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low homocysteine and B12 deficiency

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by lizw118, Aug 5, 2010.

  1. lizw118

    lizw118 Senior Member

    I have read a lot about how B12 deficiency and high homocysteine go together in tests. I have consistently come up with deficiency in B12, but I have also have been flagged as low in homocysteine. Does anyone understand what this could mean?
  2. richvank

    richvank Senior Member

    Hi, Liz.

    You are not alone. In CFS and autism, both of which involve a partial block in the methylation cycle, people can have high, normal, or low homocysteine.
    This has not been carefully studied, to my knowledge, but I think the low homocysteine can be caused by several factors, and it may differ from one person to another. The first possibility is low methionine. This seems to be pretty common in CFS, especially in people who have polymorphisms in the CBS enzyme, which cause excessive draining of metabolites from the methylation cycle into the transsulfuration pathway. I first learned of this from Dr. Amy Yasko, and the clinical study that Dr. Nathan and I conducted (you can find the 2009 poster paper on it at gave evidence of this effect. Since homocysteine is made from methionine, it makes sense that low methionine would produce low homocysteine.

    Another possibility is a polymorphism in the MAT enzyme, which converts methionine into S-adenosylmethionine, which is upstream of homocysteine, or a low ATP status, since ATP is needed by this reaction. Another possibility is polymorphisms in AHCY, which is the enzyme that converts SAH into homocysteine. Dr. Yasko's nutrigenomics panel characterizes some CBS and ACHY polymorphisms. Methionine is measured in amino acids tests.

    Best regards,

  3. lizw118

    lizw118 Senior Member

    Wow, thanks so much, Rich. I am going to look into the link you posted and read more about this. Your post is more info than I have found anywhere on low homocysteine. Is there anything I should take for any of these things? I know from a metametrix test that my methylation system (not sure what to call it?) is not quite right, but I don't know much about this stuff yet. I have tried Sam-e once, but it didn't seem to help.
  4. richvank

    richvank Senior Member

    Hi, Liz.

    In my opinion, the best test panel to run is the methylation pathways panel offered by the Health Diagnostics and Research Institute in New Jersey. This panel evaluates the status of the methylation cycle, the folate metabolism, and glutathione. In my opinion, this is the best diagnostic panel for CFS. If this panel indicates that these aspects are abnormal, the person has CFS, in my opinion. There is a relatively simple and inexpensive nonprescription treatment protocol, described at the website I cited in my earlier post that has helped many people with CFS. This protocol is designed to correct the root issue, which is a partial block in the enzyme methionine synthase, which utilizes vitamin B12 as a coenzyme, and which converts homocysteine to methionine. SAMe is one of the four metabolites in the methylation cycle, and adding it can be helpful for some people who have ME/CFS, but this does not correct the root issue, which this protocol is designed to do.

    The contact information for the test panel is pasted below. I hope this is helpful.

    Best regards,


    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel. The panel costs $300.

    The panel requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinician’s letterhead.

    Available from:

    Health Diagnostics and Research Institute
    540 Bordentown Avenue, Suite 4930
    South Amboy, NJ 08879
    Phone: (732) 721-1234
    Fax: (732) 525-3288

    Lab Director: Elizabeth Valentine, M.D.

    Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive comments below:

    Interpretation of the Health Diagnostics
    Methylation Pathways Panel

    Rich Van Konynenburg, Ph.D.

    Several people have asked for help in interpreting the results of
    their Health Diagnostics methylation pathway panels. Here are my
    suggestions for doing so. They are based on my study of the
    biochemistry involved, on my own experience with interpreting more
    than 120 of these panel results to date, and on discussion of some of
    the issues with Tapan Audhya, Ph.D.

    The panel consists of measurement of two forms of glutathione
    (reduced and oxidized), adenosine, S-adenosylmethionine (SAM) , S-
    adenosylhomocysteine (SAH), and seven folic acid derivatives or

    According to Dr. Audhya, the reference ranges for each of these
    metabolites was derived from measurements on at least 120 healthy
    male and female volunteer medical students from ages 20 to 40, non-
    smoking, and with no known chronic diseases. The reference ranges
    extend to plus and minus two standard deviations from the mean of
    these measurements.

    Glutathione: This is a measurement of the concentration of the
    reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. From what I've seen, most people with chronic fatigue
    syndrome (PWCs) have values below the reference range. This means
    that they are suffering from glutathione depletion. As they undergo
    the simplified treatment approach to lift the methylation cycle
    block, this value usually rises into the normal range over a period
    of months. I believe that this is very important, because if
    glutathione is low, vitamin B12 is likely unprotected and reacts with toxins
    that build up in the absence of sufficient glutathione to take them
    out. Vitamin B12 is thus “hijacked,” and not enough of it is able to
    convert to methylcobalamin, which is what the methylation cycle needs
    in order to function normally. Also, many of the abnormalities and
    symptoms in CFS can be traced to glutathione depletion.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. In many (but not all) PWCs, it is elevated above the normal
    range, and this represents oxidative stress.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. Adenosine is a product of the reaction that converts
    SAH to homocysteine. In some PWCs it is high, in some it is low, and
    in some it is in the reference range. I don't yet understand what
    controls the adenosine level, and I suspect there is more than one
    factor involved. In most PWCs who started with abnormal values, the
    adenosine level appears to be moving into the reference range with
    methylation cycle treatment, but more data are needed.

    S-adenosymethionine (RBC) (SAM): This is a measure of the
    concentration of SAM in the red blood cells. Most PWCs have values
    below the reference range, and treatment raises the value. S-
    adenosylmethionine is the main supplier of methyl groups in the body,
    and many biochemical reactions depend on it for their methyl
    groups. A low value for SAM represents low methylation capacity, and
    in CFS, it appears to result from a partial block at the enzyme methionine
    synthase. Many of the abnormalities in CFS can be tied to lack of
    sufficient methyation capacity.

    S-adenosylhomocysteine (RBC) (SAH): This is a measure of the
    concentration of SAH in the red blood cells. In CFS, its value
    ranges from below the reference range, to within the reference range,
    to above the reference range. Values appear to be converging toward
    the reference range with treatment. SAH is the product of reactions
    in which SAM donates methyl groups to other molecules.

    Sum of SAM and SAH: When the sum of SAM and SAH is below 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathione beta synthase (CBS)
    enzyme, though this may not be true in every case.

    Ratio of SAM to SAH: A ratio less than about 4.5 also represents low
    methylation capacity. Both the concentration of SAM and the ratio of
    concentrations of SAM to SAH are important in determining the
    methylation capacity.

    5-CH3-THF: This is a measure of the concentration of 5-methyl
    tetrahydrofolate in the blood plasma. It is normally the most
    abundant form of folate in the blood plasma. It is the form that
    serves as a reactant for the enzyme methionine synthase, and is thus
    the most important form for the methylation cycle. Many PWCs have a
    low value, consistent with a partial block in the methylation cycle.
    The simplified treatment approach includes FolaPro, which is
    commercially produced 5-CH3-THF, so that when this treatment is used,
    this value rises in nearly every PWC. If the concentration of 5-CH3-
    THF is within the reference range, but either SAM or the ratio of SAM
    to SAH is below the reference values, it suggests that there is a
    partial methylation cycle block and that it is caused by
    unavailability of sufficient bioactive B12, rather than
    unavailability of sufficient folate. I have seen this frequently,
    and I think it demonstrates that the “hijacking” of B12 is the root
    cause of most cases of partial methylation cycle block. Usually
    glutathione is low in these cases, which is consistent with lack of
    protection for B12, as well as with toxin buildup.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. It is usually on the low side in PWCs.
    This form of folate is involved in reactions to form purines, which
    form part of RNA and DNA as well as ATP.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma.
    Most but not all PWCs have a value on the low side. This form is not used
    directly as a substrate in one-carbon transfer reactions, but it can
    be converted into other forms of folate. It is one of the
    supplements in the simplified treatment approach, which helps to
    build up various other forms of folate.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. In PWCs it is lower than the mean normal value of 3.7
    nanomoles per liter in most but not all PWCs. This is the
    fundamental chemically reduced form of folate from which several
    other reduced folate forms are made. The supplement folic acid is
    converted into THF by two sequential reactions catalyzed by
    dihydrofolate reductase (DHFR). THF is also a product of the
    reaction of the methionine synthase enzyme, and it is a reactant in
    the reaction that converts formiminoglutamate (figlu) into
    glutamate. If figlu is high in the Genova Diagnostics Metabolic
    Analysis Profile, it indicates that THF is low.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. Low values suggest folic acid deficiency in the
    current diet. High values are sometimes associated with inability to
    convert folic acid into other forms of folate, such as because of
    polymorphisms in the DHFR enzyme. They may also be due to high
    supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic
    acid in the whole blood. See comments on 5-formyl-THF above. It
    usually tracks with the plasma 5-formyl-THF concentration.

    Folic acid (RBC): This is a measure of the concentration of folic
    acid in the red blood cells. The red blood cells import folic acid
    when they are initially being formed, but during most of their
    approximately four-month life, they do not normally import, export, or use
    it. They simply serve as reservoirs for it, giving it up when they
    are broken down. Many PWCs have low values. This can be
    caused by a low folic acid status in the diet over the previous few
    months, since the population of RBCs at any time has ages ranging
    from zero to about four months. However, in CFS it can also be
    caused by damage to the cell membranes, which allows folic acid to
    leak out of the cells. Dr. Audhya reports that treatment with omega-
    3 fatty acids can raise this value over time.
    Gavman likes this.
  5. Freddd

    Freddd Senior Member

    Salt Lake City
    HI Liz,

    While I can't give you the full biochemical rundown, I can tell you this about testing for b12. The homocyctein test can indicate that there is a breakown in one step of the biochemical process. It does not indicate if one has adequate b12, only sometimes low b12 and that applies to the body-mb12 characteristic only. It does not account for the brain-mb12, body-adb12 or brain-adb12 shortages at all. Treating to specific test results appears to produce unreliable and poor results in the realm of b12 and folate testing including the indirct Hcy and MMA tests. Only trying both active b12s plus methylfolate can tell you if you will respond to one, two or three of them. Also, l-carnitine fumarate may be required for any of them to work.
  6. roxie60

    roxie60 Senior Member

    Central Illinois, USA
    Hi Liz, I also have B12 def and all homocysteine tests have been low. No insight, just letting you know you are not alone.

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