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GREEN DRINK induced Paradoxical Folate Deficiency and Altitude induced Hypokalemia

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Aug 21, 2011.

  1. Freddd

    Freddd Senior Member

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    I see no reason to go off on genetically modified or bred or hybrid foods on this one. There is no reason for it here. It just creates a smokescreen and confusion. Let's try some critical thinking and consider Occam's Razor here. I'm talking about vegetable source food folate, mostly folinic acid, which is a sufficient explanantion. There could be additional rare reasons or maybe its the summation of 50 rare reasons There is no reason to go far afield on this one. Just Google [ "detox symptoms" green drinks ] with the quotation marks so that there is no reinterpretation or separated words. The advice given to people who are having the readily identifiable induced folate deficiency symptoms being labeled "detox symptoms" is to drink more of these green drinks thereby making the induced folate deficiency worse, reducing the ability to retain active b12s and generally leading to active b12 deficiency symptoms after a longer interval. As the induced folate deficiency symptoms can occur much more rapidly, within ours I doubt that there would be about 9000 hits on this search phrase, including this thread, if it were anything of a truely rare genetic variation nature. Instead it is so common as to be assumed likely to occur and many folks are giving advice about what to do with it, none of which includes discontinuance and a trial of Metafolin to observe near immediate reversal. As this kind of kind of severe induced folate deficiency increases allergic reactions, asthma, multiple chemical sensitivity, cessation of methylation and all the attendent ills of that with some starting within hours. I wouldn't be surprised if we see some people getting very ill or even possibly dead from prolonged usage of green drinks.

    Another possibility is that some of these "detox" symptoms could be the old familiar low potassium symptoms, also commonly called "detox" symptoms, because of the effectiveness of the folate in these green drinks for some people and that it starts up methylation and cell formation. As this can cause many of the same symptoms of nausea, headaches, spasms, pain and heart arythmias and even death, failure to recognize low potassium from effectiveness of the folate gives us the potential of a double bladed hazard here.

    As both sets of symptoms are erroneously called "detox", and either symptoms pattern appear to be present in various green drink users sufferring "detox" I would be inclined to say that having either these patterns possible merely adds to the confusion, misunderstandings and dangerously erroneous advice. Misidentification of induced folate deficiency for any reason or low potassium can both be dangerous to one's health in this game of YOU BET YOUR LIFE. We need to identify what is happening rather than apply wrong assumptions and identifications.
  2. richvank

    richvank Senior Member

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    Hi, Freddd.

    I would expect the "green drinks" to be loaded with potassium, since it is the main ionic species inside cells, and these drinks are made by juicing whole vegetables. So I don't think these drinks are going to cause low potassium. Maybe they produce too high a potassium level, especially in a person who has low adrenal function. I think it's best to measure the level rather than to guess about it.

    Best regards,

    Rich
  3. Freddd

    Freddd Senior Member

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    Hi Rich,

    Thank you for the clarification on the portassium. Testing for potassium could certainly clarify that. I don't know what the situation is and was offerring up possibilities based on offered descriptions. As regards the folate situation I have not read of a type of folate test that would detect paradoxical folate deficiency. Is there one? The induced folate deficiency is very clear however, and appears to be at least somewhat quantity linked.
  4. richvank

    richvank Senior Member

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    Hi, Freddd.

    I think this could be approached both genetically and biochemically.

    On the genetic side, one could run the genotype panel offered as a saliva test without a doctor's order by www.23andme.com Their panel includes 22 genomic polymorphisms in the MTHFS enzyme, which I suspect has a low activity in your case. It might be possible to figure out which polymorphisms are important by comparing your results with those of others. This panel would also give you a lot of other genomic information as well (they include about 1 million of the estimated 10 million polymorphisms in the human genome). Some polymorphisms in some of the intracellular B12 processing enzyme are included in this panel as well. The big issue is figuring out what these data mean after you have them, since most of the polymorphisms have not yet been studied, but some of the most important ones have.

    On the biochemical side, running the methylation pathways panel from Health Diagnostics and Research Institute (contact info below) would give you eight folate-related measurements, including two of folinic acid in different compartments. I think that would show folate abnormalities very well. If this were combined with the Metametrix plasma 40-amino acids panel (available without a doctor's order from www.directlabs.com), a more complete picture would emerge, and if the Genova Diagnostics Metabolic Analysis Profile were also included (also available without a doctor's order from www.directlabs.com) a great deal could be learned.

    Best regards,

    Rich


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


    Available from:

    Health Diagnostics and Research Institute
    540 Bordentown Avenue, Suite 2300
    South Amboy, NJ 08879
    USA
    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 guidance below:


    May 19, 2011


    Interpretation of Results of the Methylation Pathways Panel

    by
    Richard A. Van Konynenburg, Ph.D.
    Independent Researcher
    (richvank@aol.com)


    Disclaimer: The Methylation Pathways Panel is offered by the European Laboratory of Nutrients in the Netherlands and the Health Diagnostics and Research Institute in New Jersey, USA. I am not affiliated with these laboratories, but have been a user of this panel, and have written these suggestions at the request of Tapan Audhya, Ph.D., Director of Research for the Health Diagnostics lab, for the benefit of physicians who may not be familiar with this panel. My suggestions for the interpretation of results of the panel are based on my study of the biochemistry involved, on my own experience with interpreting panel results as part of the analysis of a fairly large number of cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) over the past four years, and on discussion of some of the issues with Dr. Audhya. I am a researcher, not a licensed physician. Treatment decisions based on the results of applying this panel and its interpretation to individual cases are the responsibility of the treating physician.

    Application: In addition to being useful in analyzing cases of ME/CFS, this panel can also be usefully applied to cases of autism and other disorders that involve abnormalities in glutathione, methylation and the folate metabolism.

    The panel includes measurement of two forms of glutathione (reduced and oxidized), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), adenosine, and seven folate derivatives.

    According to Dr. Audhya (personal communication), the reference ranges shown on the lab reports for each of these metabolites were 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 (reduced): This is a measurement of the concentration of the
    chemically reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. The reference range is 3.8 to 5.5 micromoles per liter.

    Glutathione plays many important roles in the biochemistry of the body, including serving as the basis of the antioxidant enzyme system, participating in the detoxication system, and supporting the cell-mediated immune response, all of which exhibit deficits in CFS. The level of GSH in the plasma is likely to be more reflective of tissue intracellular glutathione status than the more commonly and more easily measured red blood cell or (essentially equivalent) whole blood glutathione level, which is about three orders of magnitude greater, because red blood cells are normally net producers of glutathione. Also, knowledge of the level of the reduced form, as distinguished from total (reduced plus oxidized) glutathione, which is more commonly measured, is more diagnostic of the status of glutathione function.

    In order to be able to approximate the in vivo level of reduced glutathione when blood samples must be shipped to a lab, it is necessary to include special enzyme inhibitors in the sample vials, and these are included in the test kit supplied by these two laboratories.

    Most people with chronic fatigue syndrome (PWCs), but not all, are found to have values of GSH that are below the reference range*. This means that they are suffering from glutathione depletion. As they undergo treatment to lift the partial methylation cycle block, this value usually rises into the normal range over a period of a few months. I believe that this is very important, because
    glutathione normally participates in the intracellular metabolism of vitamin B12, and if it is low, a functional deficiency of vitamin B12 results, and insufficient methylcobalamin is produced to support methionine synthase in the methylation cycle. In my view, this is the mechanism that causes the onset of ME/CFS. This functional deficiency is not detected in a conventional serum B12 test, but will produce elevated methylmalonate in a urine organic acids test. In my opinion, many of the abnormalities and symptoms in ME/CFS can be traced directly to glutathione depletion.

    Anecdotal evidence suggests that PWCs who do not have glutathione depletion do have abnormalities in the function of one or more of the enzymes that make use of glutathione, i.e. the glutathione peroxidases and/or glutathione transferases. This may be due to genetic polymorphisms or DNA adducts on the genes that code for these enzymes, or in the case of some of the glutathione peroxidases, to a low selenium status.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. The reference range is 0.16 to 0.50 micromoles per liter.

    Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
    range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

    Ratio of Glutatione (reduced) to Glutathione (oxidized): This is not shown explicitly on the panel results, but can be calculated from them. It is a measure of the redox potential in the plasma, and reflects the state of the antioxidant system in the cells. The normal mean value is 14. PWCs often have a value slightly more than half this amount, indicating a state of glutathione depletion and oxidative stress. This ratio has been found to increase during treatment of a partial methylation cycle block.*

    S-adenosymethionine (RBC): This is a measure of the concentration of S-adenosylmethionine (SAMe) in the red blood cells. The reference range is 221 to 256 micromoles per deciliter.

    SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, coenzyme Q10, melatonin and epinephrine. This measurement is made in the red blood cells because the level there reflects an average over a longer time and is less vulnerable to fluctuations than is the plasma level of SAMe.

    Most PWCs have values below the reference range, and treatment raises the value.* A low value for SAMe represents a low methylation capacity, and
    in CFS, it usually appears to result from an inhibition or partial block of the enzyme methionine synthase in the methylation cycle. Many of the abnormalities in CFS can be tied to lack of sufficient methylation capacity.

    S-adenosylhomocysteine (RBC): This is a measure of the
    concentration of S-adenosylhomocysteine (SAH) in the red blood cells. The reference range is 38.0 to 49.0 micromoles per deciliter.

    SAH is the product of the many methyltransferase reactions that utilize SAMe as a source of methyl groups. In CFS, its value ranges from below the reference range to above the reference range. Values appear to be converging toward the reference range with treatment.

    Sum of SAM and SAH: When the sum of SAM and SAH is below about 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathionine beta synthase (CBS)
    enzyme, though this may not be true in every case. For those considering following the Yasko treatment program, this may be useful information.

    Ratio of SAM to SAH: A ratio less than about 4.5 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, because they affect the rates of the methyltransferase reactions.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. The reference range is 16.8 to 21.4 x 10(-8) molar.

    Adenosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP, and eventually, adenosine. Adenosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

    In some PWCs adenosine is found to be 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 in these patients, and I suspect that 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.

    5-CH3-THF: This is a measure of the concentration of 5L-methyl
    tetrahydrofolate in the blood plasma. The reference range is 8.4 to 72.6 nanomoles per liter.

    This form of folate is present in natural foods, and 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 important form for the methylation cycle. It is also the only form of folate that normally can enter the brain. Its only known reactions are the methionine synthase reaction and reaction with the oxidant peroxynitrite.

    When there is a partial block in methionine synthase, 5L-CH3-THF drains from the cells into the blood plasma by the so-called methyl trap mechanism. As other forms of folate are converted to 5L-CH3-THF, this mechanism depletes the cells of folates in general.

    Many PWCs have a low value of 5L-CH3-THF, consistent with a partial block in the methylation cycle. Most methylation treatment protocols include supplementation with 5L-CH3-THF, which is sold over-the-counter as Metafolin, FolaPro, or MethylMate B (trademarks), and in the prescription medical foods supplied by PamLab, including Deplin, CerefolinNAC and Metanx. There are some others on the market that include both racemic forms (5L and 5R) of this folate.

    When methylation treatment is used, the level of 5-CH3-THF 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 inavailability of sufficient bioactive B12, rather than inavailability of sufficient folate. A urine organic acids panel will show elevated methylmalonate if there is a functional deficiency of B12. I have seen this combination frequently, and I think it demonstrates that the functional deficiency of B12 is the immediate root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with such a functional deficiency. As the activity of the methylation cycle becomes more normal, the demand for 5-CH3-THF will likely increase, so including it in the treatment protocol, even if not initially low, will likely be beneficial.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. The reference range is 1.5 to 8.2 nanomoles per liter.

    This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP. It is usually on the low side in PWCs, likely as a result of the methyl trap mechanism mentioned above. This deficiency is likely the reason for some elevation of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) often seen in PWCs. This deficit may also impact replacement of cells lining the gut, as well as white blood cells.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma. The reference range is 1.2 to 11.7 nanomoles per liter.

    This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate, and may serve as a buffer form of folate. Most but not all PWCs have a value on the low side. It is one of the
    supplements in some methylation protocols. It can be converted to 5L-CH3-THF in the body by a series of three reactions, one of which requires NADPH, and it may also help to supply other forms of folate until the methionine synthase reaction comes up to more normal activity.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. The reference range is 0.6 to 6.8 nanomoles per liter.

    This is the fundamental chemically reduced form of folate from which several other reduced folate forms are synthesized, and thus serves as the hub of the folate metabolism. THF is also a product of the methionine synthase reaction, and participates in the reaction that converts formiminoglutamate (figlu) into glutamate in the metabolism of histidine. If figlu is found to be elevated in a urine organic acids panel, it usually indicates that THF is low. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. The reference range is 8.9 to 24.6 nanomoles per liter.

    Folic acid is a synthetic form of folate, not found in nature. It is added to food grains in the U.S. and some other countries in order to lower the incidence of neural tube birth defects, including spina bifida. It is the oxidized form of folate, and therefore has a long shelf life and is the most common commercial folate supplement. It is normally converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR), using NADPH as the reductant. However, some people are not able to carry out this reaction well for genetic reasons, and PWCs may be depleted in NADPH, so folic acid is not the best supplemental form of folate for these people.

    Low values suggest folic acid deficiency in the current diet. High values, especially in the presence of low values for THF, may be associated with inability to convert folic acid into reduced folate readily, such as because of a genetic polymorphism 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. The reference range is 9.0 to 35.5 nanomoles per liter.

    See comments on 5-formyl-THF above. Whole blood folinic acid 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 reference range is 400 to 1500 nanomoles per liter.

    The red blood cells import folic acid when they are initially being formed, but during most of their lifetime, 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 of this parameter. 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 oxidative 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 has been found to raise this value over time in one cohort.

    If anyone finds errors in the above suggestions, I would appreciate being notified at richvank@aol.com.

    * Nathan, N., and Van Konynenburg, R.A., Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia, poster paper, 9th International IACFS/ME Conference, Reno, Nevada, March 12-15, 2009. (http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf)
  5. Freddd

    Freddd Senior Member

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    Hi Rich,

    I have been thinking about the potassium levels from veggies and fruits just in passing. I was a mostly vegetarian for more than 2 decades. Even now my diet is mostly of vegetable source. Somehow, I am quite incapable of absorbing enough potassium from food for unknown reasons. A 495mg dose of potassium from almost any supplement or salt form will give me relief in 30 minutes or less on an empty stomach from low potassium symptom. Eating veggies and/or fruit that is supposed to contain 3x as much does noting at all for me in 2-3 hours. At this altitude I have to take 1800mg/day supplemental just to have a chance of not running into trouble as compared to 1200mg at home altitude and I don't stay long enough to be fully accomodated to altitude. I haven't yet located much in the way of potassium levels in green drinks but for at least some people it may not be very accessable. I don't know what the situation actually is but it may not be what it might appear. In working my way through layers and layers of assumptions I have found over and over that the assumptions are often wrong, at least in their cumulative summation, as it only takes one faulty one to make the entire logic chain flawed.

    At the moment I don't have the money to do any non-essential testing and am still paying off what one of my docs did 5 months ago.
  6. richvank

    richvank Senior Member

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    Hi, Freddd.

    It's very puzzling to me that your gut does not seem to be able to absorb potassium very well from vegetables or particularly from green drinks. I don't think there are any assumptions involved in knowing that vegetables have high potassium content. Likewise, squeezing the juice out of vegetables clearly ruptures the cells and releases the intracellular fluid, which is where the potassium is located. I don't think there are any assumptions there, either. The more I learn about your metabolism, the more interesting it becomes! What form of potassium supplement do you take? Is it the citrate? It may be that the supplement you take is more absorbable by your enterocytes than the potassium in vegetables, though I don't know why.

    Best regards,

    Rich
  7. Freddd

    Freddd Senior Member

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    To put the cap on this conversation I can now provide some clarifications. Absorption from food causes serum potassium to peak 14 hours after consumption but has a very short serum halflife. If it isn't distributed into the tissues rapidly some have claimed it to be a potentially fatal amount possible from food. So 14 hours after eating is a 3 hour window for availability, basically the period of absorption. I eat two meals a day. That gives me an estimated 6 hours a day of potassium sufficiency and 18 hour of insufficiency. I have had these nighttime leg spasms all my life so I have always had some kind of problems with potassium. Maybe I distribute it very quickly into tissues and don't get it out of tissue easily. Who knows. 400mg at bedtime prevents problems all night reliably. I take the potassium gluconate and I've tried the chloride with no perceptible difference except stomach comfort.

    However, with 3 more years of experience I can clearly say that folinic acid can block 20x the amount of methylfolate and the people unable to use vegetable folates start showing symptoms as children, often as allergies, asthma, MCS and the like.

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