Captain David Williams davidwms@interpoint.netUpdate: July 1999
http://www.newtreatments.org/Adrenals/ga/123/Licorice%20%21%20
plus add this to the above by copying and pasting: How%20to%20use%20successfully%20for%20adrenal%20insufficiency
In a healthy person, 80% of the T-cells are resting and 20% are activated to fight off normally encountered pathogens, but in a person with chronic fatigue syndrome (myalgic encephalomyelitis),60-80% of the T-cells are activated. Simply put, the immune system in chronic fatigue syndrome is in over drive.
Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are both upregulated in chronic fatigue syndrome abstract) (abstracts). IL-6 is especially upregulated after fatiguing activity (abstract).
Some researchers suggest the root cause of this hyperimmunity might be a re-activating HHV-6Avirus (abstracts) (abstract). Others suggest an unknown virus. Some believe a mycoplasma bacteriais responsible (abstracts). A few think it’s yeast (abstracts). It might be an allergy (abstracts) according to other experts.
The Low Cortisol (Glucocorticoid) Connection
The term glucocorticoid applies to adrenal steroids with the main action on cellular metabolism. The principal glucocorticoid is cortisol (aka hydrocortisone). The actions of the cortisol in the body include the regulation of protein, carbohydrate, fat, and nucleic acid metabolism. Cortisol raise the blood glucose by acting as an insulin antagonist and by suppressing the secretion of insulin, thereby inhibiting glucose uptake in peripheral tissues and promoting the synthesis of glucose(gluconeogenesis) in the liver.
Depressed cortisol levels would result in excessive amounts of insulin and contribute to hypoglycemia.
Cortisol also has anti-inflammatory properties (abstract), which are probably related to their actions on the microvasculature as well as to cellular effects. The anti-inflammatory action includes the inhibition of interleukin-6 (IL-6) (abstract), known to be upregulated in chronic fatigue syndrome(abstract) and in fibromyalgia (abstract).
The hormone maintains normal vascular responses to vasoconstrictors and opposes the increase in capillary permeability characteristic of acute inflammation. Cortisol can cause an increase in leukocytes; the circulating leukocyte mass is increased due to release from the bone marrow ofmature cells as well as to inhibition of their egress through the capillary wall. Extra amounts of thehormone can also produce depletion of circulating eosinophils and of lymphoid tissue, specifically T-cells (thymus-derived lymphocytes). The mechanism is by redistribution from the circulation into other compartments. Thus excessive cortisol can impair cellular-mediated immunity.
On the other hand, cortisol also inhibits the production or action of the local mediators of inflammation such as the lymphokines and prostaglandins. The hormone also inhibits the action and production of immune interferon by T lymphocytes and the production of lymphocyte-activatingfactor (interleukin 1) by macrophages. The action of cortisol in suppressing fever may be explained by the latter effect, since IL-1 appears to be identical to endogenous pyrogen, which can activate the hypothalamic fever center. Cortisol can also inhibit the production of T cell growth factor (IL-2) by Tlymphocytes. The hormone reverses macrophage activation and antagonize the action of migration-inhibiting factor (MIF), leading to reduced adherence of macrophages to vascularendothelium.
Cortisol also inhibits prostaglandin and leukotriene production by inhibiting the activity of phospholipase A2, thus blocking release of arachidonic acid from phospholipids. Finally, cortisol inhibits the inflammatory actions induced by bradykinin and serotonin, such as increased vascular permeability. It is probably only at pharmacologic dosages that antibody production is reduced andlysosomal membranes stabilized, thereby suppressing the release of proteolytic acid hydrolases stored in these cytoplasmic organelles.
Cortisol, with the help of thyroid hormones, also stimulates The production of growth hormone(abstract) (abstract). Cortisol levels are responsive within minutes to physical trauma, surgery, exercise and psychological stresses such as anxiety and depression. Normal adrenal secretion on a tranquil day is 20 – 30 mg, but can increase in a healthy person to 200 – 300 mg under stress!
Hypoglycemia is also potent stimuli of ACTH and cortisol secretion in healthy people, but, in someone with a defective response in the hypothalamus/pituitary axis, such as those with chronic fatigue syndrome and fibromyalgia, the cortisol response to low blood sugar would be blunted allowing insulin to over-control blood sugar, sending the person with CFS and FM into a hypoglycemic attack! People with this illness are required to reduce high glycemic index foods from their diet in order to prevent low blood sugar. A high protein diet is the number one recommended change in this recovery protocol (link). The stress of dealing with a serious illness like chronic fatigue syndrome or fibromyalgia requires lots of extra cortisol, yet most doctors refuse to supplement hydrocortisone even though their patients show borderline low levels and no cortisol reserve. If their patients suffer from trauma, they would quickly give HC yet they back away from the drug with severely stress patients with a chronic illness. The reasons why elevated glucocorticoid levels protect the organism under stress are not understood, but in the absence of glucocorticoids, such stresses may cause hypotension, shock, and death. For these reasons, glucocorticoid administration should always be increased in individuals with hypofunction of the pituitary-adrenal axis during stress. People with CFS and FM should wear a medical bracelet begging for hydrocortisone in case of emergency!
Cortisol also has a major action on the distribution and excretion of body water. It subserves the extracellular fluid volume by retarding the flow of water into cells. It promotes renal water excretion by suppressing the secretion of vasopressin, increasing the rate of glomerular filtration, and acting directly on the renal tubule, the consequence being to guard against water intoxication by increasing solute-free water clearance. Glucocorticoids also have weak rnineralocorticoid-like properties, and increasing doses produce renal tubular sodium reabsorption and increased urine potassium excretion. Glucocorticoids also can influence behavior; emotional disorders may occur with either excesses or deficits of cortisol. Lastly, cortisol suppresses the secretion of pituitary POMC and peptides derived from this precursor molecule (ACTH, P-endorphin, and P-lipotropin) as well as the secretion of hypothalamic CRH and vasopressin.
Cortisol also stimulates erythropoiesis (the building of new red blood cells) which is extremely important function in chronic fatigue syndrome and fibromyagia (abstract). It could be suggested that low levels of serum cortisol might be a factor in the borderline anemia observed in these illnesses since low levels of this important hormone has been noted (abstracts).
In additon, glucocorticoids have been shown to enhance thyroid releasing hormone (TRH) gene expression in three different cell systems in vitro, an effect that occurs, at least in part, through transcriptional activation (abstract). The synthetic glucocorticoid dexamethasone substantially elevated the synthesis of TRH prohormone and its intermediate products of processing in culture danterior pituitary cells, an observation that is consistent with an overall upregulation of both the synthesis and degradation of the TRH precursor. Synthetic cortisol caused a significant 75.7% increase in newly synthesized TRH prohormone, suggesting that the glucocorticoid raised the translation rate.
Thyroid hypofunction has been noted in hypoadrenalism; However, it has been found counterproductive to treat this dysfunction with thyroid hormones (link). Rather, treating the glucocorticoid deficiency in reported to be more successful in raising thyroid output.
Could low cortisol be the cause of the immune pattern observed In chronic fatigue syndrome and fibromyalgia? In the opinion of this researcher, the answer is, “Almost, but not quite!” If we also consider the effects of low DHEA coupled with low cortisol, the pattern of hyperimmunity that would emerge will fit the pattern observed in CFS and the mystery of hyperimmunity in CFS is solved!
The Low DHEA Connection
DHEA levels are also controlled by the same factors that control the production of cortisol so that both should be low is only a natural conclusion. If you have low cortisol–you have low DHEA! If you have low DHEA–you have low cortisol!
DHEA is much easier to measure than cortisol so if there is any single test you should seek out it should be plasma DHEA levels.
Fact is, findings of low levels of DHEA in CFS might even be considered as a marker for CFS according to researchers at Trinity College Medical School in Dublin, Ireland (abstract). It should also come as no surprise that DHEA has been found low in this illnesses by every effort to measure the hormone to date(abstract)! A blunted DHEA response to ACTH has also been noted in chronic fatigue syndrome (abstract).
DHEA is quantitatively the most abundant hormone in humans and mammals, with a wide variety of physiological effects, including major regulatory effects upon the immune system (abstract). Two of the most striking aspects of DHEA are a steady decline in DHEA with age and a significant deficiency in DHEA in patients with several major diseases, including chronic fatigue syndrome, cancer, atherosclerosis, and Alzheimer’s disease. The hormone is secreted in a non-sulfated (DHEA)and sulfated form (DHEA-S). The two are apparently interchangeable, and it appears likely that its physiological effects are achieved by derivative molecules that have yet to be identified. DHEA has other positive effects on immunity (abstract). The neurohormone also inhibits IL-6, known to be upregulated in CFS (abstract) (abstract). Research has shown that DHEA benefits people with Lupus (abstract).
The release of DHEA and cortisol from the adrenal glands is controlled by ACTH. ACTH is controlled by CRH. Recent evidence has been published indicating that there might be a defect in CRH secretion from the pituitary gland (abstract) in CFS. Research done in women with fibromyalgia also indicates a HPA axis problem (abstract).
So, in summary, the evidence indicated that the hyperimmunity in CFS is caused by secondary hypoadrenalism due to a blunted response to CRH and vasopressin and the resulting low cortisol and DHEA.
Yet, many doctors still refuse to supplement with hydrocortisone and/or DHEA! They site a recent study sponsored by NIH which indicated that people with chronic fatigue syndrome treated with daily low doses of hydrocortisone fail to report a significant recovery (link) (abstract).
A study done in the UK got better results, but still not a remarkable recover as would be expected.(link) Does this rule out hypoadrenalism in chronic fatigue syndrome and fibromyalgia?
Absolutely not! Failure to respond to daily low doses of hydrocortisone should have been expected simply because daily dosing with an external source of cortisol would, via feedback mechanisms within the HPA axis, lower the person’s own production by the exact amount taken by mouth. Letters to the editor of JAMA about the article discuss all the various ways that the study might have gotten better results (letters) but none of the authors seem to address the problem straight forward.
The whole concept that low doses of hydrocortisone would improve chronic fatigue syndrome and fibromyalgia, and yet not cause feedback to the adrenal gland was promoted by Professor William McK Jefferies in his book, “Safe Uses of Cortisol” (Link).
To a certain extent, the evidence suggests that he is right. Low dose cortisol did not cause measurable adrenal suppression in ~30% of the subjects in the studies mentioned above providing the doses were kept below a certain level.
Was the non-suppressing dose high enough to reverse the disease process? Likely not.
People with chronic fatigue syndrome and fibromyalgia do make a remarkable and quick recovery for the first few days when first starting daily hydrocortisone if the dose is high enough, indicating that increasing cortisol bioactivity eliminates most of the symptoms of the illness. But these marvelous improvements in health are quickly lost on a continued daily schedule because feedback quickly lowers the production by the same amount taken daily in ~70% of those studied.
In fact, the NIH scientists should have known the daily dosing protocol used to increase cortisol activity in a PWC was doomed to a high failure rate from the beginning. The money to do the study should have been spent in a trial of EVERY THIRD DAY (ETD). Since ETD gives the patient one day off for every two days of increased cortisol bioactivity, the chances of HPA axis suppression are reduced to almost nil.
Alternated Day Therapy is a well known tool used for 30+ years in hormone dosing (abstract).
Regardless, it’s not easy to get around feedback because most fast acting synthetic cortisol drugs are bioactive for about 36 hours. Hydrocortisone, a natural cortisol, is bioactive for about 24 hours, and might be better for reducing feedback due to its shorter bioactivity.
Recommended Dosing Schedule to Get Around Feedback Problems
Every Third Day (ETD) dosing is a more effective schedule than Alternate Day Therapy. Through trial and error with daily and then with Alternate Day schedules, it was found that ETD was necessary to get around feedback. The recommend dose of hydrocortisone is 0.6 milligram per kilogram of body weight (~1/4 mg per pound) first thing in the morning on day one. This dose is equal to the same given in the studies, only given in one dose every three days verses dosing everyday.
At bedtime that evening, take a small dose of valium or klonopin to increases GABA receptors in the brain if you can’t sleep (more on this later).
Also, since physical activity burns cortisol, make day one your primary activity day, doing your entire house cleaning, shopping, mowing the lawn and etc. You can also schedule lots of exercise on this day. Fact is, start planning an exercise program based on every Three Day schedule.
The hydrocortisone will naturally feedback and reduce the production of cortisol the next day. The increased cortisol bioactivity on day one also sends a signal to the brain to increase 11beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme that deactivates cortisol (abstract). In other words, a person taking a large amount of cortisol on day one, can expect to experience a drop in adrenal cortisol output the next day, along with an increase in the production of the enzyme that deactivates cortisol. If you kept this high dose up for
two weeks, your adrenal glands will shutdown and be extremely difficult to restart. Because the chronic use steroids can lead to detrimental systemic side effects due to feedback, many doctors are afraid to give hydrocortisone to a chronic fatigue syndrome or fibromyalgia patient. There has been so much publicity about permanent adrenal failure (Addison’s Disease) due to steroid use, that most doctors block out all conversation about an effective way to take the hormone. They figure that there is just no way around feedback!
But there is a simple way to prevent feedback and allow for effective dosing of steroids! This is the genius in the ETD protocol. Since 11 beta-HSD is the enzyme that deactivates cortisol, if a person could take an 11 beta-HSD inhibitor on day two, less of their cortisol would be deactivated, allow the lowered output to go much further than normal. An 11 beta-HSD inhibitor would not increase the cortisol level on day two, inhibiting the inhibitor of cortisol would only extend the time that the low level of cortisol remained bioactive. In other words, the low cortisol would still be low, but it would last much longer and be able to offer you more benefit. Feedback mechanism would sense low cortisol and signal the HPA axis to halt its cut in cortisol production.
Author’s note: This researcher thought that he was allow in seeing the value of combining an 11 beta-HSD inhibitor within the context of a steroid treatment protocol but recently found evidence that a similar method is being used at the University of Utah School of Medicine to treat skin disease(abstract). It appears that the Utah researchers might have got the idea from work done in the UK with glycyrrhizic acid (abstract). Researchers in Berlin working on breast cancer also show an understanding of the concept of extending cortisol bioactivity via 11 beta-HSD inhibition (abstract).
Glycyrrhizic acid in licorice extract, progesterone, and flavonoids in grapefruit, are the only known effective inhibitors of 11 beta-HSD readily available. (How progesterone alters 11 beta-HSD is not understood by this researcher at this time.) You could eat 10 – 15 grapefruit or take about ~4 grams of licorice extract on the morning of day two to inhibit the enzyme. This method can potentiate cortisol bioactivity up to 10 fold, making it possible to get great benefit from low levels on day two. Feedback mechanisms sense the lowered 11 beta-HSD activity on day two and signal the body to increase production. Similar mechanisms also sense the lower cortisol on day two and tell the HPA axis to increase production because the big blast of cortisol on day one was just a fluke!
Things tend to balance out on day three and the person with chronic fatigue syndrome or fibromyalgia feels like they do normally. Since day three is an off day, you plan your schedule so that you can relax and conserve all the cortisol you can. Avoid physical activity and stress as much as possible and day three will go great.
The recommended dose of licorice extract is based on your response to the herb, and on the amount of glycyrrhizic acid in each gram of extract you use. Personal experience indicates 5 to 6 milligrams per kilogram of body weight (2.27 mg per pound) or about 500 milligrams for a 220 pound man. You can also take a half-dose about 3 PM if you feel the need for a little lift.
Day two should also be an activity day, doing all you can do without over doing it. But be sure to be as physically active as your energy level will allow. In order words, don’t lay around like normal–getup and get going!
Day three is off day for both hydrocortisone and glycyrrhizin, and will reset both your cortisol and 11beta-hydroxysteroid dehydrogenase homeostasis and get you ready for a return to high doses of hydrocortisone on the next day.
As an extra precaution to make sure adrenal suppression is not occurring, skip an extra day (4 days) every 9 days. You can also go off hydrocortisone and glycyrrhizin completely for 1 week every 6-8weeks. Work with your doctor closely and, between the two of you, work out a plan that will assure both of you that feedback is not occurring. This protocol has not been tested in large numbers of people so make sure you use caution and go off often to insure yourself and your doctor that this program will be successful.
One other point should be made here if one is to get the complete cortisol picture. Doctor PM Stewart, a researcher at Queen Elizabeth Hospital in UK, feels that medical professionals are missing the boat by being obsessed with levels of hormones as now measured. He makes a strong point that the bioactivity of cortisol, thyroid and other hormones is controlled by the enzymes that deactivate the specific hormone in the targeted organ (abstract).
As mentioned above, cortisol is converted to the inactive metabolite, cortisone, by 11 beta-HSD. If a PWC has high levels of 11 beta-HSD in the kidneys or other targeted organs, more of their own cortisol will be converted to cortisone in less time than someone with normal levels of 11 beta-HSD. Cortisol levels in blood or saliva of someone with chronic fatigue syndrome and/or fibromyalgia often show low normal levels, indicating low cortisol is not causing the symptoms.
However, cortisol measured in such a fashion does not determine cortisol bioactivity in the targeted organ, especially the kidney. Simply measuring cortisol in the doctors office might
be a waste of time and money and could be very misleading, resulting in strong resistance to any treatment program supplementing hydrocortisone.
The best way to accurately measure cortisol activity in a person with chronic fatigue syndrome and fibromyalgia is to measure the ratio of free cortisol to free cortisone in urine collected over a 24 hour period (abstract). And, this must be done on a day when the patient feels like crap. Run the test on a day when the patients feels great and everything shows normal. My strong advice is to always INSIST on being tested when you feel the worse! Getting a test done when you feel great is like taking your car to the mechanic when it’s running perfect! You might want to spend the day before your scheduled 24 hour urine cortisol test exercising as much as you can to burn off some cortisol. Exercising before such a test is not cheating.
Healthy people can and do perform work and exercise the day before most test. Fact is, being underactive before a cortisol test as most people with chronic fatigue syndrome and fibromyalgia usually are, could be a major factor is why cortisol levels sometimes are normal in people with this illness.
Copy this Physician’s Information sheet and discuss this issue with your doctor!
NITRIC OXIDE
If the topic of nitric oxide is new to you, it will help a lot if you take the time to review some general background on this toxic agent. Click here for nitric oxide basics!
An increase in nitric oxide during immune activation lowers overall adrenal output and, coupled with low DHEA, will cause the same clinical picture now evident in chronic fatigue syndrome and fibromyalgia (abstracts). Read a few of the abstracts and you will see that increased levels of NO will not only lower cortisol, but also lower aldosterone, DHEA, pregnenolone and catecholamine secretion.
The most direct evidence that NO alter adrenal function comes from work with rats. Dr. CB Cymeryng, et al, at the University of Buenos Aires found that NO significantly decreased corticosterone (the same as cortisol in man) production both in unstimulated and in corticotrophin-stimulated zone fasciculate adrenal cells, in a dose-dependent manner. The production of pregnenolone from cholesterol was also significantly reduced. This effect was reversed by ferrous hemoglobin (abstract).
But primary hypoadrenalism due to weakened adrenal glands is not as much in evidence in CFS and FM, as is secondary hypoadrenalism (defect in pituitary-hypothalamus axis). The evidence in chronic fatigue syndrome and fibromyalgia all point to a reduced ACTH response to CRH and vasopressin.
But it does not matter in this theory whether you have primary or secondary hypoadrenalism! Upregulated nitric oxide due to hyperimmunity (coupled with another toxic gas, carbon monoxide) also alters hypothalamus-pituitary function and would create the exact same pattern now evidenced in these illnesses (abstract).
A vicious circle begins to form! Low cortisol and DHEA allows the immune system to become hyper; hyper immune response (upregulated nitric oxide and other cytokines) alters HPA axis function, resulting in low cortisol.
If one were looking for a single factor that would completely explain chronic fatigue syndrome, including every single crazy symptoms known to occur in this illness, you would need only look at upregulated nitric oxide (NO).
Dr. AM Levin (Link) has examined this nitric oxide theory and is able to tie it in seamlessly with yeast infections. I suspect that he is on target, but I would also add that I believe many other pathogens can also connect and cause the same situation. Still, I do like his work in this area. He is the first MD to jump on the bandwagon of upregulated NO as a major factor in
CFS.
As mentioned earlier, Tumor Necrosis Factor-alpha (TNF-a) is known to be increased in CFS. Taking DHEA supplements helps down-regulates TNF. (abstracts))
Tumor necrosis factor-alpha and other Th1 cytokines upregulates the production of nitric oxide (NO)and nitric oxide synthase (NOS) (abstracts) therefore, it is safe to say nitric oxide is upregulated in CFS (abstract).
Even though no studies have been done to date about the strong connection between TNF-alpha(known to be increased in CFS) and NO, there is evidence showing a strong possibility of upregulated NO is CFS. As a matter of fact, evidence suggest that autoimmune pathogenesis initiated by inflammatory responses within the CNS may result in part from a vicious cycle in which TNF-alpha and NO mutually provoke each other’s production
(abstract).
Another important body of evidence is that fact that natural killer cell cytotoxicity, found low is CFS, is also shown dose-dependently low when chemical NO donors are added during afferent phase of NK stimulation with IL-12 and TNF-alpha. Conversely, when an inhibitor of NO synthase was added, a subsequent increase in the cytotoxicity of the effector cells towards the NK-sensitive target cells (K562) was observed (abstract). In other words, upregulated nitric oxide lowers natural killer cell activity and accounts for the evidence found in CFS.
In support of this view of upregulated nitric oxide in CFS, other medical researchers are also beginning to suspect this simple gas in playing a major role in CFS. One theory involves N-methyl-D-aspartate (NMDA) receptors in the brain. When brain function is balanced, GABA and NMDA receptor activity is balanced. In CFS, however, NMDA receptors become substantially more active than GABA receptors. HealthComm International feels that a key component in the upregulation of NMDA receptors in CFS involves the overproduction of nitric oxide. They state, “This molecule, itself a neurotransmitter, has been associated with stimulation of the NMDA receptor system when released into the nervous system (Link). HealthComm is using an aspect of nitric oxide’s function in the brain to show evidence of upregulation in CFS.
It look’s like they could be on to part of the problem in CFS–nitric oxide does upregulate NMDA receptors (abstract). However, I suggest this is a pattern that is more closely associated with
the symptoms of hypoadrenalism, than it is a single cause of CFS.
Here is where the valium every 3 days can help. The drug enhances GABA binding and increases GABA receptors (abstract), which, like a see saw, will lower NMDA receptors, but tolerance does happen rapidly so dosing every third day is mandatory in the benefit is to be continued.
One might also try low dose trazodone every day as a way of down-regulating the NMDA receptors(abstract). This could also be the manner in which low doses of selective serotonin reuptake inhibitors (SSRIs) help some with CFS since these drugs also
down regulate NMDA receptors, at least in the rat (abstract).
Recent research also shows that the amino acid homocysteine is elevated in the spinal fluid and brain of PWC (abstract). This evidence supports the view that nitric oxide is also elevated in CFS since nitric oxide inhibits the enzyme that breaks down homocysteine.
Nitric oxide is the most potent vasodilator known. Excessive production of this simple molecule causes the drastic fall in blood pressure during shock. Nitric oxide is also now known to drastically reduce the pain threshold and to be responsible for increased sensitivity to pain, especially fibromyalgia-like pain (references). Nitric oxide is manufactured in cartilage cells (chondrocytes)(abstracts). Since nitric oxide stimulates the reception of pain (abstracts), there can be little doubt that NO is responsible for fibromyalgia pain in CFS!
NO also can stimulate insulin secretion by deenergizing mitochondria (abstract). Insulin also increasex the release of NO in the vascular system (abstract)(abstract).
Since NO is a potent vasodilator, insulin produced in response to a high carbohydrate meal will cause increased vasodilation making a PWCs with neurally mediated hypotension feel much worse. In other words, insulin and NO have a close association that will lead to hypoglycemic reactions in PWCs, making a high protein diet mandatory in treating CFS. The activated immune system in chronic fatigue syndrome and fibromyalgia also reduces the manufacture of new healthy red blood cells (erythropoiesis) (abstract).A strong connection exist between the local activation of bone marrow T-lymphocytes, increased production of cytokines, and reduced levels of red blood cells.
In addition, both inflammatory cytokines and nitric oxide (NO) interferes with the way the body metabolizes iron (references) (abstract). Not only does NO cause problems with iron metabolism, but defects in iron utilization and reutilization results in reduced performance of many iron-requiring enzymes and proteins (references).
Research has found that when the immune system is activated, the critical period in the development of nutritional iron deficiency occurs after 30 to 40 days without iron supplementation. The person is unable to maintain hemoglobin levels without endangering the iron-requiring enzyme groups which are essential for life (abstract). This indicates that any single illness or combinations of factors that can stimulate the immune system and increase nitric oxide production for longer than 30 to 40 days, could progress into CFS in selected individuals.
A similar iron metabolizing problem exists in AIDS. As HIV infection advances, progressive anemia is established. The study of iron metabolism in these patients shows a pattern similar to that of the Anemia of Chronic Disease (see below). A group of Spanish researchers think that these changes in AIDS might be due to iron sequestration in phagocytic cells induced by release of cytokines from the immune system (abstract).
Red cell hemoglobin is the most important iron-requiring protein likely defective in CFS. Hemoglobin is the MAJOR scavenger of excessive NO, therefore, an inability to remove this toxic immune agent quickly before it vasodilates blood vessels excessively and over reacts with healthy cells can result in many of the symptoms, particularly fatigue, neurally mediated hypotension, and joint pain. In addition, if nitric oxide is not being properly scavenged, then problems with excessive NO can occur even if NO is not upregulated.
As unbelievable as all this sounds, the very latest evidence indicates that nitric oxide also controls the amount of oxygen reaching the cells. If you do not read any link in this article, you should struggle to read this one (Link. The researchers found that the loss of oxygen flips a switch that releases nitric oxide in the arteries to dilate blood vessels and increase blood flow so that the remaining oxygen can be delivered to tissue. On the return trip to the lungs, the oxygen that was lost in the arteries is recaptured in the veins, giving the appearance of inefficient oxygen delivery. The researchers measured blood flow and oxygen concentration in several regions of rat brain while the rats breathed air with varying oxygen levels. They showed that hemoglobin releases a form of nitric oxide in the small arteries that regulate blood flow, thus
promoting oxygen delivery. When the animals breathed oxygen under higher air pressure, oxygen levels increased in tissue, and hemoglobin compensated by halting NO release and contracting blood vessels.
The finding also clears up another puzzle. In test tube experiments, hemoglobin scavenges NO and constricts blood vessels. Yet in the body, hemoglobin does not have this effect under normal conditions. “This tendency to constrict blood vessels seems to oppose hemoglobin’s job of delivering oxygen,” one researcher said. “Our findings explain why hemoglobin doesn’t constrict blood vessels in the body. It releases NO in the arteries to counteract the NO it scavenges.”
But what if something goes wrong with this system? As mentioned above, cortisol reverses macrophage activation, therefore, it can be assumed that low cortisol will allow macrophages to become easily activated by stimuli. Since these white cells dump loads of NO into the system when they are activated, maybe one major problem with chronic fatigue syndrome is activated macrophages. Release of NO from macrophages has been visualized in the mouse (abstract). Their activation in chronic fatigue syndrome is theorized to be similar to the manner in which a cancer drug (Taxol) primes macrophages in cancer patients (abstract).
Nitric oxide primed macrophages are ready to dump their NO at the least disturbance. This theory suggest that increased stress of the faster blood flow through the vessels, after isoproterenol is injected in the TTT, releases this “primed” nitric oxide, intensifying the effects of the drug causing the person with activated macrophages to go into syncope rather
easily. The increased NO stimulates the release of large amounts of prostacylin, which causes bradycardia (slowing of heart rate)(references).
Physical activity would increased the release of NO from primed macrophages simply because the stress of muscle activity would put pressure on the primed macrophages causing them to dump their NO. The action of the heart muscle would also place alternating pressure on the macrophages. Flow stress of the blood flowing more rapidly through the vascular system during exercise would also release a lot of NO. So would a sudden drop in barometric pressure. These factors would explain why chronic fatigue syndrome and fibromyalgia are noted for an increase in symptoms after physical activity. Some with CFS and FM swear they feel worse just before a weatherfront moves in, which would agree with the release of NO due to a drop in
atmospheric pressure.
Hemoglobin is not the only iron-requiring enzyme likely Defective in chronic fatigue syndrome and fibromyalgia. The cytochrome p450 liver enzyme system (abstract) is also likely defective. These enzymes are responsible for metabolizing toxic chemicals and drugs (most antidepressants) into metabolites that can then be removed from the body in the bile or by the kidneys (link).
As mentioned earlier, inflammatory stimuli, such as TNF-alpha, Are increased in chronic fatigue syndrome. TNF-alpha increases nitric oxide production and nitric oxide reacts with the iron complexes in the cytochrome p450 enzymes thereby inhibiting
the action of these important liver enzymes. (abstracts) (abstract).
Defects in cytochrome p450 liver enzymes due to excessive nitric oxide (abstract) will result in a build up of environmental chemicals in the body and a super-sensitivity to certain drugs. (references)
Most chemicals use in food processing do not cause problems for healthy people simply because healthy people have normal liver enzymes and can metabolize these chemicals and flush them out of the body. But in people with defective cytochrome p450 enzymes, these chemicals can build up in the body to the point where they become toxic. Most chemicals can cause this toxicity. (link)
The normal dosage of certain drugs can also cause toxic reactions if they are not being properly metabolized due to a defect in the p450 enzymes. (link) A person with this illness might have to reduce dosages of certain drugs to as low as 1/10th of the normal dose to avoid reactions. Other drugs might not work simply because they must be metabolized into their bioactive metabolite in order to become effective.
Fact is, the failure of the cytochrome p450 liver enzymes to detoxify the body is likely somewhat responsible for multiple chemical sensitivity and may even be related indirectly to what is now thought to be responsible for Gulf War Syndrome. Researchers at the University of Texas believe they know what causes Gulf War Syndrome. A long term study of members of
an Alabama Seabee unit that served in the Persian Gulf War strongly indicated that many veterans who became ill do not carry a specific gene that attempts to neutralize the nerve gas Sarin.
That lends more support to the claim that soldiers in the Gulf War were exposed to small amounts of nerve gas. (link) The genetic defect could explain why some soldiers were afflicted with the syndrome — which has a wide range of symptoms resembling chronic fatigue syndrome. The biggest questions about Gulf War syndrome has been why one person got sick when the person next to him didn’t. But now experts suspect a genetic reason why some people got sick, linking the illness to damage from certain chemicals.
Writing in the journal Toxicology and Applied Pharmacology, the research team said a gene that controls production of an enzyme known as type Q paraoxonase, or PON-Q, which helps the body destroy toxins, might be responsible.
It is highly specific for the chemical nerve agents Sarin and Soman as well as for the common pesticidediazinon. Fact is, several organophosphorus insecticides are detoxified through the cytochromeP450/paraoxonase (PON1) pathway (abstract). The researchers found strong statistical links between Gulf War syndrome and veterans’ reports of exposure to combinations of chemicals like pesticides and low-level chemical nerve agents. They predicted in 1997 that it might be due to aPON-Q deficiency, and now that’s what they have found. Human serum paraoxonase (PON 1)exists in 2 major forms (Q and R), which differ in the amino acid glutamine and arginine, respectively. These PON allozymes hydrolyze organophosphates and aromatic esters, and both also protect LDL from copper ion-induced oxidation.
The group had linked three different neurological syndromes to the use of pesticide-containing flea collars, highly concentrated insect repellent and pills formulated with pyridostigmime bromide to counteract the effects of nerve gas, as well as exposure to low-level chemical nerve agents.
Other researchers have theorized about a similar mechanism in chronic fatigue syndrome (abstract)involving toxicity through the GABAa receptor. Corrigan, et al, discuss the possible involvement of organochlorine compounds which are widespread in the environment and may have similar toxic effects through damaged cholinergic input to the dentate gyrus of the hippocampus where cholinergicand GABAergic transmission are closely linked.
Researchers in Australia also found a close association between organochlorines and chronic fatigue syndrome(abstract) (abstract).
A defect in iron-requiring P450 liver enzymes might alter the cytochrome P450/paraoxonase(PON1) pathway, affecting paraoxonase-Q in people with chronic fatigue syndrome, but it will likely take decades before researchers answer this question.
Liver enzymes might also play the major role in many food allergies due to certain toxic compounds contained naturally in some foods.
Food allergies are also likely due to Leaky Gut Syndrome (link). In this illness, the stomach wall is weakened and allows tiny particles of undigested food and food chemicals to enter into the bloodstream where they are picked up by immune cells as pathogens. The immune reaction following the intrusion of food particles and food chemicals can cause severe migraine type headaches, depression and insomnia (link). The likely cause of this problem in chronic fatigue syndrome is hyperimmunity, including upregulated IL-6 and nitric oxide.
The way it appears, anything that can activated the immune system over a long period of time can lead to cytochrome p450 liver enzyme dysfunction and result in chronic fatigue syndrome and fibromyalgia!
Since pregnenolone, progesterone, and DHEA are all biosynthesized from cholesterol by p450iron-requiring enzymes, the failure of this enzyme system due to an iron metabolizing problem caused by hyperimmunity can lead to low levels of these neurohormones (abstracts). Low levels of these neurosteroids are known to cause brain fog, especially pregnenolone.
Problems with iron metabolism can also contribute to loss of energy, reduced oxygen utilization, reduced blood pressure control, altered sleep, reduced brain perfusion, difficulty in concentration, and many other symptoms noted in CFS.
At least one researcher is interested in the association between a defect in iron metabolism and increased nitric oxide production. (link)
The secondary and/or primary hypoadrenalism found in CFS Causes dehydration, decreasing the water content in the blood by up to 40% in some individuals (reference). When there is less water in the body, there is an equal less amount of water in the blood and the blood thickened! Since RBC and hemoglobin measurements are based on a percentage of drawn blood, hemoconcentrated blood is artificially increased in red cell numbers and hemoglobin, causing an elevated reading in the drawn blood of a person with chronic fatigue syndrome. This false
increase in RDC indices prevents any iron related blood problem from being detected. People with chronic fatigue syndrome and fibromyalgia are anemic and neither they nor their doctor are
aware of it!
The type of anemia is called, Anemia of Chronic Disease (ACD) (link) . ACD is common in patients who have a long standing disease in which the immune system is activated. The causes are complex and incompletely understood, but probably involve inflammatory cytokines and nitric oxide. (link)
In ACD the production of new red cells is insufficient for the degree of anemia and RBC length of survival is shortened and there is an impaired re-utilization of iron.
ACD is fairly easy to diagnose if iron deficiency anemia (IDA) can be ruled out, and it is easy to diagnose IDA in an otherwise healthy person. But the differential diagnosis of ACD and IDA in a patient who has a chronic disease like chronic fatigue syndrome, who also has an iron metabolizing problem, is extremely difficult. The differential diagnosis requires assessment of iron status, but that assessment is complicated by the fact that ACD causes changes in the parameters of iron status.
With chronic disease, Total Iron Binding Capacity (TIBC) decreases, counteracting the usual increase due to iron deficiency. Serum iron decreases, mimicking iron deficiency.
The single most important diagnostic mark of iron deficiency is low serum ferritin, but ferritin is markedly elevated as an acute phase protein in a chronic diseases, reaching many fold higher than the diagnostic point, even in clearly iron deficient patients.
Recent clinical studies demonstrate that serum transferrin receptor (sTfR), an independent parameter of iron status, adds to the power of existing diagnostic tests in diagnosis of iron deficiency in patients with chronic disease. It is, in fact, comparable to marrow aspiration, the gold standard for iron deficiency, in evaluating iron status.
Most doctors will not know how to diagnose borderline anemia in CFS, and may simply dismiss it as not possible. To get iron status properly evaluated, refer your doctor to this web site (click here).
One other point should be made before leaving the subject of iron in chronic fatigue syndrome and fibromyalgia. Not only does dehydration and low blood volume mask the presents of anemia, it also alters the flexibility of red blood cells and their ability to deform and travel through the tiny capillaries in the brain. Dehydrated red blood cells show signs of reduce elasticity (abstract) and could be the cause of reduced blood flow in the brain noted in CFS.
Tilt Table Test
The results of Tilt Table Tests (TTT) in which 95% of CFS patients are positive for neurally mediated hypotension is likely due to increased nitric oxide production in CFS coupled with certain factors during the administration of the TTT. The beta-adrenergic agonist, isoproterenol, is injected to increase heart rate and decrease the amount of time spent in the tilted position. In healthy folks with normal nitric oxide levels, the drug vasodilates the blood vessels and speeds the heart rate. But this vasodilation is nitric oxide dependent so that when NO is inhibited, the vasodilation is decreased(abstracts). Conversely, when NO is upregulated as is theorized here, the response to isoproterenolis greatly exaggerated and syncope can occur.
Many PWCs complain that the TTT cause the same type of flare brought on by a period of intense exercise. This is understandable since the same release of NO by primed macrophages would occur when the heart rate increases during exercise. The flare from post-exercise fatigue and a TTT would be similar since they are both caused by the same phenomena.
The Aspirin Test High doses of aspirin is also known to relieve a severe flare in symptoms after exercise. Aspirin not only inhibits prostacylins, the drug is also a nitric oxide inhibitor (abstracts). Taking 3-4 aspirin during a severe case of fatigue should cause you to recover about 30 minutes later. The aspirin test should reveal to you that your NO is upregulated and causing your fatigue. Taking aspirin when you feel fine will do nothing so wait till you feel your worse to conduct this test.
Taking aspirin before having a TTT would likely insure negative results for NMH. Aspirin can also help you reduce post-exercise fatigue. But one caution here: If you suffer a lot of headaches that seemed food related, you likely have leaky gut syndrome and taking aspirin can aggravate this condition and bring on more headaches.
Why Are So Many Women Affected?
Chronic Fatigue syndrome and fibromyalgia are predominately diseases of women because females naturally have ~20% less red blood cells and ~20% less hemoglobin than men. They also suffer a far greater iron loss than men due to monthly blood loss. To make matters worse for women, recent research shows that whole-body production of nitric oxide is 20+% greater in healthy women than in men (abstract).
Estrogen is the likely culprit because this hormone also stimulates nitric oxide production. Fact is, estrogen’s upregulation of nitric oxide, a potent vasodilator, is likely the reason estrogen prevents heart attacks. (abstracts) I don’t know how much comforting it is to tell a womenwith chronic fatigue syndrome that she is less likely to have a heart attack due to her illness. I would suppose that most would rather have the heart attack risk and manage it with exercise.
In support of this theory, a recent correlation of serum measures of nitric oxide production with lupus disease activity has been discovered (abstracts). Lupus is another mostly female illness, likely for the same reasons above. Maybe a nitric oxide study in CFS/FM is not far off? Certainly if Lupus was shown to be associated with NO, some CFS researcher will soon put two and two together.
Blacks and CFS
How many black people you know with CFS? None likely. Some researchers says this is because blacks don’t complain to doctors, but that’s not true. Truth is, blacks do not suffer CFS and FM nearly as often as whites simply because they respond much differently to increased levels of nitric oxide (Link) (abstract) (abstract). Blacks also have higher blood pressure and generally have higher cortisol levels.
Serotonin
People with chronic fatigue syndrome may or may not be deficient in serotonin. Upregulated nitric oxide does decreases serotonin levels by inactivating tryptophan hydroxylase, the initial enzyme in the biosynthesis of this important neurotransmitter (abstract). And, since serotonin plays an important role in inhibiting the level of TNF-alpha (abstract), reduced
serotonin levels could explain the increase in this potent cytokine found in some with CFS.
But the serotonin picture is muddle. Many people with chronic fatigue syndrome respond negatively to antidepressants taken to increase serotonin levels. Several researchers have also found evidence of high serotonin levels in chronic fatigue syndrome. There is also minor evidence that an allergic reaction to serotonin could be going on in some.
Taking 5-HTP (link), the amino acid precursor to serotonin, might help restore serotonin and downregulate TNF-alpha is some PWCs. It should also improve sleep and having a calming effect. Serotonin is an extremely important agent in chronic fatigue syndrome and may or may not play a role in many symptoms (link). This hypothesis takes the view of individual need when it comes to serotonin. Try it, but don’t hesitate to stop taking serotonin boosters if you feel worse.
Improving Red Cell Health
Eating calves liver and/or taking various vitamins and supplements to improve red cell health after you have been successful at lowering cytokine/nitric oxide output with hydrocortisone (Every Third Day Therapy) will improve overall health. However, one must first makes sure that they have controlled the upregulated nitric oxide, before taking iron supplements. The iron is sequestered away from nitric oxide in CFS for a reason. Iron forms potent and dangerous oxygen radicals when exposed to high levels of NO. Therefore, iron supplements are not recommended until NO is brought under control.
Dopamine
Dopamine likely plays a big part in the symptoms of CFS because phentermine and other dopamine stimulates (ritalin, cylert) are know to provide fantastic short term relief of chronic fatigue syndrome and fibromyalgia symptoms. But this research effort has not yet tried to unravel anything meaningful from the study of dopamine in these illnesses. Dopamine and nitric oxide are mentioned associated with each other in over 100 recent medical abstracts so anyone interested in looking into this might find some great info.
B-12
Vitamin B-12, especially hydroxocobalamin (B-12a), is known to reduce the symptoms of chronic fatigue syndrome and fibromyalgia. B-12, especially hydroxocobalamin, is also know as a nitric oxidescavenger (abstracts).
In summary
If you’ve got chronic fatigue syndrome, you also have low cortisol and DHEA due to a blunted ACTH response to CRH. You also suffer from increased cytokine production, upregulated nitric oxide, poor red cell health, defective iron-requiring enzymes and proteins and low pregnenolone. Due to your activated immunity and liver enzyme problems, you also suffer from chemical exposure and selective deficiency of certain amino acids and nutrients. These problems are collectively responsible for all your symptoms.
Since there are many different root causes, no particular drug, herb, or nutrient by itself can address all the problems. This wide variety of symptoms coming from many different aspects of the same illness has also made this an extremely difficult syndrome for the medical community and your friends and relatives to accept. They will tend to think you are faking it simply because you suffer from so many different, seemingly unrelated, symptoms.
The average person (and doctor) does not realize that dysregulated nitric oxide can cause so many different medical problems!
The best things you can do to recover is increase your cortisol bioactivity in order to lower cytokines and nitric oxide, while at the same time slowly addressing all the other medical problems. Not an easy task! You will need to go slow and by extremely patient.
Remember, you could begin one drug or nutrient to address one problem and, at the same time, suffer an increase in symptoms from a different problem, causing you to think the new nutrient you just started is not for you. Just the opposite could happen and likely has. You could try a new product and have a natural reduction in symptoms not related to the new product, causing you to think the new product is a wonder drug.
Pay close attention to the nutrients that have a proven track record for helping others. If you tried them once and failed to improve–go back and try them again.
Spending the extra time to learn about the broad consequences of increased nitric oxide activity will help you to understand you illness and accept this recovery program.
