Vitamin B12 deficiency is arguably the most under-diagnosed condition in the community. "In general, doctors are trained to recognize only the blood abnormalities associated with B12 deficiency - macrocytosis. B12 deficiency, however, mimics many other diseases and often physicians fail to confirm B12 deficiency and therefore fail to test for it."
In the past, the most common causes of vitamin B12 were thought to be.
Vitamin B12 deficiency and Improper diet or dietary choices. Until recently the most commonly quoted cause of vitamin B12 deficiency, was dietary insufficiency of vitamin B12 (Allen, 2009). Vitamin B12 does not occur in reasonable amounts in all foods, and hence a diet which does not contain the right foods, especially meat and animal products, may eventually cause a person to become deficient in vitamin B12. Hence persons who have predominantly a vegan or vegetarian diet, those who are 7th Day Adventists and Rastafarians, all have higher incidences of vitamin B12 deficiency. Evidence suggests that B12 deficiency occurs within 1 year of persons adopting a vegan diet, and around 5 years of them adopting a vegetarian diet. In both cases the B12 deficiency that results is often accompanied by lower ferritin levels and biochemical evidence of iron deficiency.
Vitamin B12 deficiency and Autoimmunity. A less common cause of vitamin B12 deficiency is due to the development of autoimmunity to either the vitamin B12 transport protein, intrinsic factor, or due to the development of autoimmunity to the cells that secrete vitamin B12, namely the Parietal cells (Lahner and Annibale, 2009). The two different forms of vitamin B12 deficiency have slightly different consequences. Hence if the autoimmunity is only to Intrinsic Factor, the uptake of other nutrients is not affected. However, if the autoimmunity is directed at the parietal cells, then there is reduced secretion of intrinsic factor and also reduced secretion of gastric acid. This lowering of gastric acid, results in the pH of the stomach being too high for the primary enzyme in the stomach, pepsin, to function properly. In this case, the release of nutrients such as iron, magnesium and riboflavin from food can be reduced.
Vitamin B12 deficiency and Drug use. Vitamin B12 deficiency has also been associated with the use of several drugs including cholestyramine, cymetidine, clofibrate, colchicine, Isotretinoin, Accutane, methotrexate, methyldopa, neomycin, omeprazole, some oral contraceptives, phenobarbital, ranitidine, tetracyclines, valproic acid, anti-epileptic drugs (carbamazipine and others) and zidovudine (AZT). Vitamin B12 deficiency can be a serious complication of Metformin™ use in people with diabetes.
Vitamin B12 deficiency and Hypothyroidism. Vitamin B12 deficiency can be caused by hypothyroidism, with as many as 50% of individuals with hypothyroidism becoming deficient in vitamin B12 (see relevant section). The process whereby hypothyroidism causes vitamin B12 deficiency, whilst obvious to those who know the biochemistry appears to be lost on those who treat hypothyroidism.
Vitamin B12 deficiency due to lack of Functional Vitamin B2. It is becoming increasingly apparent that vitamin B12 deficiency can be caused by functional vitamin B2 deficiency. This deficiency can be caused by lack of intake of vitamin B2 itself, such as by reduced intake of foods such as dairy, but it also can come from lack of intake of Iodine (less than 150 ug/day), Selenium (less than 55 ug/day), or lack of intake of Molybdenum (less than 100 ug/day). The involvement of I/Se/Mo in vitamin B2 processing is explained on the hypothyroidism section of this web-site. Dietary insufficiency of iodine, selenium and/or molybdenum can lead to functional vitamin B2 deficiency, due to their role in converting dietary vitamin B2 (riboflavin), into the two active forms of the vitamin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). The result is very similar to the effect of hypothyroidism, and supplementation with one or all of these metals is required to overcome the deficiency, even in the presence of adequate vitamin B2 (riboflavin) intake. Studies on vitamin B12 supplementation have generally totally disregarded the need for vitamin B2 itself for vitamin B12 cycling, much less the need for Iodine, Selenium and Molybdenum. Supplementation with vitamin B12, even in persons with hypothyroidism have totally disregarded the need for accompanying I/Se/Mo. As such the majority of supplementation studies have had very poor (yet curiously expected) outcomes.What is perhaps surprising is that the identification of FAD as an important co-factor in B12 cycling and the synthesis of Methionine has been known since 1963, yet appears to have been totally ignored by review after review and study after study on vitamin B12 deficiency and supplementation (Cathou and Buchanan 1963; Katzen and Buchanan, 1965), and despite its known association with demyelination as far back as 1988 (Hyland et al, 1988). The requirement for FAD/FMN and NADPH for the activity of Methionine synthase reductase has also been known for some 20 years (Leclerc et al 1988).
Vitamin B12 deficiency and Nitrous oxide and anaesthetics. Nitrous oxide was commonly used as an anaesthetic gas, yet as long ago as 1956 (Lassen et al, 1956) it was realized that it the activity of vitamin B12 was destroyed by nitrous oxide and could cause megaloblastic anemia. In 1968, Banks and co-workers demonstrated that nitrous oxide could react with the cobalt in vitamin B12 and lead to the inactive NO-CoB12 complex. The destruction of the activity of vitamin B12 is dependent upon the time and dose of administration of nitrous, with over 50% of individuals producing signs of megaloblastic depression of bone marrow function (Nunn and Chanarin, 1978). As early as 1978 (Amess et al, 1987) the use of nitrous oxide for anaesthesia was found to be contra-indicated, yet to this day it is still used, and many individuals report signs of B12 deficiency following use. One of the problems with Nitrous inactivation of vitamin B12 activity is that the levels of B12 in serum still remain high, yet paradoxically the B12 is inactive - as per the discussion on paradoxical vitamin B12 deficiency.
Vitamin B12 deficiency and Poor Intestinal Absorption. Intestinal Conditions that affect Absorption including weight loss surgery, such as bowel resection or gastric by-pass surgery , frequent use of acid reducing medications such as PPIs, achlorhydria, Chron's disease, celiac disease, bacterial overgrowth, intestinal parasites such as Giardia, fish tapeworms, and atrophic gastritis (a condition that affects 10-30% of the elderly), H. pylori infections (Mwafy and Afana, 2018; Kountouras et al, 2015), can all lead to reduced absorption of vitamin B12, which resultant vitamin B12 deficiency.
Genetic conditions. There are a number of genetic conditions that have been associated with improper intracellular processing of vitamin B12, hence leading to vitamin B12 deficiency. The most common is cblC, but there are also cblA, cblB, cblD, cblE and cblF. in addition, mutations in MTHFR, MTR and MTRR all affect B12 cycling and regeneration.
Vitamin B12 Deficiency and Obesity. In recent times it is become apparent that obesity may also be associated with vitamin B12 deficiency. Given that obesity can be associated with an inability to burn fat, then the link between obesity and vitamin B12 deficiency, may be lack of functional B2, which would affect both MTHFR and MTRR enzymes.
There are various other causes of vitamin B12 deficiency, including, but not limited to
Pancreatic disease - resulting in poor release of B12 from haptocorrin due to insufficient activity of pancreatic enzymes
Medications that affect absorption of metabolism, such as cholestyramine and metformin
Miscellaneous - HIV infections, nitrous oxide anaesthesia, smoking (Green et al, 2017)
Lahner, E and Annibale, B. 2009 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773890
Allen LH Causes of vitamin B12 and folate deficiency Food Nutr Bull. 2008 Jun;29(2 Suppl):S20-34; discussion S35-7
Cathou and Buchanan 1963 Enzymatic synthesis of the methyl group of Methionine JBC 238, 1746-1751
Katzen and Buchanan, 1965 Enzymatic synthesis of the methyl group of Methionine.. JBC 240, 825-835
Hyland, et al, 1988 Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurol, 39,459-62
Leclerc et al, 1998 Cloning and mapping of a cDNA for methionine synthase reductase, flavoprotein defective in patients with homocystinuria PNAS, 95 2059-64.
Mwafy and Afana. 2018 Hematological parameters, serum iron and vitamin B12 levels in hospitalized Palestinian.... Haem. Trans. Cell Ther 40, 160-5
Kountouras et al, 2015 Helicobacter Pylori-related vitamin B12 deficiency: A potential contributor in neuropsychiatric disorders. Ind. J. Psych. Med. 37, 475-6.
Green et al. Vitamin B12 deficiency. Nature Reviews 2017 3: article 17040
Lassen et al, 1956 Treatment of tetanus,. Severe bone-marrow depression after prolonged nitrous oxide anaesthesia. Lancet 1, 527
Banks et al. 1968 Reactions of gases in solution. Part III: Some reactions of nitrous oxide with transition-metal complexes. J. Chem. Soc (A) 2886
Nunn and Chanarin 1978 Nitrous oxide and vitamin B12 BJA 50, 11
Lancet, 12, 339-42 .
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The statements on this site compose a compendium of generally recognized signs of vitamin B12 deficiency, and problems that can then ensue They also are formulated from a summary of relevant scientific publications. In addition they may contain some forward looking statements of a general nature.
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