Dr. Sarah Myhill
September 2005 I think this is one of the most important handouts I have ever produced in terms of my understanding of CFS and what to do in order to recover! So please read this very carefully and several times over because for many sufferers it contains the keys to unlock their illness!
WHAT IS CHRONIC FATIGUE SYNDROME? (August - September 2005)
Chronic fatigue syndrome is the symptom caused by mitochondrial failure. This results in slow recycling of adenosine triphosphate (ATP), the currency of energy in the body, so all bodily functions go slow. The following cycle illustrates what happens initially:
ATP (3 phosphates) recycles approximately every 10 seconds in a normal person - if this goes slow, then the cell goes slow and so the person goes slow.
However if the CFS sufferer really pushes himself he can get some energy by converting adenosine diphosphate (ADP - 2 phosphates) to adenosine monophosphate (AMP -1 phosphate), but this cannot be recycled and is lost in urine. The body then has to wait for new ATP to be made. It can be made very quickly from a sugar D-ribose, but D-ribose is only slowly made from glucose. But the problem is that if the body is very short of ATP it can make a very small amount directly from glucose by converting it into lactic acid. Two problems here - firstly lactic acid quickly builds up especially in muscles to cause pain, heaviness, aching and soreness ("lactic acid burn"), secondly none is available in order to make D-ribose! So new ATP cannot be made when you are really run down. Recovery takes days!
Treatment of CFS therefore is a two pronged approach.
Firstly feed the mitochondria the raw material necessary to heal themselves and work efficiently. This means feeding the mitochondria correctly so they can heal and repair.
Secondly address the underlying causes as to why mitochondria have been damaged. This must also be put in place to prevent ongoing damage to mitos. In order of importance this involves:
- Pacing activities to avoid undue stress to mitos
- Getting excellent sleep so mitos can repair
- Excellent nutrition with respect to: i. taking a good range of micronutrient supplements ii. stabilising blood sugar levels ii. identifying allergies to foods
- Detoxifying to unload heavy metals, pesticides, drugs, social poisons (alcohol, tobacco etc) and volatile organic compounds all of which which poison mitos.
The Perfect Test for Chronic Fatigue Syndrome
The central problem of chronic fatigue syndrome is mitochondrial failure resulting in poor production of ATP. ATP is the currency of energy in the body and if the production of this is impaired then all cellular processes will go slow. It is not good enough to measure absolute levels of ATP in cells since this will simply reflect how well rested the sufferer is. The perfect test is to measure the rate at which ATP is recycled in cells and this test has now been developed by John McLaren Howard at Biolab in London.
Not only does this test measure the rate at which ATP is made, it also looks at where the problem lies. Production of ATP is highly dependant on magnesium status and the first part of the test studies this aspect.
The second aspect of the test measures the efficiency with which ATP is made from ADP. If this is abnormal then this could be as a result of magnesium deficiency, of low levels of Co-enzyme Q10 or of L-carnitine.
The third possibility is that the protein which transports ATP and ADP across mitochondrial membrane is impaired and this is also measured.
The joy of this test is that we now have an objective test of chronic fatigue syndrome which clearly shows this illness has a physical basis. This test clearly shows that cognitive behaviour therapy, graded exercise and anti-depressants are irrelevant in addressing the root cause of this illness. If you wish to order this test, please phone my office or email me - the cost is £105. When the results come through, I will write to your GP with interpretation. The cost of the letter to your GP is £25.
To get the full picture I also recommend combining this test with measuring levels of Co-enzyme Q10 and NAD.
The two other important co-factors are L-carnitine and D-ribose. The latter is used up so quickly by cells that measuring levels is unhelpful. I do not know of a test as yet to look at L-carnitine levels, but the main source of L-carnitine is from meat and therefore a high protein diet should supply the necessary. If you are vegetarian or eat red meat no more than once or twice a week, you should supplement with acetyl L-carnitine (best absorbed form) by taking 2 - 3 grams daily.
You will find more about the interpretation of ATP profiles on page 8 of this handout.
CFS is Heart Failure Secondary to Mitochondrial Malfunction
Two papers have come to my notice recently which make great sense of both my clinical observations and also the idea that CFS is a symptom of mitochondrial failure. The two symptoms I am looking for in CFS to make the diagnosis is firstly very poor stamina and secondly delayed fatigue. I think I can now explain these in terms of what is going on inside cells and the effects on major organs of the body (primarily the heart). More importantly, there are major implications for a test for CFS and of course management and recovery.
If mitochondria (the little batteries found inside every cell in the body) do not work properly, then the energy supply to every cell in the body will be impaired. This includes the heart. Many of the symptoms of CFS could be explained by heart failure because the heart muscle cannot work properly. Cardiologists and other doctors are used to dealing with heart failure due to poor blood supply to the heart itself. In CFS the heart failure is ,caused by poor muscle function and therefore strictly speaking is a cardiomyopathy. This means the function of the heart will be very abnormal, but traditional tests of heart failure, such as ECG, ECHOs, angiograms etc, will be normal.
Thanks to work by Dr Arnold Peckerman www.cfids-cab.org/cfs-inform/Coicfs/peckerman.etal.03.pdf we now know that cardiac output in CFS patients is impaired. Furthermore the level of impairment correlates very closely to the level of disability in patients. Dr Peckerman was asked by the US National Institutes of Health to develop a test for CFS in order to help them to judge the level of disability in patients claiming Social Security benefits. Peckerman is a cardiologist and on the basis that CFS presents with low blood pressure, low blood volume and perfusion defects, he surmised CFS patients were in heart failure To test this he came up with Q scores.
"Q" stands for cardiac output in litres per minute and this can be measured using a totally non-invasive method called Impedence Cardiography. This allows one to accurately measure cardiac output by measuring the electrical impedence across the chest wall. The greater the blood flow the less the impedance. This can be adjusted according to chest and body size to produce a reliable measurement (this is done using a standard algorithm). It is important to do this test when supine and again in the upright position. This is because cardiac output in healthy people will vary from 7 litres per min when lying down to 5 litres per min when standing. In healthy people this drop is not enough to affect function. But in CFS sufferers the drop may be from 5 litres lying down to 3.5 litres standing up. At this level the sufferer has a cardiac output which causes borderline organ failure.
This explains why CFS patients feel much better lying down. They have acceptable cardiac output lying down, but standing up they are in borderline heart and organ failure. CFS is therefore the symptom which prevents the patient developing complete heart failure. Actually, everyone feels more rested when they are sitting down with their feet up! The subconscious has worked out that the heart has to work less hard when you are sitting down with your feet up - so we do so because we feel more comfortable!
This means there are two tests for CFS
Firstly, we can test the rate at which ATP is recycled inside cells as above.
Secondly, it is possible to measure cardiac output whilst standing and sitting using the Impedence Cardiograph. This test has been proven in the US in the assessment of disability in CFS - the Q score is an extremely accurate prediction of disability. However, what this test does not do is tell you why there is disability (i.e. post exertional fatigue). As this test is not easily available to CFS patients in this country, I feel that the ATP test will give us all the answers needed for the management of CFS.
Low cardiac output explains the symptoms of CFS
The job of the heart is to maintain blood pressure. If the blood pressure falls, organs start to fail. If the heart is working inadequately as a pump then the only way blood pressure can be sustained is by shutting down blood supply to organs. Organs are shut down in terms of priority, i.e. the skin first, then muscles, followed by liver, gut, brain and finally the heart, lung and kidney. As these organ systems shut down, this creates further problems for the body in terms of toxic overload, susceptibility to viruses which damage mitochondria further, thus exacerbating all the problems of the CFS sufferer.
1. Effects on the Skin
If you shut down the blood supply to the skin, this has two main effects. The first is that the skin is responsible for controlling the temperature of the body. This means that CFS patients become intolerant of heat. If the body gets too hot then it cannot lose heat through the skin (because it has no blood supply) and the core temperature increases. The only way the body can compensate for this is by switching off the thyroid gland (which is responsible for the level of metabolic activity in the body and hence heat generation) and so one gets a compensatory underactive thyroid. This alone worsens the problems of fatigue.
The second problem is that if the micro-circulation in the skin is shut down, then the body cannot sweat. This is a major way through which toxins, particularly heavy metals, pesticides and volatile organic compounds are excreted. Therefore the CFS sufferer's body is much better at accumulating toxins, which of course further damage mitochondria.
2. Symptoms in Muscles
If the blood supply to muscles is impaired, then muscles quickly run out of oxygen when one starts to exercise. With no oxygen in the muscles the cells switch over to anaerobic metabolism, which produces lactic acid and it is this that makes muscles ache so much.
As well as the above problem, muscles in the CFS patient have very poor stamina because the mitochondria which supply them with energy are malfunctioning.
3. Symptoms in the Liver and Gut
Poor blood supply to the gut results in inefficient digestion, poor production of digestive juices and leaky gut syndrome. Leaky gut syndrome causes many other problems such as allergies, autoimmunity, malabsorption, etc., which further compound the problems of CFS.
If liver circulation is inadequate, this will result in poor detoxification, not just of heavy metals, pesticides and volatile organic compounds, but also toxins produced as a result of fermentation in the gut again further poisoning the mitochondria.
4. Effects on the Brain
Last October I attended a conference sponsored by the late Dr John Richardson. A Canadian physician Byron Hyde showed us some functional scans of the brains of CFS patients. If I had not known the diagnosis, I would have diagnosed strokes. This is because the blood supply to some area of the brain was so impaired. The default is temporary and with rest, blood supply recovers. However, this explains the multiplicity of brain symptoms suffered from, such as poor short term memory, difficulty multi-tasking, slow mental processing and so on. Furthermore brain cells are not particularly well stocked with mitochondria and therefore they run out of energy very quickly.
5. Effects on the Heart
There are two effects on the heart. The first effect of poor micro-circulation to the heart is disturbance of the electrical conductivity which causes dysrhythmias. Many patients with chronic fatigue syndrome complain of palpitations, missed heart beats or whatever. This is particularly the case in patients with poisoning by chemicals since the chemicals are also directly toxic to nerve cells.
The second obvious result is poor exercise tolerance. Heart muscle fatigues in just the same way that other muscles fatigue. Symptomatically this causes chest pain and fatigue. In the longer term it can cause heart valve defects because the muscles which normally hold the mitral valve open also fatigue.
The difference between this type of heart failure and medically recognised congestive cardiac failure is that patients with CFS protect themselves from organ failure because of their fatigue symptoms. Patients with congestive cardiac failure initially do not get fatigue and often present with organ failures such as kidney failure or overt heart failure. At present I do not know why there is this difference.
THIS APPROACH TO TREATING HEART DISEASE IS EXACTLY THE SAME REGARDLESS OF THE CONVENTIONAL DIAGNOSIS. So patients with angina, high blood pressure, heart failure, cardiomyopathy, some valve defects as well as patients with cardiac dysrhythmias also have mitochondrial problems and will respond in the same way to nutritional therapies and detox therapies.
6. Effects on Lung and Kidney
The lung and kidney are relatively protected against poor micro-circulation because they have the largest renin angiotensin system, which keeps the blood pressure up in these vital organs. Therefore clinically one does not see patients with kidney failure or pulmonary hypoperfusion in CFS.
Explanation of the Fatigue Problems in CFS Patients
Energy to the body is supplied by mitochondria, which produce NAD (nicotinamide adenosine diphosphate) and ATP (adenosine triphosphate). These molecules are the "currency" of energy in the body. Almost all energy requiring processes in the body have to be "paid for" with NAD and ATP, but largely ATP. The reserves of ATP in cells are very small. At any one moment in heart muscle cells there is only enough ATP to last about ten contractions. Thus the mitochondria have to be extremely good at re-cycling ATP to keep the cell constantly supplied with energy.
If the cell is not very efficient at re-cycling ATP, then the cell runs out of energy very quickly and this causes the symptoms of weakness and poor stamina. The cell literally has to "hibernate" and wait until more ATP has been manufactured.
In producing energy, ATP (three phosphates) is converted into ADP (two phosphates) and ADP is re-cycled back through mitochondria to produce ATP. However, if the cell is pushed when there is no ATP about, then it will start to use ADP instead. The body can create energy from ADP to AMP (one phosphate), but the trouble is that AMP cannot be re-cycled. The only way that ADP can be regenerated is by making from fresh ingredients, but this takes days to do. This explains the delayed fatigue seen in chronic fatigue syndrome.
So to summarise, the basic pathology in CFS is slow re-cycling of ATP to ADP and back to ATP again. If patients push themselves and make more energy demands, then ADP is converted to AMP which cannot be recycled and 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 at all.
Implications for Treatment
The vast majority of patients I see get well with my standard work up with respect to vitamins and minerals, diet, pacing, sleep, B12, magnesium, detoxing, etc, etc. All these things must be put in place to repair and prevent ongoing damage to mitochondria so allowing them to recover. For mitochondria to recover they need all the essential vitamins, minerals, essential fatty acids and amino acids to manufacture the cellular machinery to restore normal function.
However, despite doing that, I am still left with a hard core of patients that I still struggle with. This is where direct micronutrient support for mitochondria may prove to be an extremely useful intervention. I have learned what to do through reading a book "The Sinatra Solution" produced by an American metabolic cardiologist, Dr Stephen Sinatra, who has used these techniques for treating patients with heart disease such as congestive cardiac failure, angina, arrhythmias and so on. Sinatra worked initially using entirely conventional techniques - drugs, pacemakers, surgery or whatever. However, he realised that cardiac disease was not all about poor blood supply to the heart. For many the problem was heart muscle disease due to mitochondrial failure. Once he tackled this aspect, patients made dramatic recoveries, were able to come off medication, avoid surgery and return to their normal jobs and sporting activities.To understand his ideas, you need to understand a little bit about how mitochondria work.
How Mitochondria Actually Work
The job of mitochondria is to get the energy contained inside foods (ie sugars and fats) and convert it into a form the body can use, i.e. NAD and ATP. This requires a series of reactions (Kreb's citric acid cycle for the chemists in the audience!). This process is called oxidative phosphorylation and chemically speaking needs electrons to move about from one molecule to another changing their chemical make up as they go. These reactions require enzymes, which are made up of many different vitamins, minerals, fatty acids and amino acids. However one of the most important electron handlers is Co Enzyme Q 10.
Once ATP has been made, it then has to be delivered to where it is needed, ie out of the mitochondria, through its membrane. This it does with a shunting reaction. ATP is made inside mitochondria from ADP and has to be shunted across the mitochondrial membrane so the cell can use the energy in the ATP by converting it back to ADP. ADP then needs to be shunted back across the cell membrane. This shunting reaction involves acetyl L-carnitine, which effectively shunts energy in the form of ATP from inside mitochondria, through the mitochondrial cell membrane into the cell, where it gives up its energy and converts to ADP. L-carnitine then shunts ADP back through the mitochondrial membrane, where it is reformed into ATP. Obviously, if this shunting reaction does not run smoothly, energy supply will be impaired.
All the molecules involved here are re-cycled. There is another essential element which is magnesium. If you think of glucose and short chain fatty acids as the fuel of the engine, acetyl L-carnitine and Co-enzyme Q10 are the oil and magnesium is the spark plug!
In order to make new ATP, one needs a sugar, namely D-ribose. Normally the body can manufacture this for itself from glucose, but if energy levels are very low, then it may be unable to synthesise this essential sugar. So when the CFS sufferers push themselves too much, ADP is converted into AMP, which they cannot recycle. It normally takes a few days to make new ATP from D-ribose, but the CFS sufferers may be unable to make D-ribose.
In order to make new NAD one needs vitamin B3.
Implications for Treatment - details
If the body is functioning normally and has access to all essential minerals, vitamins, essential fatty acids and amino acids, it can make all these essential ingredients, in particular co-enzyme Q 10, acetyl L-carnitine and D-ribose. Magnesium must be supplied. This explains why most patients get well on my standard work up of treatment because this supplies all the essential ingredients for the body to heal itself.
However, for those who do not get well, it is likely that there is some sort of metabolic defect which prevents them from manufacturing these essential ingredients. I call this metabolic dyslexia! It may well be that genetically poor mitochondrial function alone is the problem, or there may be toxins or pesticides stuck in the system which stop the mitochondria functioning properly. It may well be that once the patient has dropped below a certain critical level, all cellular processes are going so slow that the sufferer is unable to manufacture the very things required to restore health. With age, our metabolism becomes less efficient anyway and we may need more raw materials in order to maintain the status quo.
Either way there is a cocktail of micronutrients that could be taken to kick start the system. This cocktail is already of tried and tested value. It has been used in America by many metabolic cardiologists to treat cardiomyopathies, ischaemic heart disease, dysrhythmias, congestive cardiac failures, high blood pressures and anginas with great success. Not only have patients felt better, but they have come off all their medication and avoided life threatening interventions such as cardiac transplants, arterial surgery, pacemakers and so on.
Dr Sinatra has developed several schemes for age management, high blood pressure, arrhythmias, mitral valve prolapse, congestive cardiac failure, syndrome X, for professional and world class athletes, but also for fibromyalgia, chronic fatigue syndrome and mitochondrial cytopathies. He recommends the following daily cocktail for CFS:
Co-enzyme Q 10 300 - 360mg (the oil of the engine - moves electrons from one molecule to another)
L-carnitine 2,000 - 3,000mg (the oil of the engine - moves ATP and ADP across mito membranes)
D-ribose 15grams (raw material to make new ATP)
Magnesium 400 - 800mg (the spark plugs - fires up many enzyme reactions)
To this I would also add niacinamide 500mgs daily (the raw material to make NAD).I would expect this cocktail of supplements to work best taken together, not as individual supplements.
"The Sinatra Solution: Metabolic Cardiology" - Stephen T Sinatra
Incidentally this helps explain why some CFS sufferers have such problems with drug medication and indeed this may help to point towards treatment. All my CFS patients feel much worse on statins because these stop the body from making its own Co Q 10. Beta blockers, tricyclic antidepressants and phenothiazines also block Co Q 10 synthesis.
There is no point taking this cocktail until you have done my standard work up to treating CFS. This is because normally the body is perfectly capable of making its own Coenzyme Q 10 and its own D-ribose so long as it has all the vitamins, minerals, EFAs and amino acids to do so. Vitamin B3 and magnesium comes from supplements and acetyl L-carnitine from red meat.
The supplements in the Sinatra protocol are expensive, so for those who would like to try it I suggest:
Measure levels of Co Q 10 to show there is a deficiency.Phone the office to order a kit, cost £27 (5mls blood red speckled top tube).
Measure NAD levels. Phone office to order a kit, cost £32. (Green top lithium heparin tube)
Eat red meat daily for acetyl L carnitine. Vegetarians will have to take the supplement. If you have poor digestion then you may need to supplement with L carnitine anyway. I can supply Acetyl-L-carnitine 120g for £10 plus P+P £2.
SODase (superoxide dismutase) - £28, order as above.
Cell-free DNA is another significant test which assesses the level of cell degradation and cell death (as a result of which DNA material is released from the cell into the bloodstream). This gives an indication of the level of damage to cells and when positive, proves the physical nature of CFS.
The five individual tests (ATP profiles, CoQ10, NAD, SODase and cell-free DNA) have been combined into a single "CFS biochemistry profile". The price is £175. Again, when the results come through, I will write to your GP with interpretation. The cost of the letter to your GP is £50. To order the test, please, send in your name, date of birth and address, your GP's name and address and your cheque for £225 made payable to Sarah Myhill Limited.
If You Are Found To Be Deficient:
Co-enzyme Q 10. This must be in a hydrosoluble or oil form or it is not well absorbed. Co Q 10 is fairly widely available - Lamberts 01892 554 312 do a preparation of 100mgs Co Q 10. Your GP can also prescribe on the NHS - details below.
L-carnitine - this is an amino acid with highest levels in meat. This may explain why vegetarians are at risk of CFS. It also partly explains why my CFS patients do best on high protein diets. Eat red meat (the word carnitine comes from carne - meat). I can supply Acetyl-L-carnitine 120g for £10 plus P+P £2.
D-ribose - needs to be taken throughout the day. I have found a reasonably priced source and can dispense 500gms for £23 plus £4 P+P.
Niacinamide 500mgs available from Solgar 01782 634 744
Magnesium in Myhill's Magic Minerals (or other such mineral supplement). But if there is a severe deficiency, then magnesium by injection may be required.
How long before you see improvement?
Not sure at the moment. However, heart transplant patients whose cardiac output is improved overnight can take up to a year before they start to feel fully well again. However, I would expect sufferers to see improvements after a few weeks of supplements
What is important is that these interventions are done in combination with all my other recommendations with respect to diet, micronutrients, pacing, sleep, detoxing, etc. Firstly get the regime tight, then start to feel better and then start to increase activity.
Interpretation of ATP Profiles Test (September 2005)
The ATP profiles test is a measure of mitochondrial function. The only job of mitochondria is to provide energy for cell metabolism in the form of ATP. Whilst all cells of the body are different, mitochondria are the same and so this test has huge implications not just for CFS but also for the pathophysiology of many degenerative diseases such as heart disease, Alzheimer's, Parkinson's and many others. Indeed it is the rate at which mitochondria slow down and degenerate which determines the natural ageing process. There is now good evidence that the basic pathophysiological defect in chronic fatigue syndrome is slow recycling of ATP and this elegantly explains the symptoms of CFS. ATP profiles can therefore be used to make the diagnosis of CFS, to assess the level of disability objectively, to identify where the biochemical lesion lies and give pointers as to how to further elucidate and correct that biochemical lesion.
The biochemical lesion may result from a nutritional deficiency, from a stress (which may be endogenous free radical stress, or exogenous toxic stress) or from a metabolic dyslexia - i.e. some enzyme block which inhibits the production of essential nutrients. The best documented is enzyme blockage by statins which inhibit the endogenous production of co-enzyme Q 10, the most important acceptor and donor of electrons in Krebs citric acid cycle (oxidative phosphorylation). Not only do statins almost invariably worsen fatigue syndromes but probably also accelerate the normal ageing process.
Levels of ATP
The first thing to look at are the absolute levels of ATP and ADP. This suggests two things. Firstly, poor ability to make 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. However, if this is malfunctioning, D-ribose is made slowly. Indeed this probably explains the delayed fatigue in CFS. The treatment is to supplement with D-ribose starting with three teaspoonfuls daily (15gms) and adjusting according to response. Sufferers often see changes within a few days. Clinically I expect to see less delayed fatigue and improvement in muscle pain and aching.
Secondly, low levels of ATP may mean that the sufferer is not pacing properly. When one overdoes things, ADP is created faster than ATP can be made. This results in a build up of ADP and some is inevitably shunted into AMP (the monophosphate) which cannot be recycled. Thus the cell has to make de novo ATP from D-ribose.
Release of energy from ATP (A)
Next look to see the rate at which ATP is converted to ADP with the accompanying release of energy. This is a magnesium dependent process, and if slow, results from magnesium deficiency. Since I first became interested in fatigue syndromes in 1982, I have found magnesium to be the knottiest problem I have come across! Sufferers do not simply replete through taking magnesium supplements - although this must be tried! Some need magnesium by injection to get the desired result. I usually start with 2mls of 50% Evans magnesium sulphate weekly and adjust the dose according to clinical response. Some people prefer to inject smaller amounts (say 1/2ml) every other day using a fine insulin syringe.
Movement of ATP and ADP across mitochondrial membranes (C)
This is dependent on translocator protein which sits in the mitochondrial membrane and shunts ATP and ADP to and fro. If this is malfunctioning then it suggests blockage by some sort of toxin. As yet we are not sure which are the most likely toxins involved but this will become apparent with time and experience. Many toxins can do this, they could be endogenous toxins (from free radicals) and they could be exogenous from heavy metals, pesticides, VOCs or whatever. However, these exogenous toxins can all be got rid of by sweating regimes. Exercise is obviously the most physiological method but impossible for CFS sufferers! I would recommend a sweating detox at least three times a week and my preferred technique is with far infra-red saunaing. (See FIR sauna information).
Oxidative phosphorylation - the recycling of ATP from ADP (B)
Look at the rate at which ADP is converted to ATP. The whole process is done by oxidative phosphorylation and carried out in Krebs citric acid cycle (dig out those old "O level" biochemistry books at once!). There is lots of potential for things to go wrong here! The bits we know about (and there will be others!) which may make oxidative phosphorylation go slow include:
Vitamin B3 is vital as the raw material to make NAD - most people replete on 500mgs of niacinamide, but some people seem to need 3,000mgs daily to get a result. At levels above 500mgs, liver function tests need checking every month for three months then every 6 months.
Magnesium deficiency - Mg catalyses many reactions in KCA cycle. Mg may have to be given by injection to replete levels.
Acetyl-L-carnitine - to get fuel for oxidative phosphorylation to burn, one needs it to be transported across the mitochondrial membrane by acetyl L carnitine. This is normally present in mutton, lamb, beef and pork. If these foods are not consumed then I recommend taking acetyl L carnitine 2 grams daily.
However, clinical experience, which I have nicked from the American Cardiologist Dr Stephen Sinatra, is that co-enzyme Q 10 is vitally important as the main shunter of electrons in oxidative phosphorylation. Funnily enough, I sometimes see normal ATP production but low levels of Co-Q 10 which suggests to me that Co-Q 10 is not directly involved in oxidative phosphorylation. I suspect Co-Q 10 is an important antioxidant which prevents free radical damage
If you burn fuel to produce energy you make smoke. One cannot create energy without smoke damage in the form of free radicals. Co-Q 10 is a vital scavenger of electrons which prevents secondary free radical damage. So it is well worth measuring co-Q10 levels and clinical experience is that levels should be above 2.5 umol/l. However, if oxidative phosphorylation goes really slow, like a smouldering fire it produces even more free radicals, in particular superoxides and nitric oxide. These two free radicals stick together to make peroxynitrite which is even more toxic. These quickly use up available antioxidants. So if ATP production is slow it is worth also measuring superoxide dismutase (to mop up superoxides) and giving B12 by injection (which mops up nitric oxide and peroxynitrite).
If free radicals persist, they damage the cell. This may initially just be enzyme damage which makes the cell go slow (and worsens all the above problems) or actual structural damage even resulting in cell death. If the cell dies it releases its contents into the blood stream. John McLaren Howard can test for this by measuring cell free DNA in the blood. Cell free DNA is a measure of tissue damage. When tissues are damaged, cells rupture and release their contents into the blood stream as fragments. These fragments include DNA, so when this is found not contained within a cell membrane, it is as a result of tissue damage. Cell free DNA is raised in, for example, tissue damage due to sepsis, trauma, cancer, radiotherapy, chemotherapy and other such pathologies. It is also raised in CFS and accurately reflects the degree of fatigue.
The problem with high levels of cell damage are:
It takes time for new cells to be made and this may partly also explain the delayed fatigue in CFS. The immune system may react against these bits of cell floating about thereby switching on allergies. The immune system may react against these bits of cell floating about thereby switching on autoimmunity.
Correcting the Biochemical Blocks
A running team can only go as fast as the slowest runner. The same is true in biochemistry. If one corrects one aspect of what is going wrong, one may not see improvements because suddenly another rate limiting step becomes apparent and the sufferer is slowed for another reason. So it is vital to keep the regime tight and in place as long as possible. It is no good getting the biochemistry perfect if you then can't sleep! That alone would cause fatigue. So as well as putting in place all the nutritional supplements it is vital to continue with PACING, DIET and SLEEP.
One final word about PACING, and this applies to people who do not suffer from CFS. If you push your mitochondria too much you will cause a disproportionate amount of damage because of the secondary and tertiary effects - just because you feel better, do not be tempted to do too much - or you will simply create damage elsewhere and postpone your recovery further! If my horse has worked hard during a long day hunting, she has complete rest in the field with lots of good food for four days before being ridden again. That way she stays fit and healthy! The key is:
GET THE REGIME TIGHT, then FEEL WELL AT REST, then GRADUALLY INCREASE ACTIVITY SO LONG AS THERE IS NO DELAYED FATIGUE.
The pathological defect in patients with chronic fatigue syndrome is slow recycling of ATP. Normally there is enough ATP in a heart cell to last about ten beats - this means that roughly speaking ATP needs to be re-cycled every ten seconds. Steve Redgrave probably recycles ATP every five seconds, but patients with fatigues may be recycle ATP every minute. Therefore I can do in ten seconds what Steve Redgrave can do in five seconds, but it might take one of my fatigue syndrome patients a minute to achieve the same!
ATP in releasing energy is converted to ADP (2-phosphates) which is recycled back through mitochondria to ATP (3-phosphates). However, if the system is really pushed then the body can extract energy from ADP by converting it into AMP (1-phosphate). The problem is that AMP is very slowly recycled if at all and most is lost from the cell. This means that the body has to make brand new ATP. This it does from D-Ribose and this it can do very quickly. The trouble is the body making D-Ribose. Normally this is made from glucose. However if the cell is lacking in energy then any glucose lying around can be converted to lactic acid to generate energy. The problem here is twofold - first of all the lactic acid causes pain. Secondly any glucose that is swilling around is not available to make D-ribose.
Even when glucose supply is plentiful, production of D-ribose in the cell by the glucose pentose shunt is very slow. It looks like when the Almighty designed the cell at a metabolic level there were some fundamental faults!
D-ribose is therefore useful for at least three reasons:
1. It is immediately available for the generation of new ATP
2. It helps re-cycle AMP and thereby re-convert it back to ADP and ATP
3. It has antioxidant properties, i.e. the effects of many damaging substances on cells can be negated
Because D-ribose is a simple sugar, it is extremely well absorbed.The clinical experience of cardiologists using D-ribose to treat heart failure due to mitochondrial failure is that it is very effective and free from side effects. The dose depends on the severity of the illness, but the clinical experience is that sufferers should be started on high doses and then it can be adjusted to a maintenance dose. Therefore I recommend that my CFS patients use 5 grams (1 scoop) three times a day, with food or fruit juice. Effects should be seen within a few days. Whilst levels of energy improve and continue to improve then I recommend staying on 15 grams daily. At the point at which it levels off, experiment with lower maintenance doses. However, should the sufferer overdo things on a particular day then it is as well to take extra D-ribose in order to rescue the situation.
D-ribose is going to work best when the other aspects of mitochondrial metabolism are addressed, namely Co-enzyme Q10, L-carnitine, magnesium and vitamin B3.
Anything which can be done to prevent damage to mitochondria will also be extremely helpful. There are many ways in which mitochondria can be damaged such as viral infection, pesticides, heavy metals, hormone imbalances, allergies, low blood sugar or high blood sugar, micronutrient deficiencies, lack of sleep, etc. D-ribose is, therefore, an adjunct to my standard work up for treating chronic fatigue syndrome. Clinically I expect D-ribose to improve the symptom of delayed fatigue in sufferers as well as improve stamina.
I have already had one patient contact me "D-ribose is rocket fuel"!
Co-enzyme Q10 in Chronic Fatigue Syndrome
Chronic fatigue syndrome is a symptom of mitochondrial failure, resulting in poor production of ATP which is the currency of energy in the body. To produce ATP, mitochondria need certain essential raw materials, namely Co-enzyme Q10, D-ribose, L-carnitine, magnesium and vitamin B3.
In a normal healthy person, Co-Q10 can be synthesized, but it requires the amino acid tyrosine, at least eight vitamins and several trace elements. Vitamins include folic acid, vitamin C, B12, B6 and B5. Synthesis of Co-Q10 is inhibited by environmental toxins and chronic disease. I am coming to the view that many of my CFS patients are metabolically dyslexic - that is to say even when all the raw materials are available, they cannot make their own Co-Q10 in sufficient amounts and therefore levels need to be measured and supplemented.
The question is how much Co-Q10 should be given. The normal range in blood given by Biolab Medical Unit is 0.55 - 2.0 mmol/L. This is equivalent to 0.637 - 2.3 ?g/ml. However, Co-enzyme Q10 has been widely used in the treatment of heart failure, which we now know is what happens in patients with chronic fatigue syndrome. There have been a great many studies done looking at Co-enzyme Q10 levels in heart disease and although the optimal dose of Co-Q10 is not known for every pathological situation, most researchers now agree that blood levels of 2.5 ?g/ml and preferably 3.5 ?g/ml are required to have a positive impact on severely diseased hearts.
Clearly not all patients I see with chronic fatigue syndrome have severely diseased hearts, but my view is that we should be aiming for a level of 2 - 2.5 ?g/ml (i.e. 1.72 - 2.15 mmol/L - the Biolab units) in order to stand a chance of seeing a therapeutic response.
Again, the dose of Co-Q10 in order to achieve a response has been worked out for cardiac patients and this varies from 200 - 600 mg daily.
It is important that a hydro-soluble form of Co-enzyme Q10 is used in order to ensure good absorption. Therefore I am recommending that people use the Lamberts Co-enzyme Q10 100 mg, partly because this is a well absorbed preparation and partly because my patients qualify for trade prices and Co-enzyme Q10 is not cheap. (Lamberts tel: 01892 554 312). The absorption of Co-Q10 can be improved if it is taken with a fatty or oily meal. Or you could empty a capsule into a teaspoon of olive oil before swallowing the lot. It is possible for Co-Q10 to be prescribed on an NHS Prescription! Co-Q10 is not in the British National Formulary, but it has not been blacklisted in capsule form, so is prescribable. If your GP is willing to help, then ask him to prescribe ubidecarenone 100mg capsules. The chemist can order any brand that is available to him and the Prescription Pricing Authority will honour the prescription.
So I am estimating that the following doses of Co-Q10 will be required:
|Blood levels Co-Q10||1.5 - 2.0 umol/l||100mg Co-Q10|
|Blood levels Co-Q10||1.0 - 1.5 umol/l||200mg Co-Q10, split the dose: 100 mg twice a day|
|Blood levels Co-Q10||0.5 - 1.0 umol/l||300mg Co-Q10, split the dose: 100 mg 3 times a day|
|Blood levels Co-Q10||<0.5 umol/l||400mg Co-Q10, split the dose: 200mg am, 100mg lunch, 100mg evening|
Once a therapeutic effect has been achieved, then it should be possible to reduce the dose to a lower maintenance dose, but a blood test may be required to re-check that levels are adequate.
Co-Q10 can be expected to work best in conjunction with magnesium (available in the MMMs), D-ribose (see enclosed handout), L-carnitine (this should be available through eating red meat, especially mutton, lamb, beef and pork) and NAD (levels can be measured, but most people need 500mg of NAD daily - available from Solgar on 01782 634744).
It may take up to 30 days to get blood levels up to a good level and therefore start to see clinical response. Most studies of use of Co-Q10 in heart disease assess patients at three months. I would also expect to see improvements in heart related symptoms such as chest pain, dysrhythmias, exercise tolerance, shortness of breath and mitral valve disease. There are virtually no side effects.