Hypothesis for origin of water loss in CFS
Hi, all.
I would like to offer my hypothesis for the origin of the water loss to the urine in CFS, leading to the low blood volume, which in turn contributes to the low cardiac output and the orthostatic intolerance.
I agree with Dr. Teitelbaum in that the problem traces back to the hypothalamus, which is not producing enough antidiuretic hormone (also called arginine vasopressin). But the more fundamental question is why isn't the hypothalamus putting out enough of this hormone?
This hormone is part of a class of substances in the body called the secretory proteins. These are proteins that are made inside cells, but are exported from the cells to do jobs outside the cells, in this case, to travel to the kidneys in order to tell them how much water to extract from the blood and excrete into the urine. This particular hormone works backwards; in other words, more of the hormone causes less excretion of water. So if there is not enough of the hormone sent to the kidneys, they dump too much water, and the person becomes hypovolemic (i.e. they have low total blood volume, compared to normal). They also become thirsty, and they tend to keep drinking fluids, but they usually aren't able to catch up with the water loss, and they continue to run somewhat hypovolemic. This contributes to the orthostatic intolerance (together with HPA axis dysfunction and diastolic dysfunction of the heart).
Among the secretory proteins, some are made with cystine double bonds. These help to maintain the shape of the protein molecules, which is important for their function, since they operate by a "lock and key" mechanism with their receptors, and they have to have the right shape to "fit."
In order to form the proper cystine double bonds, which are made between two cysteine molecules at different locations in the string of amino acids that makes up the protein, the correct partners have to be joined together. If the wrong partner cysteine molecules are joined together, the protein will have the wrong shape and will not do its job well.
In order to put the proper partners together, the cell needs to control the process of protein synthesis carefully. First, it strings the appropriate amino acids together in a chain, based on the pattern in the appropriate messenger RNA molecule that gets its pattern from the DNA in the nucleus. Some of these amino acids are cysteine molecules.
These cysteine molecules have to be restrained from forming partners with each other before the proper time (sounds like teenagers, right?
-)
In order to to this, the cells have to control what's called the redox potential, which is sort of the market value of electrons in the cell in energy currency terms. If the redox potential becomes too oxidizing (i.e., electrons less available than they should be), the cysteines will form cystine double bonds prematurely.
O.K., we finally come to the critical substance--Glutathione! The glutathione in the cell is what controls the redox potential, by the ratio of reduced to oxidized glutathione. This ratio has to be high enough to keep the cysteines from joining together until the proper time. So the cytosol, which is the fluid inside the cell that is not contained in any organelles, is normally kept in a reducing state, and that keeps the cysteines apart so that they can be used to form the amino acid chain. As it is formed, the chain is passed into an organelle called the endoplasmic reticulum. The redox potential is maintained in a more oxidizing state inside this organelle. There are also special proteins called "chaperones" (yes, the analogy continues. That's really what they are called.) The chaperone molecules bring the proper partners together, so that the protein has the right shape, and it is then exported from the cell in a regulated way to do its job, in this case to regulate the water lost to the urine.
By now you probably know where I'm going. If the reduced form of glutathione becomes depleted, this mechanism does not work right. The result is that the quality control system in the cell detects some of the misshapen proteins and sends them to recycling, so that they don't leave the cell. Others make it out, but they aren't able to do their jobs well, because they are deformed. Note that some good ones are still made, because the glutathione is only partially depleted. That's why the resulting "diabetes insipidus" (D.I.) (not the same as diabetes mellitus, which involves blood sugar and insulin) is usually a "mild" case in CFS. I know it doesn't seem mild, but severe D.I. really is severe. Doctors often don't diagnose these cases of D.I., because they are trained to look for more extreme cases.
So the fundamental cause of this problem in CFS, in my hypothesis, is glutathione depletion in the hypothalamus. The longterm fix for this is to lift the partial methylation cycle block, which will allow glutathione to come back up automatically. Direct efforts to raise glutathione usually only work temporarily, and one has to keep doing them, in order to hold the glutathione levels up.
There is specific information in the files section of the cfs_yasko group's website about how to lift this partial block. Cort's website also discusses a lot of the background of this hypothesis.
Incidentally, this same mechanism explains a lot of other features of CFS, according to my hypothesis. These include the HPA axis dysfunction (from faulty production of ACTH), the low activity of natural killer cells (resulting from low perforin production), low growth hormone, and low oxytocin, among others.
I hope this is helpful.
Best regards,
Rich
