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Chronic Fatigue Syndrome and Myalgic Encephalitis: It's Mitochondria, Not Hypochondria.

Dr. Sarah Myhill, a veteran clinical physician based in the UK, is the
author of Diagnosis and Treatment of Chronic Fatigue Syndrome and
Myalgic Encephalitis (Chelsea Green Publishing, 2018). In this book,
Dr. Myhill examines the essential role of our mitochondria and why it
is key to understanding and overcoming chronic fatigue syndrome (CFS)
and the inflammation that often accompanies it: myalgic encephalitis
(ME). She reviews the new research and clinical findings on this
debilitating disease and includes insights on why CFS/ME is the most
poorly treated condition in Western medicine, the role of the gut, the
causes of inflammation, how to reprogram the immune system, and more.
The following excerpt is adapted from her book, Diagnosis and Treatment
of Chronic Fatigue Syndrome and Myalgic Encephalitis and is reprinted
with permission from the publisher.


A more detailed look at the biochemistry of mitochondria explains a number of the symptoms of CFS/ME. It is important to emphasize that in the early stages of mitochondrial failure, the mitochondria look normal; for this reason, a muscle biopsy to look at mitochondria in CFS is rarely helpful. It is a bit like having a car with a spark plug that does not work--an MRI scan of a car would come back completely normal, but if you tried to start it, nothing would work. Two key symptoms in patients with CFS/ME which I believe reflect mitochondrial dysfunction are:

* Very poor stamina, both mental and physical. The patient can function, but only for a few seconds before tiring. This is due to slow recycling of ATP.

* Delayed fatigue, mental and physical. Symptoms persist for 24 to 96 hours if these patients overdo things. When mitochondria are stressed, all the energy molecules (ATP, ADP, and AMP) are drained out and cells must wait one to four days for new energy molecules to be made, via the pentose phosphate shunt.

Energy Production in the Mitochondria

Energy production starts with fuel in the bloodstream, which can come to the cells in several forms, listed in form of possible order of preference (metabolic ease):

* Ketone bodies. Produced by the burning of medium-chain fats, such as coconut oil, chocolate fat, butter, animal fats, and our own fat deposits

* Glucose. Released directly from the gut when the liver is overwhelmed, as happens when too much sugar is consumed or absorbed in the mouth, bypassing the liver

* Short-chain fatty acids. Derived from the fermentation of vegetable fiber by friendly bacteroides in the colon

* Pyruvate. Results when lactic acid is recycled via the Cori cycle, following an episode of anaerobic metabolism

* Glucose in the liver and muscle. Released directly from glycogen stores

* Glucose from protein stores in the liver. Produced via gluconeogenesis

* Long-chain fats. These are broken down in peroxisomes (organelles in the cell), cytoplasm that contains enzymes including catalase and often some oxidases) to medium -chain fats which can be used as fuel. Oddly, some CFS sufferers do not seem to be able to do this. Sources of long-chain fats include fish, and the oil of nuts, seeds, and vegetables.

In short, the basic pathology in CFS/ME is slow recycling of ATP to ADP and back to ATP again. If patients push themselves and make more energy demands, ADP is converted to AMP, which cannot be recycled. It is this which is responsible for the delayed fatigue. This is because it takes the body several days to make fresh ATP from new ingredients. When patients overdo things and "hit a brick wall," this is because they have no ATP or ADP to function.

When the System Is Stressed

When energy is used faster than it can be supplied, there are at least two mechanisms by which the body can make emergency energy. This energy may save you from being caught by a saber-tooth tiger, or it's modern day equivalent, but both mechanisms have dire biochemical outcomes in the longer term.

* The adenylate kinase reaction. Two molecules of ADP can combine to make one of ATP and one of AMP. Great news about the extra ATP, but making AMP is a problem, because it can only be recycled very slowly, if at all. This means that the pool of circulating ADP and ATP is rapidly diminished, and mitochondria soon start to go slow. The body has to make brand new ATP. ATP can be made very quickly from the sugar, D-ribose, but D-ribose can only be made from glucose via the pentose phosphate shunt, which takes from one to four days. This delay is one possible explanation for the biological basis of delayed fatigue.

* Switch into anaerobic metabolism with the production of lactic acid. Again, this is short-term gain and long-term pain. One molecule of glucose, used anaerobically in its conversion to lactic acid, produces two molecules of ATP. This compares with 32-36 molecules of ATP (depending on the efficiency of mitochondria) when glucose is burned aerobically. Worse still, to convert lactic acid back to glucose requires six molecules of ATP (the Cori cycle). CFS sufferers simply do not have the ATP to do this, so the lactic acid burn is very persistent. The resulting muscle pain may persist for hours, often days.

The good news is that AMP can be recycled, but it happens very slowly. For practical purposes, for patients who are very fatigued, this recycling is so slow that it is clinically insignificant. Interestingly, the enzyme which facilitates this recycling (cyclic AMP) is activated by caffeine. The perfect pick-me-up for CFS sufferers could be a real black organic coffee with a teaspoon of D-ribose and a large dollop of coconut cream to supply medium-chain fats.

Mitochondria Can Slow Due to Deficiencies

Deficiencies that can lead to mitochondria slowing are principally D-ribose, magnesium, niacinamide (B3), acetyl-L-carnitine, coenzyme Q10, and vitamin B12.

D-Ribose. If the absolute level of ATP present in the cells at any time is low, then this may point to poor production of de novo ATP from its raw material D-ribose. D-ribose in an individual with normal metabolism can be made from glucose via the pentose phosphate shunt (converting six carbon sugars into five carbon sugars, the starting point for making de novo ATP.) However, this takes time and D-ribose is made slowly. The treatment is to supplement with D-ribose, starting with three teaspoonfuls daily (15 grams) and adjusting according to response. Sufferers may see changes within a few days. Clinically, I expect to see less delayed fatigue, as well as improvement in muscle pain and aching. D-ribose has a very short half-life and ideally should be taken in small doses throughout the day in drinks (hot or cold). Interestingly, caffeine may enhance the effects of D-ribose so I recommend taking it with coffee, green tea, or equivalent, so long as those are tolerated. It is worth supplementing D-ribose, even with low normal results, because I have had so much happy feedback from patients taking this supplement.

Some people with a fermenting gut may ferment D-ribose and worsen the situation. Many CFS sufferers have to reserve D-ribose only for use as a rescue remedy for situations in which they have overspent their energy. (A low-carb diet, used in the treatment of fermenting gut will starve out fermenting microbes; as a result, levels become so low that the occasional large dose of D-ribose will not ferment before it is absorbed.)

A few people may not tolerate D-ribose because it is derived from corn and small amounts of corn antigen may remain, to which they can react allergically. Many will react to preparations on the market that purport to be corn free.

Very low ATP may mean the patient is not pacing activity well--the moment the CFS sufferer has energy, it is all too tempting to spend it, because they have already missed out on so much. However, pacing is essential to a sustained and substantial recovery.

Magnesium. The release of energy from ATP is magnesium dependent, as is the synthesis of ATP from ADP, so magnesium is of central importance in mitochondria. Magnesium deficiency is one of the knottiest problems I encounter. Having low levels of magnesium inside the cells and mitochondria is a symptom of CFS/ME, but also a cause of it. This is because 40% of resting energy simply powers the ion pumps for sodium/potassium (Na/K) and calcium/magnesium (Ca/Mg) across cell membranes, a process essential for life. When energy supply is diminished, there is insufficient energy to fire these pumps, so magnesium cannot be drawn into cells for oxidative phosphorylation to work. If there is insufficient energy to drag magnesium into the cells, then there is a further diminishing of energy delivery. This is just one of the many vicious cycles in CFS/ME.

Sufferers do not simply replete their magnesium levels through taking supplements, although this must be tried. This is because the problem is not just magnesium deficiency but also magnesium in the wrong department. Some CFS/ME sufferers need magnesium by injection to get the desired result. I think this is rather like kick-starting an engine to get it going. CFS/ME sufferers may need a spike of magnesium in the blood to push it into cells to fire up the mitochondria. I suggest patients self-inject perhaps 1/2 ml of 50 percent magnesium sulphate subcutaneously daily, usually into the roll of fat round the tummy that we all get when we sit down, using a fine insulin syringe. It astonishes me that such a tiny amount can make a big difference. Such an injection contains approximately 25 mg of elemental magnesium, when the recommended daily amount is at least 300 mg. This is a hypertonic solution, which means that the injection can be painful and may leave small lumps, though with time the lumps do disappear. I also suggest warming the injection to blood heat to make it less painful. What seems to be additionally helpful is to administer the injection very slowly. This gives the magnesium a chance to disperse and dilute, rendering it less of an irritant.

Some people find magnesium by nebulizer works as well. Indeed, nebulized magnesium is an excellent treatment for asthma. (Please see my web page for instructions on making up a solution of magnesium sulphate for nebulizing. All that is needed are Epsom salts dissolved in water, and a nebulizer through which the dissolved Epsom sales are bubbled. For additional information, see http://drmyhill.co.uk/wiki/Magneium_by_nebuliser)

Niacinamide. Low levels of nicotinamide adenine dinucleotide (NAD) may be a symptom of poor function of Krebs citric acid cycle (KCA). Measuring NAD is a functional test, and it does not just reflect vitamin B3 levels in the blood. The job of KCA is to take energy from acetyl groups and convert it into NADH (nicotinamide adenosine diphosphate), which is then converted to NAD in the process of driving chemi-osmosis. Therefore, to see normal levels of NAD needs not only an adequate supply of B3, but also a properly functioning Krebs citric acid cycle.

I initially used 500 mg of supplementary vitamin B3, but increasingly I use 1,500 mg of slow-release niacinamide. In theory there is potential for NAD to cause liver damage. However, I have never seen this in clinical practice. I believe this is because toxic effects of drugs and vitamins result from micronutrient deficiencies. Where these are being adequately replaced, the potential for toxicity is virtually zero. I recommend using niacinamide, which does not cause flushing.

Acetyl L-carnitine. To get fuel to burn for oxidative phosphorylation, it needs to be transported as acetate across the mitochondrial membrane by acetyl L-carnitine. This is normally present in red meat, but generally not in large enough quantities to replete the deficiencies found in fatigued states. As a routine, I recommend taking supplementary acetyl L-carnitine 1-2 grams daily.

Coenzyme Q10. I often measure levels of CoQ10, but less so now simply because I know the result will be low. Indeed, I have never seen a normal level of CoQ10 in someone who is not already taking supplements of this nutrient. I recommend using ubiquinol 200 mg daily, often more. Dr. Stephen Sinatra, the cardiologist who pioneered the use of CoQ10 in the treatment of all forms of heart disease (the Sinatra Solution) sometimes uses one gram a day. Like the majority of nutritional supplements, it has no known toxicity so over-dosing is virtually impossible. (It is, however, very expensive.)

Vitamin B12 by injection. Vitamin B12isa big player in CFS/ME. It multitasks and is an essential aspect of the methylation cycle, protein synthesis, energy delivery mechanisms, detoxification, and, of course, making new red blood cells. Furthermore, the doses of B12 that work best for individuals vary enormously. This means we have laboratory guidelines that give us a level of B12 in the serum that is sufficient to prevent pernicious anemia. However, this may not be sufficient to allow people to function at their full potential. This means we cannot rely on any measurement of B12 to determine if a person has adequate levels.

There are probably epigenetic influences here as well--for example, we know that Japanese prisoners of war who suffered severe malnutrition for some years required much higher doses of B vitamins generally in order to remain healthy for the rest of their lives. This is obviously an extreme example: nutrient depletion can take many forms. Being a vegetarian, for instance, is a major risk factor for CFS/ME, and vegetarians have a lower intake of B12 than carnivores. B12 at high doses is a safe and reasonable thing to do.

However, B12 is very poorly absorbed in the digestive tract--its absorption requires a sufficiently acid stomach and the presence of intrinsic factor in the gastric juice, together with a normal section of terminal ileum. As we age, our ability to absorb B12 declines, but our requirement for it increases as we become biochemically less efficient. Therefore, at a certain age (perhaps 50 and certainly 60 onwards) we would all benefit from a monthly injection of vitamin B12.

Dr. Patrick Kingsley in his work with patients with multiple sclerosis found that some patients did not respond clinically until they received up to 20 mg (20,000 mcg) a day by injection. In patients with CFS/ME we know there is a proinflammatory tendency. Professor Martin Pall identified a proinflammatory cycle he terms the NO/ONOO cycle; it happens that B12 is an essential aspect of damping this down.

I am also aware clinically that for many people, injections are superior to oral supplements. I suspect the reason for this is that an injection spikes the level of B12 in the blood and therefore forces it into the system by the law of mass action. The only way to ensure good B12 status is a trial of vitamin B12 by injection. Ideally this should be in the form of methyl cobalamin, since this is the one which needs the least processing in the body to be effective. In the past, we were able to obtain vitamin B12 in 5 mg/ml strength, but that is much more difficult to get now, so we must make do with lower concentration solutions.

Putting the regimen in place. If you are unable to access mitochondrial function tests, these regimens can still be safely put in place with no risk of toxicity problems. It is my experience that the abnormalities I see are so predictable, if finances are tight, I would prefer to see money spent on treatment regimens rather than on tests (Table 1).

Mitochondria Can Slow Due to Blockages

Blocking can occur in mitochondria in the synthesis of ATP (conversion of ADP to ATP) and/or because of poor translocator protein function. We do not currently know all the causes of blockage, but essentially, they divide into two major categories:

* Blockages resulting from toxins due to internal metabolism (endogenous)

* Blockages from toxins in the external world (exogenous)

Blockages from Internal Metabolism

Lactic acid. This dynamic prevents athletes from breaking records. CFS/ME sufferers who do not pace their activities properly and continue to push themselves perform less well. This is somewhat like athletes in a state of chronic over-training. However, telling my patients to do less is difficult.

Sugar. Running a high blood sugar level decreases energy. I suspect this partly explains the fatigue of metabolic syndrome and diabetes.

Aldehydes. John McLaren-Howard of Acumen Lab often finds evidence of malondialdehyde adhered to translocator protein. This is a symptom of poor antioxidant status. I treat this with B12 injections, together with nutritional supplements (zinc, copper, manganese, selenium, glutathione, and CoQ10).

Products of the fermenting gut. These products include bacterial endotoxins, various alcohols, aldehydes, and acetones, hydrogen sulphide, D-lactate, and many other possible nasties. They do not show up on translocator protein studies, possibly because they are volatile. The treatment, of course, is as per fermenting gut.

Blockages Due to Chemicals from the External World

These blockages result from toxic metals and volatile organic compounds. They can also come from prescription drugs. A very useful resource is the report, Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity. (1) The report concludes that many drugs with organ toxicity have a "mitochondrial liability". A screen of more than 550 drugs revealed that 34 percent of the medications evaluated had mitochondrial liabilities (Table 1). The severity of these adverse effects was observed to be idiosyncratic.

Mitochondrial Impairment by Drugs with a Black Box Warning

The potential for mitochondrial harm can result from the use of certain drugs, notably those with black box warnings, the strictest caution in the labelling of prescription drugs or products by the FDA when there is reasonable evidence of serious hazard with a drug.

Liver mitochondria:

* Antivirals. Abacavir, didanosine, emtricitabine, entecavir, lamivudine, nevirapine, stavudine, telbivudine, tenofovir, tipranavir, zalcitabine, zidovudine

* Anticancer. Dacarbazine, flutamide, gemtuzumab, methotrexate, pentostatin, tamoxifen

* Antibiotics. Isoniazid, streptozocin, trovafloxacin

* Antifungals. Ketoconazole (oral)

* CNS disorders. Dantrolene, divalproex, sodium felbamate, naltrexone, nefazodone, and valproic acid

* Hypertension. Bosentan

Cardiovascular mitochondria:

* Anthracyclines. Daunorubicin, doxorubicin, epirubicin, idarubicin

* NSAIDS. Celecoxib, diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, thioridazine, tolmetin

* Anesthetic. Bupivacaine

* Anticancer. Arsenic trioxide, cetuximab, denileukin, diftitox, mitoxantrone, tamoxifen

* Beta-blocker. Atenolol

* Antiarrhythmics. Amiodarone (oral), disopyramide, dofetilide, ibutilide

* CNS amphetamines. Atomoxetine, droperidol, methamphetamine, pergolide

* Diabetes medications. Pioglitazone, rosiglitazone

Conclusion

Mitochondrial dysfunction is key to the mechanisms that drive CFS. In the UK, we now have an objective test, the Mitochondrial Function Profile Test or ATP Profiles, that gives us a precise measurement of that level of dysfunction. The ATP Profiles also identify where things are going wrong and why, providing further clues to treatment. These treatments essentially fall into two categories: a deficiency in raw materials, for which the treatment is supplementation, and blockage(s) in the biochemical pathways, for which the treatment involves various methods of detoxification. In the case of blockage, further testing (translocator protein studies) can identify which toxins are causing these blockages. Such blockages can be treated via chelation with DMSA, selenium, zinc, clays such as zeolite, high dose vitamin C, iodine, and heating regimens such as soaks or saunas. Dr. McLaren-Howard has many other innovative tests he uses which are helpful clinically, but not yet available generally. Our first step is to find another lab that can do all the above commercially. If this is of interest, you can reach us via Dr. Myhill--office@doctormyhill.co.uk

(1.) Dykens JA. Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity. Pfizer Drug Safety Research & Development. 2007. www.mitoaction.org/files/Dykens%20for%20Mitoaction.pdf. Accessed 28 September 2016.

by Dr. Sarah Myhill, MB, BS

Dr. Sarah Myhill is a clinical physician based in the UK and a leader in the treatment of chronic fatigue syndrome. She has focused her career on identifying and treating the underlying causes of health problems and is a frequent lecturer on topics such as organophosphate poisoning, the problems of silicone, and chronic fatigue syndrome. She is the author of Sustainable Medicine, Diagnosis and Treatment of Chronic Fatigue Syndrome and Myalgic Enchephalitis, and The PK Cookbook.
Table 1. Mitochondrial Support Supplementation

When            What         Dosage                How

Away from food  Glutathione  250 mg                Sublingually
With            CoQ10        200 - 400 mg          Orally
breakfast
                Niacinamide  1500 mg slow-release  Orally
                Carnitine    1-2 grams             Orally
                Copper       1 mg                  Orally
                D-ribose     5 grams               In coffee or tea
                Magnesium    1/2 ml 50%            Subcutaneous
                             magnesium             injection
                             sulphate
                Vitamin B12  0.5 to 5 mg           Subcutaneous
                                                   injection
Lunch           D-ribose     5 grams               In coffee or tea
                Manganese    3 mg                  Orally
Supper          D-ribose     5 grams               No tea or coffee
Bedtime         Zinc         30 mg                 Orally
                Selenium     300 mcg               Orally

When            Why

Away from food  Vital for glutathione peroxidase and to detox toxic
With            metals Mops up free radicals
breakfast
                Essential intermediate between Krebs citric acid cycle
                and chemiosmosis
                Gets fuel inside the mitochondria for burning
                Give if SOD is low
                Raw material to make new ATP. Good for delayed fatigue.
                Take care if there is fermenting gut.
                Kick-starts the mitochondrial engine
                Improves energy delivery. Excellent for fatigue, foggy
                brain, mood, detoxification, protein synthesis, etc.
Lunch           Last dose of caffeine 2 pm
                If SOD is low
Supper          Caffeine disturbs sleep
Bedtime         If SOD is low, but arguably for life, since zinc
                deficiency is pandemic
                Especially if glutathione peroxidase is low, but
                arguably for life since selenium deficiency is pandemic
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Title Annotation:Book Excerpt; Diagnosis and Treatment of Chronic Fatigue Syndrome and Myalgic Encephalitis
Author:Myhill, Sarah
Publication:Townsend Letter
Article Type:Excerpt
Date:Nov 1, 2018
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