I still don't understand the link between MCAS, adrenal exhaustion, methylation block, leaky gut, viral load, Lyme, ... which so many of us suffer from.
Hi, Marlene.
Here's a speculation. I won't dignify it by calling it a hypothesis
:
As I think you know, I believe that the core of the pathophysiology of ME/CFS is the vicious circle mechanism that involves a partial block in the methylation cycle and glutathione depletion.
The adrenal exhaustion is really a problem higher up in the HPA axis for most PWMEs: glutathione depletion in the pituitary interferes with the amount and diurnal variation of the ACTH secretion, and this causes the low and poorly regulated cortisol output from the adrenals.
Leaky gut is caused by bacterial dysbiosis in the intestine. This could have come before the onset of ME/CFS, such as from the use of antibiotics without probiotics. It could also be caused by the vicious circle mechanism, by a variety of pathogenetic pathways: Low glutathione removes protection of the gut from oxidative stress, pathogens and toxins. Low folates interfere with formation of new DNA to make cells to replace those that are sloughed off. The lifetime of enterocytes is only a few days. Usually there is low secretory IgA, which may be caused by the cortisol abnormality, which in turn is caused by low glutathione.
The viral load is a consequence of dysfunction of cell-mediated immunity, which in turn is caused by glutathione depletion, which prevents proper formation of perforin in the NK and killer T cells.
Lyme disease is likely the first cause of the illness in many cases, and others may be exposed to tick bites after the onset of ME/CFS. Lyme and its coinfections lead into ME/CFS in those who are genetically predisposed, because they cause oxidative stress (in some of the infections directly, such as Babesiosis, and in others by the inflammatory response of the immune system to them, and Borrelia take cysteine from their host, which is the rate-limiting amino acid for making glutathione.
Now, the mast cells are a new feature that I have not thought much about yet. Here's the speculation: We know that mast cells make histamine,among other things. Histamine is made from the amino acid histidine. Normally, a lot of the histidine is converted to formiminoglutamate and is then metabolized by reacting with tetrahydrofolate. If folate is depleted, as in the vicious circle mechanism I have described, the breakdown of histidine is partially blocked. Presumably this would raise the level of histidine, and that might cause more histamine to be produced. In addition, there are two reactions tha normallybreak down histamine. One is inside the cells, and it requires methylation, which is partially blocked when the vicious circle is operating. The other is diamine oxidase, which operates outside the cells. This requires B2 and B6 as well as copper. For various reasons, PWMEs tend to go low in B2 and/or B6, probably mainly because they have to use it a lot for amino acids transaminase reactions, because they burn more amino acids for fuel than normal, again because glutathione depletion blocks use of carbs and fats at normal rates.
So probably more histamine is being made, and the reactions to break it down are working less rapidly.. This leads to high histamine. Now, histamine is known to be a neurotransmitter, and mast cells are known to be located near nerves. What if the histamine stimulates the nerves, producing hypersensitivity to pain, and then the neurons produce more substance P or other neuropeptides, which in turn are known to stimulate mast cells? Then we would have a dirty little vicious circle mechanism that would cause the pain sensitivity and the skin rashes, and it all comes back to the GD-MCB vicious circle mechanism.
Now pure fibromyalgia is different. It's beginning to look like the mast cell-nerve interaction is going on there, too. But possibly something else kicks it off, other than the GD-MCB vicious circle that we find in ME/CFS. Once it gets going, it is a vicious circle itself, and I think it could account for the chronic nature of fibromyalgia. I would like to know more about pure fibro, because it affects a lot of people. It looks like some good things are happening in fibro research these days.
Again, I am just speculating and don't have a lot to back this up with.
Best regards,
Rich
