Glutathione measurements in CFS

Discussion in 'Fibromyalgia Main Forum' started by richvank, Jun 13, 2008.

  1. richvank

    richvank New Member

    Hi, all.

    I wrote the following in response to posts on another board, but I think it might be of interest to people here, too:

    I want to explain what I think the situation is with the measurement
    of glutathione in CFS.

    First, I want to emphasize that the parameters that are directly
    important for the function of glutathione in the biochemistry of the
    body are the concentrations of the reduced or active form of
    glutathione (GSH) and the ratio of the concentrations of the reduced
    to oxidized forms of glutathione GSH/GSSG inside cells. The
    concentration of GSH is important because it determines the rates of
    intracellular reactions that use glutathione. The ratio GSG/GSSG is
    important because it buffers the reduction-oxidation (redox)
    potential inside the cells. It is important for the cells to
    maintain a normal redox potential, because this potential determines
    the rates of many reactions in the cell, including those in the
    mitochondria that involve production of ATP for powering many of the
    cell's reactions.

    Furthermore, it is of particular interest in CFS to determine these
    parameters inside the particular cells that are associated with the
    symptoms of CFS. These include the cells of skeletal muscle, heart
    muscle, the brain and nervous system, the immune system, and glands
    that secrete certain hormones that are found to be deficient in CFS.

    It is not convenient or justifiable to do biopsies of tissues for
    routine diagnosis of CFS. The most accessible media for use in
    assessing glutathione levels are the blood and the urine. In
    interpreting the results of measurements on these media, it is
    necessary to infer what they mean in terms of the values of the above
    parameters in the cells of interest.

    The types of blood samples that can be analyzed include whole blood,
    red blood cells, blood plasma, blood serum, and various types of
    white cells.

    Normal levels of glutathione in the red blood cells are 2.2
    millimoles per liter for GSH (Beutler, E., 1984) and 3.6 micromoles
    per liter for GSSG (Srivastava, S.K., and Beutler, E., 1968).

    Normal serum levels are 2.6 micromoles per liter for free GSH (James,
    S.J., et al., 2008), 7.3 micromoles per liter for total GSH (James,
    S.J., et al., 2008), and 0.24 micromoles per liter for GSSG.

    Because of its relatively high normal level of glutathione, the red
    blood cell has often been the sample of choice of laboratories for
    evaluating glutathione status. However, these cells are quite
    different from the cells of interest, listed above, in terms of their
    structure, their function, their access to substrates for the
    synthesis of glutathione, and their means of obtaining glutathione.
    A mature red blood cell has neither a nucleus nor mitochondria. It
    derives its useful energy from glycolysis of glucose (blood sugar),
    rather than from oxidative phosphorylation (and thus does not use
    fats or amino acids as fuels), and it exports lactate to the blood.
    Its major role is to carry oxygen from the lungs to the cells of the
    body, and to carry carbon dioxide back. It also has roles in
    controlling oxidative stress and in scavenging toxins. These roles
    place heavy demands on glutathione. Accordingly, red blood cells
    have direct, early access to substrates for synthesizing glutathione,
    which are supplied to the blood by the liver and the kidneys, among
    them the rate-limiting amino acid, cysteine. Red blood cells do not
    incorporate the gamma glutamyl cycle, which many cell types use to
    break down circulating glutathione in order to import its amino acids
    and resynthesize it intracellularly. Instead, red blood cells
    synthesize their glutathione ab initio from the amino acids carried
    in the blood. These differences can be expected to impact the
    relative glutathione status of red blood cells and the cells of
    interest in CFS when system-wide glutathione and cysteine depletion
    occur, which puts into question the representativeness of red blood
    cell glutathione levels for the diagnosis and study of the
    pathogenesis and pathophysiology of CFS.

    Glutathione is normally compartmentalized in the body. This means
    that different cells, tissues and organs have differing normal levels
    of glutathione, differing means of obtaining glutathione, differing
    access to substrates, differing capacity for synthesis of glutathione
    because of differing gene expression of the enzymes involved, and
    differing demands for glutathione.

    As I noted above, the rate-limiting amino acid for the synthesis of
    glutathione is cysteine. In an average diet, only about half of the
    cysteine needed by the body is supplied in the diet. The rest must
    be synthesized in the body from methionine. In order to do this,
    both the methylation cycle and the transsulfuration pathway are
    necessary. The methylation cycle is found in all true cells of the
    body, but a complete transsulfuration pathway has so far been found
    in the cells of only a few vital organs: liver, kidneys, intestines,
    pancreas, lens of the eye, and, with a much smaller capacity, the
    brain. It can be expected that when cysteine and glutathione become
    depleted, the cells that do not have a complete transsulfuration
    pathway will likely be most impacted. These include the cells of the
    organs that are most associated with CFS symptoms, as discussed
    above: the skeletal muscles, heart muscle, brain and nervous system,
    immune system, and certain glands. This is one of many observations
    that are consistent with the Glutathione Depletion—Methylation Cycle
    Block hypothesis for CFS.

    The liver is normally the main producer of glutathione in the body,
    and it normally exports glutathione to the blood for use by other
    organs, tissues and cells. Liver cells normally have the highest
    concentration of glutathione in the body, about 10 millimoles per
    liter. When the liver is not able to produce glutathione in amounts
    beyond its own basic needs, the other organs that it normally
    supplies can be expected to suffer depletion of glutathione.

    The best practical type of sample for inferring the glutathione
    status inside the cells of interest in CFS is blood serum. The
    reason is that these cells are essentially in contact with the blood
    serum (via the extracellular fluid). These cells receive their
    supply of reduced glutathione (GSH) from the blood serum, and if they
    are in a state of oxidative stress, they export GSSG to the blood

    Unfortunately, the published measurements of glutathione levels in
    CFS were generally not made on blood serum, and many include only
    total glutathione levels. However, there is a growing unpublished
    database on blood serum measurements of both GSH and GSSG from the
    Vitamin Diagnostics, Inc., methylation panel, and these measurements
    are showing depletion of GSH or elevation of GSSG, or both, in the
    majority of PWCs whose results I have seen. This corresponds very
    well to the situation in autism, which appears to share similar
    genetic and biochemical issues with CFS.

    Urine amino acids testing can also give insights on the glutathione
    status of a person with CFS. Typically, pyroglutamate is found to be
    low in CFS, and this reflects low glutathione status in the kidneys,
    the intestines, or both. Since these organs have a complete
    transsulfuration pathway, it can be inferred that if they are low in
    glutathione, the organs that are of most interest in CFS are likely
    even lower in glutathione status. Another helpful indicator that is
    often seen in CFS is elevation of citrate accompanied by low levels
    of downstream Krebs metabolites, such as alpha ketoglutarate. This
    most likely indicates a partial block at aconitase, caused by
    oxidizing free radicals, indicating glutathione depletion. This
    indicator most likely reflects the condition in the skeletal muscles,
    considering that they represent a large fraction of the total
    cellular mass that contributes to urine Krebs metabolites.

    While I realize that the published reports of glutathione
    measurements on their surface may lead one to doubt whether depletion
    of glutathione is widespread in CFS, I am observing that when
    measurements are properly done on the most appropriate sample media,
    they reveal no doubt that glutathione depletion is a major factor in
    most cases of CFS in which these measurements have been made. The
    excellent agreement between the biochemical observations and symptom
    reports from PWCs with a variety of aspects of the Glutathione
    Depletion—Methylation Cycle Block hypothesis for CFS is further
    evidence of the pivotal importance of glutathione depletion in CFS.
    The growing success of treatment directed at lifting the methylation
    cycle block and allowing glutathione to rise to normal levels also
    supports the validity of glutathione depletion in CFS.

    Best regards,

  2. Dlebbole

    Dlebbole New Member

    As a patient of Dr. Salvato, I received 20 IM injections of glutathione (ouch). She liked to use NK levels as a measure of progress. There was actually very little change, but a slight increase. But when I started taking amino acid capsules, my NK levels went up much more, and most importantly, I FELT better.

    I wonder if IM injections simply supply glutathione locally, and therefore don't address a systemic, multi-organ problem.

    Also, while I did get a slight herx from the amino acids, mostly they just make me feel BETTER. I have received my 5 supplements, but I am almost paralyzed with anxiety about actually staring them. I have a history of severe chemical sensitivity (was a prisoner in my home for several years) and I have learned to take extremely small doses of the normal starting dose of drugs/supplements. I think I read about Rivka dividing up the powders into 1/32 or so. When I started doxycycline (which ended up helping quite a bit), I literally took a speck out of a capsule and got HUGE herx effects. I am considering doing as Rivka does, but then diluting the small amount in water and taking a teaspoon or so. I'd really like to find the dose that doesn't do anything!!! If the supplements cause so much herx, why do I feel better/more energetic when I eat liver (vitamin B12)?

    BTW, do you find anything in the MCB to explain gout or pseudogout? Best regards, Diane
  3. deliarose

    deliarose New Member

    Can you say more about the amino acid capsules? How long did it take to see an effect, what dosage, what brand etc?

    Amino acids are part of the yasko protocol,but I've neglected them cos of cost.

  4. Dlebbole

    Dlebbole New Member

    Hi Deliarose, you used "Debbie" in your title, but I assume you are talking to me, Diane! ;)

    I use Allergy Research Group's Free Aminos. The suggested use is 1 or 2 capsules, one to three times daily. My standard practice with capsules is to open it up, empty a tiny amount into an empty gelatin capsule, wait four days, and assess things. With the fraction of a capsule, I got an "accentuation" of my normal symptoms - at that time, weakness/fatigue. When I got through that stage (usually lasts one day), I noticed that I had more energy. I remember it clearly because my son was young and I was walking alongside of him riding his bike and he needed a boost. I pushed him for a few steps and thought "wow, this should be making me feel weak, but it isn't." So it was a subtle thing. But real.

    I asked about gout or pseudogout because the free aminos also produced a sore toe, a common symptom of gout/pseudogout. Currently, I am taking just two capsules (my top dose was 6) and I am also taking one packet of Imuplus. I hope this helps - any more questions, just ask! DE
  5. deliarose

    deliarose New Member

    thank u .. sorry about the confusion over yr name...

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