I do think that biotoxins are a big issue in some cases. I don't know whether they will show up as depleted or oxidized glutathione, but I suspect so. Slayadragon has found studies showing that glutathione is depleted by some of the mold toxins. There are also some papers (without clinical data) that claim that mold toxins can lower the B12 status. We know from Dr. Shoemaker's work that the innate immune system is very much involved in biotoxin illness, and that involves inflammation, which involves oxidative stress, which can be expected to impact glutathione, but I haven't put all of this together in a coherent way yet.
...treatment to remove mold toxins from your body, such as cholestyramine, Questran or Welchol, as recommended by Dr. Shoemaker.
With regard to the question about C4a, it's true that we measured it and some other parameters at the recommendation of Dr. Ritchie Shoemaker. Several of the patients in the study had abnormal values, even after 6 months of methylation treatment. As you know, most of the patients in the study, while reporting significant benefit, were not completely recovered.
Dr. Shoemaker believes that several of them had biotoxin illness, perhaps from mold exposure in their homes. He may be right about that. Our study was limited, and we were not able to go on to explore these issues. My current view is that the methylation treatment does indeed address the core of the pathophysiology of ME/CFS. However, for most PWMEs, this is not enough to produce complete recovery. My view at this point is that in most cases it is also necessary to treat the etiologies, i.e. the root causes that brought about the glutathione depletion and produced the vicious circle mechanism that the methylation treatment deals with. In addition to the etiologies, I think that other toxins and pathogens can accumulate during the illness, because the immune system and the detox system are not functioning normally and are not able to dispose of toxins or defeat pathogens. Even though the methylation cycle function can be brought closer to normal and glutathione can be raised in most PWMEs wth methylation treatment, the etiologies and accumulated toxins and/or pathogens in most cases will need to be treated directly and specifically as well. The particular ones differ from one case to another, but the possibilities of which I'm currently aware, based on experience with cases, are as follows: Lyme disease and coinfections; biotoxin illness, especially due to water-damage in buildings; high body burdens of toxic metals, especially mercury; entrenched viral and possibly retroviral infections that are able to hide from the immune system, such as by producing nagalase; HPU (hemopyrolactamuria, also called KPU or kryptopyroluria); serious gut dysbiosis; and deficiencies of essential nutrients.
Here are some possible reasons for non-response on the methylation protocol:
1. The person does not have a partial methylation cycle block. I think this one is unlikely if a person has the symptoms of ME/CFS, since nearly all who have these symptoms do have the partial block, based on testing of many people at this point. Nevertheless, I think this is a possibility. The methylation pathways panel from Health Diagnostics or the European Lab. of Nutrients will determine whether the partial block is present.
2. The person is lacking enough of the supporting vitamins and minerals for the enzymes in the methylation cycle and related pathways. Having HPU (hemopyrrollactamuria) is one possible cause of this. It depletes zinc, B6, biotin, and manganese. Testing is also available from the above labs for vitamins and minerals as well as for HPU.
3. The person has a high body burden of one or more of the toxic heavy elements that bind to sulfhydryl groups: mercury, lead, arsenic or cadmium. These elements can block enzymes in this part of the metabolism. Testing is available for these as well.
4. The person suffers from something that is holding down their glutathione. This might be mold illness or other biotoxin illnesses, Lyme disease and its coinfections, or viral infections. I think this one is more likely to hinder progress on the treatment, rather than to cause no response at all.
there are some other tests that can be helpful. As Freddd mentioned, extensive testing can be costly. For some patients, the costs are not a problem, and they can order what they want. For most, this is not the case, and they need to prioritize and get the most value they can for the resources they have. I would suggest the following additional tests, if the resources are available, starting with what I think is the most helpful and cost-effective, and working down to others that are helpful if it is feasible to run them:
1. Genova Diagnostics Metabolic Analysis Profile or MAP (This is a urine organic acids test. Somewhat similar tests are the Metametrix Organix panel and the Great Plains Lab OAT.) This type of test looks at several aspects of the overall metabolism, and can give information about vitamin and mineral deficiencies. The MAP includes both methylmalonic acid and formiminoglutamic acid and can therefore give indirect information about the status of the methylation cycle and the folate metabolism. This panel can also give indirect information about the status of glutathione.
2. Plasma amino acids panel. I like the Metametrix 40 plasma amino acids panel, because the printout is easy to interpret, but Life Extension offers a 40 plasma amino acids panel at a lower cost. Genova Diagnostics offers one with 42 amino acids. Doctor's Data offers one, also. I like the plasma data, because it's closer to the cells. However, the urine amino acids data is helpful, also. It is more sensitive, but requires some interpretation, because it depends on kidney function. It's very helpful to have this one together with the organic acids panel, because they help to interpret each other.
3. Toxic and essential elements. I have most of my experience with the Doctor's Data urine panel, but there are others, for both urine and blood (whole blood or red blood cells). These panels are helpful for detecting mineral deficiencies as well as assessing whether toxic metals are an important issue in a given case. If the toxics are too high, they may prevent lifting of the partial methylation cycle block. There are also hair tests for minerals and fecal tests for toxic elements that can be helpful.
4. If there are problems with the digestive system, comprehensive stool testing is needed. I like the Diagnos-Techs Expanded G.I. Panel, but there are also stool tests offered by Genova Diagnostics, Metametrix, and Doctor's Data.
5. Beyond these, there are other tests that I suggest depending on the issues that a particular person has. If Lyme disease or its coinfections seem like a good possibility, then I suggest Igenex testing. There is a new culture test offered by Advanced Laboratory Services that promises to be more definitive. If mold or other biotoxin illness seems like a good possibility, I suggest the visual contrast sensitivity test offered by Dr. Ritchie Shoemaker at
www.chronicneurotoxins.com, and if it is positive, then an ERMI test of the home by
www.mycometrics.com and the HLA panel by LabCorp. If hemopyrolactamuria (HPU) looks like a good possibility, then I suggest the HPU test from Health Diagnostics and Research Institute. If heavy metal toxicity looks like a good possibility, then I suggest a DMSA-provoked urine collection test, as from Doctor's Data. If entrenched viral infections appear to be present, then I suggest serum immunoglobulin testing for the range of viruses commonly found in ME/CFS.
There are others, but I think I will stop here. There are some combination profiles, such as the Genova Diagnostics NutrEval profile, and the Metametrix ION profile. These incorporate some of the above tests and some others. They may not be optimum sets of tests, but the combinations can be less expensive, and a lot can be learned from them, especially about nutrient deficiencies, but also about the metabolism in general.
I view the genetic polymorphism tests as interesting and as having a lot of potential for the future. Amy Yasko's nutrigenomic panel can be of some help, as can the less expensive but more comprehensive 23andme.com panel. These give tendencies, but do not give direct information about what is actually going on in the biochemistry at present. They can be helpful in trying to understand why a particular person became ill.
The interpretation of the above tests is not always straightforward. It takes some experience to understand how they fit together. The book that is sold by Metametrix is very helpful, but it is also necessary to understand the biochemistry of ME/CFS to properly interpret these tests, and that is not included in the book.
Best regards,
Rich
