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HIgh Vitamin B12

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by RachelSkates, May 19, 2011.

  1. RachelSkates

    RachelSkates

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    I have been reading with great interest these links.

    I always test high for Vit B12 and they always say, "Oh you must be taking supplements" I tell them I am not because I have too much, or so it seems and they just do nothing.

    But it looks like one may have a deficiency that shows high B12 because it is not processes?

    I have a lot of neuro symptoms, neuropathy in hands and feet, emotional, eating problems......but all brain scans are normal.

    Can this be a deficiency? Should I see someone new? What kind of Dr?

    These posts are really making me think.
     
  2. L'engle

    L'engle moderate ME

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    I had high b-12 on blood tests as well. It could still be a deficiency. I'm improving on the b-12 protocol. I'm not sure of what doctor can help though.
     
  3. richvank

    richvank Senior Member

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    Hi, RachelSkates.

    It's possible to have a functional deficiency in vitamin B12, rather than an absolute deficiency. In this case, a conventional serum B12 test can show a normal or high B12 level, but it is not meaningful, because this type of test measures the total B12 in the blood serum. Most of this is bound to haptocorrin, and is not available to the cells of the body in general, but only to the liver cells for reprocessing. Only the fraction bound to transcobalamin is available to the cells in general.

    You can check this out by running a urine test for methylmalonate. If it's high (or even somewhat elevated), you likely have a functional B12 deficiency. If your doctor won't run such a test, you can order one without a doctor's order yourself, from www.directlabs.com. Order the Genova Diagnostics Metabolic Analysis Profile. This is a urine organic acids panel, which includes methylmalonate. You can collect the urine sample yourself at home, and ship it to the lab in the mailer provided. You will get the results back directly by email and/or postal mail.

    I don't know where you are located, and not sure how far you are willing to travel, so am not able to suggest a physician. Generally speaking the naturopaths, complementary or integrative physicians, members of ACAM. functional medicine doctors, DAN! autism doctors, and some of the osteopaths (D.O.'s) are the ones most likely to be up to speed on this.

    Best regards,

    Rich
     
  4. lampkld2

    lampkld2

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    Rich,

    Is it possible to have a low urine MMA and still have a B12 "issues" (I'm being purposely vauge) and or methylation block?
     
  5. richvank

    richvank Senior Member

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    Hi, lampkld2.

    Yes, it is. There are some genetic inborn errors of metabolism that affect the use of B12 for the methylation cycle, but not for the mitochondria. Thus, enough adenosyl B12 is formed to avoid elevated MMA, but there is still a problem with use of B12 to form methyl B12 for the methylation cycle.

    Rich
     
  6. lampkld2

    lampkld2

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    Thank you. Would that be MTRR?
     
  7. Freddd

    Freddd Senior Member

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    Hi RachaelSkates,

    A study with methylb12 done in the UK a few years ago accepted people by neurological symptoms such as yours. The average b12 level measured before treatment was over 700pg/ml with the highest levels over 1500pg/ml. 63% of positive responders would have been excluded by tests having "normal" or "high" serum cobalamin level, "normal" MMA and "normal" Hcy. These tests are normed on a population that is chronically deficient of b12 and folate and based on average plus and minus 2 standard deviations or thereabouts. That means that 95% of people fall into that range. It is NOT based on levels needed to be asymptomatic and what little clinical basis it has is based on mostly "normal" range red cell size. First alert on red cell size 50 years ago was >92. Now it is based on >100, also due to the same chronic deficiency of folate and b12. These tests do not ever indicate sufficiency. That is a misuse and misinterpretation of the test. The ONLY definitive test is a methylb12 trial and I would also include Metafolin and cofactors. The food supply has been invaded by the pseudo vitamins cyanocbl, hydroxycbl and folic acid. These can provide ""normal" serum levels yet don't work at all for some 1/3 of people and poorly for the rest.

    In Japan, with the "low" alert set at 550 instead of 170 or so the Alzheimer's rate is 20% of the USA. Japan is also the only country that uses methylb12 as it's standard form of b12.

    You need to try the active b12 protocol. You can be substantially healed in a year if you have mb12, adb12 and/or Methylfolate deficiencies. Delay time matters. The longer you wait the worse the neuropathies get until the become permanent, and damage up to and including brain damage and even death. I've been there and done that.

    Extremely high levels of b12 in serum without supplements can indicate liver damage. What were your numeric levels?
     
  8. richvank

    richvank Senior Member

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    Hi, lampkld2.

    Mutations in three different genes have been found to produce problems in the methylation cycle (with elevated homocysteine in the urine) without giving rise to elevated MMA. These genes are MTR, MTRR, and MMADHC. Note that these are serious mutations (so-called inborn errors of metabolism), not the more common polymorphisms that are evaluated by Amy Yasko, for example. These mutations generally produce serious problems that show up early in a person's life.

    In Freddd's case, based on his reported inability to produce enough methylcobalamin or adenosylcobalamin from hydroxocobalamin, cyanocobalamin, or glutathionylcobalamin, I suspect that he has a mutation in one of the following genes: MMACHC, MMADHC (variant 2) or LMBRD1.

    Best regards,

    Rich
     
  9. Freddd

    Freddd Senior Member

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    Hi Rich,

    That's quite possible. However as long as I was eating meat I got sufficient b12 to appear reasonably normal. I was a baby in the days before cyanocbl and folic acid in baby formula. Other genetic problems are inferable from my inability to utilize folic or folinic acid. We don't know why folks with FMS and CFS have low CSF cobalamin levels regardless of body level. It might be genetic and that is something I share with the FMS/CFS cohort. Since the glutathione induced folate deficiency is easily demonstrable in just about anybody who fulfills certain criteria; having big response to mb12 and Methylfolate with massive reversal of symptoms before taking the glutathione and then the induced folate and mb12 and adb12 deficiency crash. The difference was that my crash was faster, worse and longer lasting with more lasting damage done. However in 6 weeks 100% of 10 people all had the same deficiency crash and the similar treatment reversed it mostly. I share the multi-deficiency crash. My genetics made it worse but I don't think that the glutathione induced deficiencies were genetically induced. It is easily demonstrated by those meeting the criteria.
     
  10. Freddd

    Freddd Senior Member

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    Hi RachaelSkates,

    I wanted to include one other aspect I didn't have a chance to in my previous response. A reason a person may have lots of neurological symptoms and "high" serum cobalamin level is that the cerebral spinal fluid cobalamin level can be quite independent of if and be considerably lower than normal despite a high blood serum cobalamin level. This can be a low CSF level of mb12 which may cause elevated CSF Hcy level and/or a low CSF level of adb12 which may cause elevated CSF MMA level or no elevated HCY or MMA. The various patterns of these items exists in CFS, FMS, Alzheimer's, Parkinson's, MS, ALS and some others. So the CSF cobalamin deficiency may be of adb12, mb12 or both. A similar situation exist in the body; separate adb12 (can be indicated by high MMA) or separate mb12 (can be indicated by high Hcy or both. In all there are 4 distinct deficiencies that may be present in any combination. There are different trial methods that can detect the presence of each one of those 4 deficiency types. There are no definitive lab tests.
     
  11. aprilk1869

    aprilk1869 Senior Member

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    I came across this report that came out in March this year, I think it's confirming what you're saying but don't fully understand it...

     
  12. ukme

    ukme Senior Member

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    Can anyone explain what this report is saying?
     
  13. richvank

    richvank Senior Member

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    Protection of aquo/hydroxocobalamin from reduced glutathione by a B12 trafficking chaperone

    We identified a bovine B(12) trafficking chaperone bCblC in Bos taurus that showed 88% amino acid sequence identity with a human homologue. The protein bCblC was purified from E. coli by over-expression of the encoding gene. bCblC bound cyanocobalamin (CNCbl), methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) in the base-off states and eliminated the upper axial ligands forming aquo/hydroxocobalamin (OH(2)/OHCbl) under aerobic conditions. A transition of OH(2)/OHCbl was induced upon binding to bCblC. Interestingly, bCblC-bound OH(2)/OHCbl did not react with reduced glutathione (GSH), while the reaction of free OH(2)/OHCbl with GSH resulted in the formation of glutathionylcobalamin (GSCbl) and glutathione disulfide (GSSG). Furthermore we found that bCblC eliminates the GSH ligand of GSCbl forming OH(2)/ OHCbl. The results demonstrated that bCblC is a B(12) trafficking chaperone that binds cobalamins and protects OH(2)/OHCbl from GSH, which could be oxidized to GSSG by free OH(2)/OHCbl.

    Hi, ukme.

    Thank you for posting this. Here's what I believe it is saying:

    The study involves one of the intracellular (inside the cells) vitamin B12 processing proteins, taken from the cow. It is called the CblC in the human, but is called bCblC in the cow, with the b standing for bovine. This protein serves as a trafficking chaperone. That means that it protects and conveys cobalamin (B12) between steps in the intracellular processing pathways that start with various forms of B12 received by the cell, and end with it being converted to the two active coenzyme forms, methylcobalamin and adenosylcobalamin. It is necessary to protect B12 during this process, because it is very chemically reactive, and will react with toxins and be lost if it is not protected and channeled within the proper biochemical pathways.

    The authors report that the bovine version of this protein is similar to that of the human in its amino acid sequence, differing by only 12% of its amino acids.

    The authors produced a large enough quantity of the pure bCblC by using E. coli bacteria to make it, by grafting the gene for the cow's protein into the bacteria DNA, and then separating the bCblC protein out after it was produced by the bacteria. They then studied it in vitro, i.e. isolated in the laboratory, rather than in the living cells of the cow. This is done because it is a much simpler chemical system, in which individual reactions can be isolated and observed.

    By adding different forms of B12 to a solution containing bCblC, they found that this chaperone would bind all of them under aerobic conditions (that is, in contact with the atmosphere). (Note that the interiors of cells in the body are under less oxiziding conditions than was this solution exposed to the air, so this needs to be considered when oxidation/reduction reactions are involved, and presumably the authors did consider this.) When bCblC bound any of these B12 forms (cyanocobalain, mmethylcobalamin, or adenosylcobalamin), it removed the upper axial ligand (cyano-, methyl-, or adenosyl-) and converted them all to aquocobalamin (this is the same as hydroxocobalamin, because aquocobalamin exists in equilibrium with its dissociated or ionized state, which is hydroxocobalamin, at the pH of the cells). When these forms of B12 are bound to bCblC, they are bound in the base-off configuration. That means that the ligand that is on the other ("bottom") side of the B12 molecule shifts into a different configuration, but is still attached to the molecule.

    While the B12 (cobalamin) was bound to bCblC, it would not react with glutathione. That is, it was protected from reacting (i.e. "chaperoned.") However, free (unbound) hydroxocobalamin will react with glutathione to form glutathionylcobalamin and glutathione disulfide (oxidized glutathione). This means that the aquo-/hydroxo-cobalamin is chemically reduced by glutathione and is then bound to another glutathione molecule. Glutathione disulfide is the oxidized form of glutathione. When glutathione chemically reduces another molecule, it becomes oxidized in doing so. Oxidation and reduction go hand-in-hand in chemistry, because they involve transfer of an electron from one species to another. The one that gives up the electron is oxidized, and the one that receives it is reduced. "Chemically reduced" in this case means that the cobalt ion in the cobalamin molecule is given an electron, which reduces its oxidation state. This ion can have three different oxidation states, i.e. +1, +2, and +3. When it is reduced, it is much more chemically reactive, that is to being oxidized by other species.

    They also found that bCblC will react with glutathionylcobalamin, removing the glutathionyl ligand and converting it to bound aquo-/hydroxo-cobalamin.

    They conclude that bCblC is a trafficking chaperone that binds cobalamins (this was already known) and that it also prevents aquo/hydroxo-cobalamin from reacting with glutathione, which it will do in its free state.

    The complete intracellular B12 processing pathways have not been worked out in detail yet, but it is known that the CblC protein plays an important intermediate role. This protein enables the cell normally to use the whole variety of forms of B12. It first removes whatever ligand is attached to the molecule, and then, using other proteins (enzymes), it normally re-forms as much methylcobalamin and adenosylcobalamin as it needs.

    Some people inherit mutations in the CblC protein's gene, and this causes them not to be able to carry out this normal pathway. Freddd may be a person who has such a mutation, since he has reported that his body is not able to use cyanocobalamin, hydroxocobalamin or glutathionylcobalamin to make the active coenzyme forms of B12 effectively, so he must give his cells the active forms directly. Apparently he must give them in large dosages directly into the blood by sublingual application or injection so that enough will diffuse across the cell membranes to supply what his cells need.

    The exact position of glutathione in the intracellular B12 processing pathways has not been completely worked out. It is known that glutathione will protect B12 from reactions with foreign substances, and this work shows that glutathione will chemically reduce B12. Perhaps glutathione is able to rescue B12 that has become oxidized, and then feed it to CblC so that it can be chaperoned to the next step in the pathway. This is still an area of ongoing research. I'm very interested in this, because the GD-MCB hypothesis that I have proposed holds that glutathione normally protects B12, so that when it becomes depleted, B12 is lost from its normal intracellular processing pathways, and this shuts down the methylation cycle and brings about the onset of ME/CFS. As far as I can tell, the results of this paper would not contradict the hypothesis, but I need to get a complete copy of the paper and study it more carefully, because abstracts can sometimes be misleading or leave out a lot.

    Best regards,

    Rich
     
  14. aprilk1869

    aprilk1869 Senior Member

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  15. richvank

    richvank Senior Member

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    Hi, April.

    Thank you. I read the full paper, and also took another look at an earlier paper that was referenced in it, from Ruma Banerjee's group:

    http://www.jbc.org/content/284/48/33418.long

    As a result, I think I will modify my GD-MCB hypothesis for the pathogenesis of ME/CFS a little. In the past, I have suggested that glutathione protects B12 at an intermediate stage of its processing inside the cells. It appears from the Banerjee paper that it also plays a role in helping the CblC protein to remove the ligands from methyl B12 and adenosyl B12 so that they can be reformed later in the amounts needed by the cell. Without enough glutathione, it seems to me that this part of the B12 pathway would be blocked. Therefore, glutathione depletion would still lead to a functional B12 deficiency and a partial block in the methylation cycle.

    The paper you cited seems to imply by its title that the interaction of glutathione with B12 is something to be avoided. That is normally not the case, and in fact, it is very important that glutathione be present for proper B12 metabolism. In Freddd's case, he has found glutathione to be detrimental. I think the reason is probably that his CblC protein is mutated, such that it is not able to retrieve cobalamin from glutathionylcobalamin, as this protein is normally able to do, shown by this paper.

    Best regards,

    Rich
     
  16. Freddd

    Freddd Senior Member

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    Hi Rich,

    I would agree that b12 needs protection from glutathione. It may be quantity of glutathione related, that a "normal" self generated level is no problem but that an amount that is overwhelming would chemically overpower any enzyme limited reaction. The people doing the trial with me were a varied bunch, some purely b12 deficient by reason of vegetarianism, others with varied degrees and length of deficiencies and probably causes. 100% were hit with the induced folate deficiency symptoms and later b12 deficiency symptoms as I was. My response was the most severe, but all had the same basic effect. There was a range of effects. The vegetarian with subacute combined degeneration was almost as affected as I was. The others all had a lesser degree of damage and a lesser response. I doubt that such a group would have any cause for suspecting a genetic linkage. Of course having paradoxical folate deficiency at the same time may have caused the severity and that does appear genetic, having to do with folic/folinic acid utilization. In the literature I came across statements that some individuals had very large, unexpectedly large, neurological responses from Metafolin. Unfortunately they were just statements in passing and I didn't really do more than notice them at the time. Presumably those persons would be more severely affected neurologically by an induced methylfolate deficiency. Prior to becoming a vegetarian with b12 limited to cyanocbl I had what was clearly CNS cobalamin deficiency problems and body deficiency symptoms to a more limited degree so obviously things were working to a not quite normal extent. It was sufficient for me to be doing extensive library research by 1978-79 when I recognized that cyanocbl wasn't the real b12 for the first time and started looking for the proof, 20 years before mb12 and adb12 would become available and 3-4 years before I became a vegetarian.

    My hypothesis is easily verifiable. Select 10 persons with excellent response to mb12/adb12 and Metafolin who have experienced paradoxical folate deficiency and know what the onset of folate deficiency looks like and have them take sizable doses of glutathione precursors or glutathione infusions daily until they can verify the onset of folate deficiency (other wise known as "glutathione detox") and then stop the glutathione precursors or glutathione infusions and reverse the folate deficiency and restore mb12 and adb12. Recognition can be achieved quickly when the person has experienced the deficiency previously.

    Volunteers to experience a deficiency of limited duration may be difficult to find. Anybody that hasn't already reversed the symptoms with mb12/adb12 and Metafolin isn't going to have the experience as they will merely continue the symptoms they already have generally.

    Deplin (pure Metafolin) side effects
    Are there side effects with Deplin? http://www.deplin.com/DeplinFacts,WhatToExpect
    L-methylfolate was well tolerated in both short-term and long-term trials. Side effects did not differ from a sugar pill (placebo).15-18 Deplin has not been associated with weight gain, sexual dysfunction, nausea, or akathisia.15-21

    http://www.drugs.com/sfx/cerefolin-with-nac-side-effects.htmlCerefolin with NAC

    All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Cerefolin with NAC:
    Bloated feeling; headache; itching; mild diarrhea; mild fever; nausea; vomiting.
    Seek medical attention right away if any of these SEVERE side effects occur when using Cerefolin with NAC:
    Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); lower back or side pain.
    So we see these side effects for Metafolin with NAC and NONE of them for pure Metafolin. These NAC side effects are commonly called "NAC detox" and are in fact identical with severe induced folate effects. Notice the increase in allergic response and the IBS onset. Also identical with "glutathione detox" effects. Also identical with paradoxical folate deficiency effects. The Cerefolin with NAC list is not a complete list, just the consumer list. I'm still chasing down that professional list.
     

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