Hi, all.
Here is the latest revision of the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS:
1. Genetic predisposition is present (perhaps including SNPs in genes coding for enzymes related to glutathione that cause it to be more easily depleted, as reported in autism by Bowers et al., 2011).
2. Stressors (physical, chemical, biological and/or psychological/emotional, the mix varying from one case to another, based on patient histories) deplete glutathione by various means, some by oxidative stress, some by conjugation, some by lowering its rate of synthesis. The depletion of glutathione is demonstrated by the methylation pathways panel.
3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.
4. Glutathione depletion lowers the affinity of the CblC complementation group for cobalamin (as reported by Jeong and Kim, 2011), producing a functional B12 deficiency, thus lowering intracellular methylcobalamin and adenosylcobalamin. Anecdotal observations of elevated urine methylmalonate in the presence of normal or elevated serum B12 in ME/CFS patients confirm the presence of a functional B12 deficiency.
5. The lowered methylcobalamin inhibits the methionine synthase reaction, since it is the necessary coenzyme for this reaction.
6. The methyl trap mechanism continues the conversion of other forms of folate into methylfolate, but the lowered rate of the methionine synthase reaction decreases the demand for it.
7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma [NOTE: THIS STEP WAS CONTRIBUTED BY PROFESSOR MARTIN PALL, BASED ON PUBLISHED LITERATURE, FOR WHICH I AM GRATEFUL.]
8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel).
9. Homocysteine drains into the transsulfuration pathway, since its conversion to methionine is inhibited, and over time, methionine therefore becomes depleted (as found by Bralley and Lord,1994), leading to dysregulation and depletion of the sulfur metabolism in general.
10. The above combination of steps produces a stable vicious circle mechanism, and this is the reason ME/CFS is chronic.
11. The elements of this vicious circle mechanism lead to the abnormalities observed and the symptoms experienced in ME/CFS. Among them is mitochondrial dysfunction, which leads to an increased rate of the main glycolysis pathway and a decreased rate of the pentose phosphate shunt. The latter decreases the level of NADPH, which exacerbates the glutathione depletion by slowing the rate of the glutathione reductase reaction.
12. Boosting glutathione directly is not a successful treatment, because the glutathione reductase reaction cannot keep up with the oxidation of glutathione, due to the depletion of NADPH. [THIS IS BASED ON DISCUSSIONS WITH DR. PAUL CHENEY, FOR WHICH I AM ALSO GRATEFUL.]
13. Treatment must include a high dosage (relative to the RDA) of a form of vitamin B12 delivered to the bloodstream, such as sublingually or by injection, together with an RDA-level dosage of folate, which can be given orally. The high dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency, and the oral route is not adequate to supply this necessary high dosage (first reported by Lapp and Cheney, 1993 and 1999). The folate is necessary to compensate for the loss of methylfolate from the cells due to the peroxynitrite catabolism reaction. The B12 is best given as hydroxocobalamin or methylcobalamin. The folate is best given as methylfolate, though folinic acid works for some patients. There are individual differences in genetic polymorphisms that determine the best forms of B12 and folate for individual patients. If there are deficiencies in cofactor vitamins and minerals or in necessary amino acids, these must be supplemented in addition. Replacement of oxidatively damaged essential fatty acids is also needed. If toxic metals levels are high enough to significantly block enzymes in this part of the metabolism, chelation may be necessary before this treatment will be successful.
14. This treatment is directed at the core of the pathophysiology. However, it does not directly treat the etiologies ("stressors" in step #2 above) that brought about this pathophysiology, nor does it directly treat pathogens and toxins that may have accumulated since the onset of ME/CFS, while the body's immune and detoxication systems have been dysfunctional as a result of the dysfunction of the sulfur metabolism. Additional treatments are needed in most cases to deal with them directly, to work toward achieving full recovery, because even though the immune system and the detoxification system may be largely restored, they are often not able to overcome these etiologies and accumulated factors on their own. Some of the etiologies and accumulated factors in various cases are Lyme disease and its coinfections, biotoxin illness, entrenched viral infections (and perhaps retroviral infections), and high body burdens of toxins.
Best regards,
Rich
Here is the latest revision of the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS:
1. Genetic predisposition is present (perhaps including SNPs in genes coding for enzymes related to glutathione that cause it to be more easily depleted, as reported in autism by Bowers et al., 2011).
2. Stressors (physical, chemical, biological and/or psychological/emotional, the mix varying from one case to another, based on patient histories) deplete glutathione by various means, some by oxidative stress, some by conjugation, some by lowering its rate of synthesis. The depletion of glutathione is demonstrated by the methylation pathways panel.
3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.
4. Glutathione depletion lowers the affinity of the CblC complementation group for cobalamin (as reported by Jeong and Kim, 2011), producing a functional B12 deficiency, thus lowering intracellular methylcobalamin and adenosylcobalamin. Anecdotal observations of elevated urine methylmalonate in the presence of normal or elevated serum B12 in ME/CFS patients confirm the presence of a functional B12 deficiency.
5. The lowered methylcobalamin inhibits the methionine synthase reaction, since it is the necessary coenzyme for this reaction.
6. The methyl trap mechanism continues the conversion of other forms of folate into methylfolate, but the lowered rate of the methionine synthase reaction decreases the demand for it.
7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma [NOTE: THIS STEP WAS CONTRIBUTED BY PROFESSOR MARTIN PALL, BASED ON PUBLISHED LITERATURE, FOR WHICH I AM GRATEFUL.]
8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel).
9. Homocysteine drains into the transsulfuration pathway, since its conversion to methionine is inhibited, and over time, methionine therefore becomes depleted (as found by Bralley and Lord,1994), leading to dysregulation and depletion of the sulfur metabolism in general.
10. The above combination of steps produces a stable vicious circle mechanism, and this is the reason ME/CFS is chronic.
11. The elements of this vicious circle mechanism lead to the abnormalities observed and the symptoms experienced in ME/CFS. Among them is mitochondrial dysfunction, which leads to an increased rate of the main glycolysis pathway and a decreased rate of the pentose phosphate shunt. The latter decreases the level of NADPH, which exacerbates the glutathione depletion by slowing the rate of the glutathione reductase reaction.
12. Boosting glutathione directly is not a successful treatment, because the glutathione reductase reaction cannot keep up with the oxidation of glutathione, due to the depletion of NADPH. [THIS IS BASED ON DISCUSSIONS WITH DR. PAUL CHENEY, FOR WHICH I AM ALSO GRATEFUL.]
13. Treatment must include a high dosage (relative to the RDA) of a form of vitamin B12 delivered to the bloodstream, such as sublingually or by injection, together with an RDA-level dosage of folate, which can be given orally. The high dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency, and the oral route is not adequate to supply this necessary high dosage (first reported by Lapp and Cheney, 1993 and 1999). The folate is necessary to compensate for the loss of methylfolate from the cells due to the peroxynitrite catabolism reaction. The B12 is best given as hydroxocobalamin or methylcobalamin. The folate is best given as methylfolate, though folinic acid works for some patients. There are individual differences in genetic polymorphisms that determine the best forms of B12 and folate for individual patients. If there are deficiencies in cofactor vitamins and minerals or in necessary amino acids, these must be supplemented in addition. Replacement of oxidatively damaged essential fatty acids is also needed. If toxic metals levels are high enough to significantly block enzymes in this part of the metabolism, chelation may be necessary before this treatment will be successful.
14. This treatment is directed at the core of the pathophysiology. However, it does not directly treat the etiologies ("stressors" in step #2 above) that brought about this pathophysiology, nor does it directly treat pathogens and toxins that may have accumulated since the onset of ME/CFS, while the body's immune and detoxication systems have been dysfunctional as a result of the dysfunction of the sulfur metabolism. Additional treatments are needed in most cases to deal with them directly, to work toward achieving full recovery, because even though the immune system and the detoxification system may be largely restored, they are often not able to overcome these etiologies and accumulated factors on their own. Some of the etiologies and accumulated factors in various cases are Lyme disease and its coinfections, biotoxin illness, entrenched viral infections (and perhaps retroviral infections), and high body burdens of toxins.
Best regards,
Rich