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Paradoxical Vitamin B12 Deficiency

Many people experience symptoms of vitamin B12 deficiency yet their serum levels of vitamin B12 may be normal or much higher than normal. Subsequent examination of biochemical markers such as MMA or homocysteine may show that these markers are moderate to highly elevated. As such the symptoms and biochemical markers are indicative of vitamin B12 deficiency, yet the serum vitamin B12 levels are paradoxically high. Such persons are deemed to have "Paradoxical Vitamin B12 Deficiency".

It has been known for over 40 years that measurements for serum vitamin B12 levels can be greatly distorted by the presence of of non-functional cobalamin analogues (Kolhouse etal, 1978; Kane et al, 1978; Igarai et al, 1978), and in many cases measurement of serum B12 levels is not predictive of the levels of functionally active B12 (England and Linnell, 1980). In addition, low intracellular folate levels can often be associated with the presence of inactive analogues of cobalamin in serum (Sheppard and Ryrie, 1980). Alternatively it can be associated with inflammatory conditions such as Rheumatoid arthritis due to the overproduction of the B12 binding proteins transcobalamin and haptocorrin (Christensen et al 1983: Grindulis et al, 1984), Cystic fibrosis (Lindemans etal, 1984), and patients treated with nitrous oxide (Parry etal, 1985). Despite the almost completely non-predictive nature of serum vitamin B12 levels it is still the measurement of choice for vitamin B12 sufficiency. Its utility is arguably restricted to determining conditions such as dietary insufficiency, where serum levels are routinely low. Little wonder that so many physicians miss vitamin B12 deficiency in patients!

Causes of Paradoxical B12 Deficiency

The major cause of Paradoxical Vitamin B12 Deficiency appears to lack of functional vitamin B2, which may occur due to overt vitamin B2 deficiency in a person's diet, or due to lack of adequate intake of Iodine, Selenium and/or Molybdenum, which in turn leads to insufficient production of the two active forms of vitamin B2, namely FMN and FAD. FMN and FAD both have critical roles in cycling and maintenance of activity of vitamin B12, particularly methyl B12.

Methyl-Co(III)B12 has a major role in the body in the removal of homocysteine, and in the regeneration of methionine in the methylation cycling using the enzyme methionine synthase reductase (MTR). In the reaction, homocysteine + Methyl-Co(III)B12[MTR]  => Methionine + Co(I)B12[MTR]. The problem with this reaction is that the methyl group is lost from MethylCo(III)B12, which is reduced to Co(I)B12 and so cannot perform further methylation reactions. Theoretically if the reaction only happened once you would need approximately 13.7 gm of MethylCo(III)B12 to remethylate the 1.35 gm of homocysteine formed per day, and around 1.37 kg of the enzyme methionine synthase. Since the daily requirement for vitamin B12 is only around 5 ug, of which around 1.37 ug is MethylCo(III)B12, then clearly this does not happen.

Regeneration of MethylCo(III)B12 is performed by methionine synthase which transfers the methyl group from 5-methyl-tetrahydrofolate (5MTHF) to Co(I)B12. Thus, 5MTHF + Co(I)B12[methionine synthase] => THF + MethylCo(III)B12[methionine synthase]. If the 5MTHF was only used once, then the body would require around 459 mg of 5MTHF per day, however, the daily requirement for folate is around 1000th of this at 400-500 ug/day, so clearly some other source, apart from diet is required to supply this amount of 5MTHF.

The solution comes from within the folate cycle. Here the THF, formed above is converted to the folate derivative 5,10-methylene-THF by the enzyme serine hydroxymethyl transferase (SHMT). The enzyme methylene-tetrahydrofolate reducate (MTHFR), then converts the 5,10-methylene group to 5-methyl-THFwhich it transports of the folate cycle into the methylation cycle, in this way a single folate molecule can be recycled over 1000 times into and out of the folate cycle providing the many 5MTHF groups for regeneration of MethylCo(III)B12.

The reaction 5,10-methylene-THF [MTHFR] => 5-methyl-THF [MTHFR]

The enzyme, MTHFR, though is critically dependent for FAD and NADPH for enzymatic activity and as levels of FAD drop, the enzyme rapidly loses activity, leading to insufficient 5MTHF for remethylation of Co(I)B12 to MethylCo(III)B12. In this instance the Co(I)B12 is rapidly oxidized to the biologically inactive Co(II)B12. The body does though have a "way around this" and it uses the enzyme methionine synthase reductase plus S-Adenosylmethionine (SAM) to remethylate Co(II)B12.

Thus, Co(II)B12[MTR] + SAM[MTRR] => MethylCo(III)B12 + SAH + MTRR.

MTRR, like MTHFR is also a "Flavoprotein" and uses both of the active forms of vitamin B2, FMN and FAD for activity. Once again the activity of the enzyme is critically dependent upon the concentration of FMN and FAD. The activity of the enzyme MTRR is so critical for regeneration of MethylCo(III)B12, that certain mutations in the gene have been found to be conditionally lethal in the womb, or are associated with much higher rates of Down Syndrome, Neural Tube Defects, and increased cancer risks.

From the above it can readily be seen that if there is insufficient FMN and FAD, there will be a gradual accumulation of the inactive Co(II)B12, which is released from the cell and then starts to accumulate in serum, leading to paradoxically high serum B12.

Further, the conversion of both hydroxycobalamin and cyanocobalamin to the active Adenosyl and methyl cobalamins, also involve "Flavoproteins" and hence if a person takes or is injected with, high doses of hydroxycobalamin or cyanocobalamin and has functional B2 deficiency, the inactive hydroxycobalamin and cyanocobalamin will accumulate in serum, however the symptoms of vitamin B12 deficiency will not be resolved.

Paradoxical B12 deficiency is also apparent in certain cancers, such as lung cancer as a result of smoking. In this case one would expect a build up in inactive CN-Cbl due to the cyanide produced during smoking. The higher the serum B12, the higher the associated risk of lung cancer (Fanidi etal, 2019).

The other major cause of Paradoxical B12 occurs when people take large oral doses of B12.

Normally when one either obtains vitamin B12 from digestion in the stomach or from a low dose oral B12 supplement, a protein called haptocorrin (HC), which is secreted into saliva, binds to the B12 and protects it from acid degradation in the stomach. Relatively acid resistant analogues of B12 such as cyanocobalamin have significant hydrolysis at 37oC in the acid environment of the stomach, the more sensitive methylcobalamin, is rapidly hydrolysed in stomach acid. The amount of HC, though is relatively low, and whilst it could protect around 100 ug of B12, there is not enough HC secreted to protect the B12 in some of the high dose oral supplements. Once the B12-HC complex reaches the small intestine the HC is rapidly degraded and the "protected" B12 that has been released is bound by the B12 carrier protein, Intrinsic Factor (IF). IF is relatively non-specific in its binding to B12 and so will bind both intake and hydrolysed B12. If 90%of it is degraded then 90% of the material bound by IF will also be degraded. This mix is then taken up from the intestine and bound by the B12 carrier protein, transcobalamin (TC). TC is even more promiscuous in its binding than IF and so it will transport both the intact and degraded B12 into the cell. Once inside the cell, though the two enzymes MMA-CoA mutase and methionine synthase are very specific for Adenosyl and Methyl cobalamin, respectively, and so any inactive B12 is rapidly expelled from the cells and binds to circulating haptocorrin (HC). As more and more high dose oral B12 is administered the situation gradually gets worse and worse, because now much of the HC secreted in saliva (Collins etal 1999) already has inactive B12 bound to it, and so this HC-B12 complex can no longer protect incoming B12 from acid hydrolysis. Over time, the levels of serum B12 get higher and higher, but more and more of the B12 is inactive.

Vitamin B2 deficiency and Paradoxical B12 Deficiency

From the above it can readily be seen that if levels of the two functional analogues of vitamin B2, namely FMN and FAD are reduced the following will happen.

1. The activity of MTHFR will decrease proportionally with the decrease in FAD, thus resulting in reduced production of 5MTHF.

2. The reduced 5MTHF will result in a build-up in Co(I)B12, which over time will oxidize to Co(II)B12.

3. The reduced FMN and FAD will in turn reduce the activity of the enzyme MTRR and so the levels of inactive Co(II)B12 will build up inside the cell and will eventually be discarded from the cell resulting in a build up of Co(II)B12 in serum. A condition of Paradoxical B12 Deficiency will result.

The major cause of Paradoxical Vitamin B12 Deficiency appears to lack of functional vitamin B2, which may occur due to over vitamin B2 deficiency in a person's diet, or deficiency of Iodine, Selenium and/or Molybdenum. Such deficiencies are very common, and our studies have shown that 50% of people with CFS or ASD are deficient in Iodine, 80% in Selenium and/or 50% in Molybdenum.

See http://vitaminb12deficiency.info/hypothyroidism.htm for further information.

Conditions associated with Paradoxical B12 Deficiency

Conditions known to be associated with Paradoxical B12 deficiency include:

Conditions which are associated with functional B2 deficiency, or where Paradoxical B12 deficiency should be suspected

Determination of Paradoxical B12 Deficiency

Paradoxical B12 deficiency can be established in a number of ways:

Measurement of serum MMA levels

Measurement of urinary MMA (Norman etal, 1982)

Organic Acids Testing, in which levels of MMA are increased, as well as HVA/VMA/QA/KA and 5HIAA, and several other markers.

Treatment of Paradoxical B12 Deficiency

It is essential that for successful treatment of Paradoxical B12 deficiency that the cause of the functional vitamin B2 deficiency be addressed including supplementation with sufficient vitamin B2, Iodine, Selenium and Molybdenum. Such treatment, though, is generally not performed, but it has immense consequences as far as treatment results, and explains why literature on treatment of vitamin B12 deficiency is rife with examples in which supplementation studies using inactive forms of vitamin B12 (cyanocobalamin or hydroxocobalamin) without the co-administration of the necessary B2/I/Se and Mo have been ineffective in treatment. (see Langan and Goodbred, 2017;

References

Kolhouse et al. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. NEJM 1978 299: 785-92

Kane et al. Vitamin B12 binding protein as a tumour marker for hepatocellular carcinoma. Gut 1978 19:1105-9

Igarai et al. Serum vitamin B12 levels of patients with rheumatoid arthritis. Tohoku JEM 1978 125:287-301

England JM, Linnell JC Problems with the serum vitamin B12 assay. Lancet 1980- 15:1072-4

Sheppard K, Ryrie D. Changes in serum levels of cobalamin and cobalamin analogues in folate deficiency Scand J. Haem. 1980 25:401-6

Collins etal  Tumor imaging via Indium 111-labeled DTPA-adenosylcobalamin Mayo Clin Proc. 1999 74:687-691

Norman et al. Cobalamin (vitamin B12) deficiency detection by urinary methylmalonic acid quantitation Blood 1982 59: 1128-31

Christensen et al. Vitamin B12 binding proteins (transcobalamin and haptocorrin) in serum and synovial fluid of patients with rheumatoid arthritis and traumatic synovitis. Scand J Rheum. 1983  12:268-72

Grindulis et al, Rheumatoid arthritis: is serum vitamin B12 high in active disease? J Rheum. 1984 11:211-2

Lindemans et al. Elevated serum vitamin B12 in cystic fibrosis. Acta Paed. Scan 1984: 73: 768-71

Parry et al. Serum valine, methionine and isoleucine levels in patients anaesthetized with and without nitrous oxide. Clin Lab Haem. 1985 7:317-26

Ermens, et al. Significance of elevated cobalamin (vitamin B12) levels in blood. PMID 14636871

Langan and Goodbred. Vitamin B12 deficiency : Recognition and Management Am Fam Phys, 2017, 15, 384-389

Fanidi etal Is high vitamin B12 status a cause of lung cancer. Int J Cancer 2019 146; 1499-1503 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642017/

Bottiger A, and Nisson TK. High levels of vitamin B12 are fairly common in children with cerebral palsy. Acta Paediatr. 2020

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