necessarily reflect significant pathology. Indeed the physiology of deficiency states causing neurotoxicity seems to be distinct from haemopoietic deranged physiology and it is likely that the classic metabolic abnormalities are not the cause of some neurotoxicity. It can be easy to miss copper deficiency for example which can cause a similar neurological presentation and can co-exist[15].

History of Discovery

  • 1849 15th March 1849 Thomas Addison's first formal report in London Medical Gazette[16]
  • 1855 Thomas Addison's insidious development of pale countenance, languor and indisposition to exertion[17]
  • 1863 Improvement related to diet noted[18]
  • 1894 Fresh bone marrow used as a treatment [19]
  • 1908 Richard Cabot reported that the duration of survival among 1200 patients was usually 1 to 3 years after the onset of symptoms.[20]
  • 1926 George Minot and William Murphy successfully treat 39 out of 45 patients with diet, rapidly saving tens of thousands of lives[21]
  • 1917 George Whipple's liver diet dog experiments commence[22]
  • 1928 Edwin Cohn prepares a hundred times more potent liver extract.
  • 1929 Intrinsic factor is in gastric juice[23]
  • 1948 Isolation of pure Vitamin B12 from Lactobacilis lactis Dorner based on work by Mary Shorb[24] and commercialised following further work by Merck lead by Karl Folkers and Alexander Todd.
  • 1955 Development of Shilling test[25]
  • 1956 Clarification of B12 structure by Dorothy Hodgkin [26]
  • 1959 Horace Albert "Nook" Barker completes his work on the metabolism of vitamin B12
  • 1972 Woodward-Eschenmoser total synthesis of vitamin B12

References

  1. de Groot-Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJ, Kleefstra N. Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. The Netherlands journal of medicine. 2013 Sep; 71(7):386-90.
  2. Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. Journal of postgraduate medicine. 2013 Oct-Dec; 59(4):253-7.(Link to article – subscription may be required.)
  3. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. Journal of clinical epidemiology 2004;57:422-8. (Direct link – subscription may be required.)
  4. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. Journal of clinical epidemiology 2004;57:422-8. (Direct link – subscription may be required.)
  5. Toxicity after intermittent inhalation of nitrous oxide for analgesia http://bmj.bmjjournals.com/cgi/content/full/328/7452/1364 BMJ report and correspondence
  6. Brett A. Myeloneuropathy from whipped cream bulbs presenting as conversion disorder. Aust N Z J Psychiatry. 1997;31(1):131-2.
  7. Andrès E, Loukili NH, Ben Abdelghani M, Noel E. Pernicious anemia associated with interferon-alpha therapy and chronic hepatitis C infection. Journal of clinical gastroenterology 2004;38:382.
  8. Borgia G, Reynaud L, Gentile I, Borrelli F, Cerini R, Ciampi R, et al. Pernicious anemia during IFN-alpha treatment for chronic hepatitis C. Journal of Interferon & Cytokine research 2003;23:11-2. (Direct link – subscription may be required.)
  9. van Oijen MG, Laheij RJ, Peters WH, Jansen JB, Verheugt FW; BACH study. Association of aspirin use with vitamin B12 deficiency (results of the BACH study). Am J Cardiol. 2004;94(7):975-7
  10. Dow JL, Green T. Trichloroethylene induced vitamin B(12) and folate deficiency leads to increased formic acid excretion in the rat. Toxicology 2000;146:123-36.
  11. Oh RC, Brown DL. Vitamin B12 Deficiency. American Family Physician. 2003 Mar 1;67(5):979-986
  12. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003;(3):CD004326
  13. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygård O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2008 Aug 20; 300(7):795-804.(Link to article – subscription may be required.)
  14. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA : the journal of the American Medical Association. 2009 Nov 18; 302(19):2119-26.(Link to article – subscription may be required.)
  15. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clinic proceedings. 2006 Oct; 81(10):1371-84.(Link to article – subscription may be required.)
  16. Addison T., London Medical Gazette., 1849 43 517-562.
  17. Addison T. On the constitutional and local effects of disease of the suprarenal capsules. London: Samuel Highley, 1855:1-43
  18. Habershon,S.O. On idiopathic anaemia. Lancet 1:518, 1863
  19. Fraser TR. Bone-Marrow in the Treatment of Pernicious Anaemia Br Med J 1894;1:1172 doi: http://dx.doi.org/10.1136/bmj.1.1744.1172
  20. Cabot RC. Pernicious and secondary anemia, chlorosis and leukemia. In: Osler W, Mac CT, eds. Modern medicine. Vol. 4. Philadelphia: Lea and Febiger, 1908:612-8.
  21. Minot GR, Murphy WP. Treatment of pernicious anemia by a special diet. JAMA 1926;87:470-476
  22. Nobel prize lecture by G Whipple
  23. Castle WB. The effect of the administration to patients with pernicious anaemia of the contents of the normal human stomach after ingestion of beef muscle. Am J Med Sci 1929;178:748-763
  24. Shorb, M. S. (1947). Unidentified Essential Growth Factors for Lactobacillus-Lactis Found in Refined Liver Extracts and in Certain Natural Materials. Journal of Bacteriology 53, 669-669
  25. Schilling RF, Clatanoff DV, Korst DR. Intrinsic factor studies. III. Further observations utilizing the urinary radioactivity test in subjects with achlorhydria, pernicious anemia, or a total gastrectomy. J Lab Clin Med. 1955 Jun;45(6):926-34.
  26. Nobel lecture by Dorothy Crowfoot Hodgkin
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