To Nicola re: Diastolic dysfunction
Hi Rich
thanks for the explanation. What puzzles me about the orthostatic tachycardia is that I am on full adrenal hormone replacement (prednisolone and Florinef) so I am not sure that the low cortisol and low blood volume thing applies to me, or at least it shouldn't if I have got my dosing right. My blood pressure is normal and my intracellular magnesium is just below the top of the range, according to my last blood test. I know of people whose POTS was 'cured' by adrenal hormone support, so clearly something else is at play for me. The diastolic dysfunction is a distinct possibility - could this also cause the chest pain I wrote about it an earlier post? Is the dysfunction caused by low glutathione, or poor energy production, or a combination of both? Why would this get better with folate and B12? Does methylation play a role in energy production?
I subscribe to the view that the body reacts most strongly to the substances it needs the most - this has been my experience with a number of supplements - so I shall keep going with the methyl folate. I am surprised to have had a bigger reaction to the folate than the mB12 though, as I thought it was B12 that was depleted in mercury toxic people, not folate... Unless the folate is enabling the B12 to work more effectively... aah, so many questions and unknowns. And I really do want to understand all of this.
I really appreciate your input - it is deeply helpful. Thanks again.
Nicola
Hi, Nicola.
Diastolic dysfunction is caused by too low a rate of production of ATP by the mitochondria of the heart muscle cells. The result is that the left ventricle cannot relax as fast as it should, so it cannot take in as much blood as it should. Therefore, the heart's output is less than it should be. In my hypothesis, this results from a rise in the levels of oxidizing free radicals in the mitochondria, which block the Krebs cycle and the respiratory chain. The free radicals rise because glutathione is depleted. There is good evidence for glutathione depletion in CFS. There is also good evidence for oxidative stress, and for low ATP output by mitochondria. Oxidizing free radicals are known to be able to block both aconitase in the Krebs cycle and some of the cytochrome enzymes in the respiratory chain.
In both CFS and autism, it has been found that glutathione depletion is linked to a partial block in the methylation cycle, and it has been found that if this partial block is lifted, glutathione comes up without direct supplementation of it or its precursors. Taking B12 and 5-methyl THF together have been found to lift this partial block, since both are needed by the enzyme methionine synthase, which is where the partial block is located.
When methyl B12 becomes deficient, either because B12 in general is deficient, or because there is a problem in converting B12 into methyl B12, the folate metabolites drain out of the cells into the blood plasma, by a mechanism called the "methyl trap." The methyl trap is based on the fact that almost the only way that 5-methyl tetrahydrofolate can react is in the methionine synthase reaction (though recent work indicates that it can also react with peroxynitrite). Also, 5-methyl tetrahydrofolate does not have a tail of glutamate residues, as do other folate metabolites, and therefore is able to exit the cells into the blood plasma. So when methionine synthase is blocked, much of the folate is converted into 5-methyl tetrahydrofolate and leaves the cells. So the cells then become deficient in both folates and methyl B12, and that's why it's necessary to supplement them together to get the methylation cycle running normally again.
I'm going to paste in an explanation of my hypothesis that I wrote some time ago. Hopefully this will help to put the pieces together. Again, please bear in mind that it is a working hypothesis, not a proven theory:
1. To get an isolated case of CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. This is a topic that needs more research.
2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.
3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.
4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.
5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can't be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.
6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.
7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.
8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.
9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.
10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.
11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.
12. That's the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.
When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.
13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.
14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.
15. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.
16. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.
17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.
18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.
19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.
20. The main question I'm working on now is what else needs to be done to bring people to recovery? I don't have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I'm not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.
Rich
