Remember that this is juat a post of my blog, and it evolves, so to see the full story go to: www.pochoams.blogspot.com (English) or www.bukisa.com/people/Carlitos or (English) and www.sfc-tratamiento.blogspot.com (Spanish)
My current doc: Josepa Rigau Av Catalunya, 12, 3º, 1ª 43002 Tarragona Spain +34977220358 (I do recommend! hoeopathy and biological medicine, significant improvement)
I will comment further on this, here goes by now the results obtained which explain my "bad days" and lack of energy...
ATP (adenosine triphosphate), studies on neutrophils
ATP is hydrolysed to ADP and phosphate as the major energy source in muscle and other tissues. It is regenerated by oxidative phosphorylation of ADP in the mitochondria. When aerobic metabolism provides insufficient energy, extra ATP is generated during the anaerobic breakdown of glucose to lactic acid. ATP reactions require magnesium. ADP to ATP conversion can be blocked by environmental contaminants as can the transiocator [TLj in the mitochondrial membrane. [TL] efficiency is also sensitive to pH and other metabolic-factor changes. [TL] defects may demand excessive ADP to AMP conversion (not re-converted to ADP or through to ATP). Defects in Mg-ATP, ADP - ATP conversion and enzyme or [TL] blocking can all result in chronic fatigue - a factor in any disease where biochemical energy availability is reduced.
ATP whole cells:
With excess Mg added 1.37 nmol/106 cells 1.6-2.9
(Standard method of measuring ATP)
Endogenous Mg only 0.74 nmol/106 cells 0.9 - 2.7
(Measured ATP result is lowered during intracellular magnesium deficiency)
Ratio ATP/ATPMg 0.53………………………………….. > 0.6
ADP to ATP conversion efficiency (whole cells)ATPMg (from above) 1.37 nmol/106 cells (1*) 1.6-2.9
ATPMg (inhibitor present) 0.41 nmol/106 cells (2*) <0.3
AXpMg (inhjbitor removed) 0.78 nmol/106 cells (3*) > 1.4
ADP to ATP efficiency [(3*- 2*)/(l*- 2*)] x 100 = 38.5 % > 60
Blocking of active sites (2*/!*) x 100 = 29.9 % upto 14
ADP-ATP TRANSLOCATOR fTLj (mitochondria, not whole cells):
ATP Ref. range change % ref. range
Start 244 290-700
[TL] 'ouf 309 410-950 26.6 over 35% (Increase)
(in-vitro test) reflects ATP supply for cytoplasm
[TL] W 191 140 - 330 21.7 55 to 75% (Decrease)
(in-vitro test) reflects normal use of ATP on energy demand
Very Low whole-cell ATP. Poor ATP-related Mg availability.
30% blocking of active sites leading to: Very Poor ADP-ATP re-conversion.
Low mt-ATP and poor provision of 'new' mt-ATP. Restricted access to rrit-ATP
secondary to the 3/10 blocking of transiocator function.
Serum coenzyme Q10 0.64 jamol/L 0.55 - 2.00
Coenzme Q10 is synthesised naturally in humans and is also found in foods, such as vegetables and fish, it acts as a cofactor in the electron transfer pathway which produces energy (in the form of adenosine triphosphate - ATP) within the mitochondria of human cells. The energy is used for muscie contraction and other vital functions. It is also an antioxidant which may have a sparing effect on vitamins C and E in situations of oxidative stress
SUPEROXIDE DISMUTASE and GLUTATHIONE PEROXIDASE
A functional test looks at the in-vitro efficiency of the patient's red cell superoxide dismutase (SOD) when their neutrophil superoxide production is maximally stimulated. The activity of the individual forms of SOD are explored. General cell protection from damage by superoxide is provided by intracellular zmc:copper-SOD (Zn/Cu-SOD). Mitochondria are protected by manganese-dependent SOD (Mn-SOD). Extracellular SOD (EC-SOD - another Zn/Cu SODase) protects the nitric oxide pathways that relax vascular smooth muscle.
For each form of SODase, genetic variations are known, mutations can occur during excessive oxidative stress on DNA and polymorphisms may be present. DNA adducts can chemically block these genes. Glutathione peroxidase (GSH-PX) activity is measured in red blood cells. It is a selenium-dependent enzyme and selenium deficiency is the commonest cause of poor enzyme activity. As poor glutathione (GSH) availability is easily overlooked as an additional reason for poor GSH-PX activity, we also measure total GSH in red cells.
Blood test results:
Test Result Units Reference range
Functional test 42 % Over 40 (mostly 41 -47)
Zn/Cu-SOD 269 Enzyme activity (u) 240-410
Mn-SOD 158 Enzyme activity (u) 125-208
EC-SOD 31 Enzyme activity (u) 28-70
Sod form Gene(s) Comments
Zn/Cu-SOD chromosome 21 Normal Normal enzyme activity
Mn-SOD chromosome 6 Normal Normal enzyme activity
EC-SOD chromosome 4 Normal Normal enzyme activity
Result Reference range
Glutathione peroxidase (GSH-PX)
Red cell Glutathione peroxidase (GSH-PX) 48 U/gHb 67-90
Red cell Glutathione (GSH) 1.31mmol/1 1.7-2.6
NIACIN STATUS (vitamin B3)
Red cell nicotinamide adenine dinucleotide (NAD) is a good indicator of B3 status.
Red cell nicotinamide adenine dinucleotide = 12,7 ug/ml 14.0 - 30.0
Interpretation of result:
Reference range (14.0 - 30.0)
Mild B3 deficiency (12.5 - 13.9)
Moderate B3 deficiency (11.0 - 12.4)
Fairly marked B3 deficiency (10.0 - 10.9)
Marked B3 deficiency (8.5 - 9.9)
Severe B3 deficiency (less than 8.5)
1) Fu CS, Swendseid ME, Jacob RA, McKee RW. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte coen2ymes and plasma tryptophan. JNutr 1989: 1949 - 1955.
2) Critical review. Assessment of niacin status in humans. Nutrition Reviews 1990; 48: 318-320
The amino acid tryptophan is a precursor of niacin. However, protein synthesis has a higher metabolic priority than the conversion of tryptophan to niacin coenzyme and adequate niacin levels cannot always be obtained from tryptophan.
Cell-free DNA in blood plasma
Background. Most of the cell-free DNA present in blood plasma is associated with cell degradation. Very low levels are present in healthy people and increases are associated with serious illnesses such as malignancy, stroke, auto¬immune diseases, severe infections and Chronic Fatigue Syndrome.
Patient's result: Reference range
Cell-free DNA 22.7 ug DNA per litre plasma up to 9.5
Mild increase = 9.6 to 12.4
Some increase = 12.5 to 14.9
Definite increase = 15.0 to 20.0
Highiy significant = over 20.0
Method summary * Plasma is incubated with EDTA, a detergent and a proteinase prior to precipitation of the proteins. DNA is then precipitated with alcohol and re-dissolved in a Tris-acetate-EDTA Buffer. The DNA is measured in a Pharmacia GeneQuant™ or Jenway Genova analyser using a micro-cuvette.
*Schmidt B, Weickmann S, Witt C, Fleischhacker M. Improved Method for Isolating Cell-Free DNA. Clin Chem 2005:51(8); 1561-2
Cell-free DNA in chronic fatigue syndrome (CFS) In initial studies on 87 CFS patients, positive results were found in 93% of those with a disease duration of four months to five years (n = 75). In those with a disease duration of five to 14 years (n = 12), 75% had positive results.
Dr Sarah Myhill MB BS, Upper Weston, Llangunllo, Knighton, Powys, Wales, UK LD7 1SL
Tel: 01547550331 Fax: 01547550339 E-mail: email@example.com Website: www.drmyhill.co.uk
Dictated on 11 May 2009
Dr Josepa Rigau
Av Catalunya 12 3◦ 1a
Our ref: sm/nw
Dear Dr Rigau,
Re: Carlos Gonzalez Rodriguez
Carlos contacted me for advice about management of his chronic fatigue because I have a particular interest in environmental medicine which is all about looking for causes of illness and treating using micronutrients (for deficiencies), dietary changes (for allergies and intolerances) and identifying and reducing toxic stress. In order to make this style of medicine generally available to patients I have set up a website with information and access to medical tests. The key point to remember about chronic fatigue syndrome is that it is not a diagnosis but a symptom and the name of the game is to identify the underlying causes. Sometimes clues come from the history, sometimes from the tests; the first part of this letter indicates the main and common causes of fatigue, the interpretation of the results refers specifically to your patient and the overall approach to addressing these causes in a logical manner is at the end of this letter.
I have been in the business of treating chronic fatigue syndromes for over 25 years and have now got a very clear idea of the important things that need to be put in place to allow people to recover. I now have a very structured workup and my experience is that with the information that I supply on my website, guidance from biochemical testing, a determined patient, and a supportive GP an awful lot can be achieved. Indeed many patients who have used my website and had access to tests have made good recoveries without having to actually come and see me.
So if Carlos can work through this letter and my standard workup for treating chronic fatigue syndrome in a logical way there is no reason at all why he shouldn’t do well. Carlos tells me he already takes a number of nutritional supplements and so he needs to go through the individual supplement regime I have sent him to make sure he doesn’t double up on any.
Carlos was kind enough to send me a history and account of his symptoms. He requested tests of mitochondrial function and antioxidant status because mitochondrial failure is a very common cause of chronic fatigue syndrome and my standard interpretation of the test results is below. I have to say these tests make a great deal of sense of many of Carlos’s symptoms.
Actually these are extremely poor results with a very high cell free DNA. The lesions we see in Carlos’s case illustrates one of the vicious cycles in fatigue syndromes. When mitochondria go slow there is excessive production of free radicals. These put a strain on the antioxidant system so antioxidants become depleted. Therefore we see more tissue damage thereby impairing mitochondrial function. This self-perpetuating vicious cycle is difficult to get out of but perfectly possible – we have to tackle as many of these biochemical lesions as we can at the same time to allow the system to recover and during this time Carlos needs to carefully pace his activity in order that he doesn’t add to the sum of tissue damage.
Onset of Fatigue
Carlos has a gradual onset of fatigue over two years starting in 2003 and culminating in a nasty virus in September 2005 when he really became much more ill. The tests (see below) show clear evidence of toxic stress – that is to say he has experienced a low grade poisoning. My guess is that there are two issues here. Firstly during his work as a banker, he spent nine years working in very poorly ventilated offices. All soft furnishings these days are treated with insecticides and fire retardants which out-gas during their lifespan. Furthermore there are a great many solvents and other such volatile organic compounds in regular office use. Modern buildings often have air recycling and so the levels of these persistent organic pollutants can build up. They are readily absorbed by the body through inhalation and they bioaccumulate in fatty areas – this includes membranes on which all metabolic activity takes place. Mitochondrial energy production for example is all on the membranes. Another source of exposure could have been from toxic air on aeroplanes and I do recommend you look at www.aerotoxic.com . Cabin air is pulled in over the engines and inevitably gets contaminated with engine fumes including organophosphates used as oil conditioners, namely tricresylphosphate. Carlos flew regularly as part of his job so this would all have compounded his sick building syndrome.
On top of this we have at least two bits of information that show that Carlos is a slow detoxifier. Firstly he has raised levels of bilirubin suggesting Gilbert’s syndrome. This is generally believed to be a benign chemical abnormality; however, in Gilbert’s syndrome people are slow detoxifiers because they are unable to stick a glucuronide group onto endogenous chemicals and xenobiotics. Indeed people with Gilbert’s syndrome are at risk of fatigue. However, they can be improved with high dose micronutrients since these facilitate liver detoxification. My experience is that often these patient do well on B12 injections since this also facilitates detoxification.
Secondly Carlos had tests to look at his methylation cycle which shows low levels of glutathione and high levels of MMA – this means he doesn’t methylate. Carlos can’t use B12 in its usual form so where I recommend B12 below, I would suggest using the methylated form namely, methylcobalamin.
The results that this letter reports pertain to mitochondrial function, but from the history there may be other important clues. The following paragraphs cover the common and important causes of fatigue. Please forgive the obvious standard paragraphs, but it is the only way I can fit in all the necessary information!
Food allergy – many of my patients are intolerant of a number of foods. Food allergy is a greatly overlooked cause of symptoms, which again masquerade under other diagnoses. For example, the commonest manifestations of food allergy are migraine, irritable bowel syndrome, asthma, skin inflammations (eczema, urticaria etc.), chronic rhinitis and arthritis, all of which are symptoms. None of these constitute a diagnosis since a diagnosis implies a cause. I suspect this is why food allergy has been greatly overlooked as a diagnosis and so the stoneage diet that I recommend to all my patients with CFS may well be an important part of management. The commonest allergens are grains, dairy, yeast and sugar.
The clues from the history that suggest allergies may be a problem are• A long history of various and changing problems dating from childhood – A history of tonsillitis as a child is typical of allergy to dairy products. Indeed, a colleague of mine considered it medical negligence to remove a child’s tonsils without first trying a dairy-free diet!
• A shopping list of symptoms - in one study, over 50% of unexplained symptoms were caused by food allergy.
• A particular liking to a food – oddly sufferers often get addicted to the foods which cause them most problems. This is akin to a nicotine or alcohol addiction!
• Irritable bowel syndrome- often caused by wheat allergy.
• Bloating is often induced by wheat, sugar and alcohol and this could also point to yeast allergy. I say this partly because alcohol contains yeast and partly because sugar is often fermented in the gut by yeast and one ends up reacting allergically to endogenous yeast in the gut.
• Rashes and other obvious allergic problems such as asthma or eczema
There aren’t any reliable tests for food allergies and people simply have to do the stoneage diet.
I think that many of Carlos’s symptoms such as his sleep apnoea, vasovagal syncope, headaches, sacroielitis and alternating constipation and diarrhoea could certainly be explained by food allergy. Irritable Bowel Syndrome is not a diagnosis but just a description of gut symptoms which are often caused by food allergy and/or gut dysbiosis. The natural progression of allergy in a patient is for the incitant to remain the same but the target organ to change, which is why we see so many different pathologies throughout a lifetime. I think it is highly likely that for Carlos to do a good stoneage diet is going to be a very important part of getting well. Combined with this I suggest he also try high dose “do it yourself” probiotics and the present flavour of the month is Kefir, which can be easily grown and is very cheap because one sachet can last a lifetime.
Muscle Aching and Pain
I suspect one major overlooked feature of allergy is the allergic muscles. I know this directly from my own experience – in my case dairy products cause acute low back pain. I have to say I’m not sure I would have believed this possible unless I had experienced it myself! Symptoms of muscle stiffness and pain together with tremors and twitching is also typical of magnesium deficiency. The reason for this is that calcium is necessary to contract muscles and magnesium necessary to relax them. Relaxation is an energy-requiring magnesium dependent process, if magnesium is absent then muscle fibres effectively get sticky which means when they are stretched they tear and this results in muscle damage. This explains the symptoms of stiffness and pain and would partly explain the very high cell free DNA that Carlos has (see below).
Respectable doctors nowadays don’t like to call this candida because it has never really been proven that candida is the offending bug. We prefer to call it ‘fungal-type gut dysbiosis’ which may cause problems because a patient is allergic to yeast (and Carlos obviously has allergy problems) or it may cause problems because yeasts ferment food in the gut to produce alcohol, wind and gas which result in bloating. Yeasts interfere with both the absorption of micronutrients and the normal processes of digestion creating leaky gut, which can switch on food allergies. Different people require different levels of treatment to control this problem. The first line of approach is a low carbohydrate diet since this reduces sugars on which yeasts ferment. The second approach is high-dose probiotics and some people also need herbal antifungals and some people systemic prescription antifungals to get on top of their yeast problem.
Carlos may well be a poor digester of foods – indeed he has already identified lactose intolerance. His urinary organic acids show high levels of arabinose which is suggestive of a yeast overgrowth of the gut – yeasts often get into the gut where there is hypochlorhydria.
Carlos’s symptoms of mitral valve reflux and poor diastolic function is suggestive of magnesium deficiency and indeed this is confirmed in the tests below. Essentially one needs calcium to contract muscles and magnesium to relax them. Poor diastolic function means the heart muscles do not relax properly in order to allow the chambers to fill with blood. Carlos’s symptoms of kidney stones could indicate vitamin D deficiency – it is vitamin D that makes sure that calcium is deposited in bone. Indeed Carlos has low vitamin D at 25.2umol/L – the best source of vitamin D is sunshine but failing that I recommend he take 2,000i.u. daily of vitamin D.
I note Carlos has generally low levels of minerals from the hair analysis but his level of superoxide dismutase is good suggesting adequate mineral status here.
For further information see my website for information on PROBIOTICS and KEFIR, GUT DYSBIOSIS, HYPOCHLORHYDRIA and COMPREHENSIVE DIGESTIVE STOOL ANALYSIS.
This is an extremely common problem in which insufficient acid is secreted by the stomach for the efficient digestion of proteins. It can have many clinical symptoms including symptoms of GORD (gastro-oesophageal reflux disease) and hyperacidity (I know this sounds rather counter-intuitive but the pyloric sphincter is pH sensitive and unless a certain acidity is achieved then the stomach fails to empty), a tendency to allergies (protein foods are poorly digested and present as large, antigenically interesting molecules, which have a tendency to switch on allergies), failure to sterilise gut contents (this results in bacterial and yeast overgrowth so that food is fermented instead of being digested resulting in wind, gas and bloating and poor absorption of divalent and trivalent cations leading to micronutrient mineral deficiencies).
So, possible symptoms of hypochlorhydria would be• Gastro-oesophageal reflux disease and hyperacidity
• Poor digestion of foods with recognisable foods appearing in faeces
• Diarrhoea, malabsorption, irritable bowel and fermentation of foods
• A tendency to allergies
• A tendency to micronutrient deficiencies
• A tendency to get gut infections since acid is normally required to sterilise the contents of the stomach – indeed, I suspect this is part of the mechanism by which CFS sufferers are susceptible to gut viruses like Epstein-Barr.
The treatment is to acidify stomach contents. A traditional remedy is of course cider vinegar but many people will not tolerate the yeast contained in this. Ascorbic acid has a beneficial effect as indeed does betaine hydrochloride 1 – 4 capsules taken with meals depending on the size of the meal.
Carlos’s symptoms are highly suggestive of hypochlorhydria. We now have a test for hypochlorhydria which is to measure salivary vascular endothelial growth factor. It is very common to see hypochlorhydria with allergies and if this test is required then it’s easily arranged.
Carbohydrate intolerance and hypoglycaemia
There are two common ways in which diet can cause fatigue – firstly allergies and secondly carbohydrate intolerance. The carbohydrate intolerance is often a symptom of sugar addiction. Addiction and allergy are closely allied and indeed people get allergic to their addictions and addicted to their allergens.
The clues from the history that suggest this may be a problem are• A need for carbohydrate foods
• Missing a meal results in feeling awful – having to snack or graze on foods regularly through the day
• Feeling at one’s worst on waking
• Tendency to gain weight easily (this results from high insulin levels)
• Disturbed sleep / waking in the middle of the night and unable to drop off again – this is because the person is woken by low blood sugar and the adrenalin reaction that accompanies it.
• Anxiety and mood swings.
Because carbohydrates are so addictive, any change in diet should be done gradually – if this is done too quickly symptoms may get much worse. However for many this is an essential and possibly the most important part of treatment. We can test for hypoglycaemic tendency by measuring levels of short chain fatty acids first thing in the morning before breakfast has been taken. This is a blood test and can be arranged on request.
Carlos has been tested positive and attempted to eradicate both blastocystis hominis and endolimax nana.
It is a sine qua non that poor sleep will result in chronic fatigue. The average sleep requirement is for 9 hours sleep between 9.30pm and 6.30am – more in winter, less in summer and the most restorative hours of sleep come before midnight when melatonin is produced. Sleep doesn’t creep up on us during the course of the evening, it comes in waves and there is a sleep wave roughly every 90 minutes. So I would like Carlos to catch the relative sleep wave and use whatever herbs or medications necessary to help him achieve this. If combined with a sleep dream, this produces a Pavlovian conditioned reflex and this prevents problems of tachyphylaxis and dependency. See SLEEP section in my CFS book.
Hypothyroidism is both a clinical and a biochemical diagnosis and can certainly present with fatigue. Anybody suffering CFS could well be hypothyroid! So I would very much like to see the results of a recent or new free T4, free T3 and TSH.
The clues from the history that suggest this may be a problem are• A gradual descent into fatigue often attributed to ageing
• Feeling cold, cold hands and feet, low basal body temperature
• Slow pulse and inability to get fit (relative to current ability), shortness of breath
• Dry hair, skin, loss of hair, loss of eyebrows
• Other members of the family also affected by thyroid problems.
Adrenal stress problems
If one thinks of oneself as a car, the mitochondria represent the engine of that car, the thyroid gland the accelerator pedal and the adrenal gland is the gearbox. It allows one to move up into fourth gear or fifth gear when one is stressed and this allows individuals to achieve extraordinary feats! However it is not sustainable long term. If there is unremitting stress (and this may be financial, physical, mental, emotional, nutritional, infectious stress or whatever) then the adrenal glands fail, output of stress hormones falls dramatically and effectively one is left stuck in first gear. With prolonged rest the adrenal glands do eventually recover but in the interim adrenal supplements can be helpful. Adrenal tests show that Carlos has low cortisol and high DHEA levels.
There is a clear clinical difference between fatigue and depression. In depression there is no volition, but often when people are made to do things they feel better as a result. In fatigue the desire is there but the patient does not have the energy to undertake the task, and indeed, quickly discovers that if they do push themselves to do something it makes them feel very much worse. This is an important difference to make clinically and failure to do so has resulted in many wrong diagnoses. It is not unusual for patients to become frustrated by their inability to do things and, indeed, are possibly secondarily depressed because nobody is addressing the root cause of their problems. There is a difference between depression and being “pissed off”! This can usually be discerned from careful history taking. However this has major implications for choice of medication. This is because the stimulating antidepressants such as the SSRIs increase the desire to do things but do very little for the performance and thereby increase the frustration factor. The important point is that SSRIs may be making some patients with fatigue worse.
Actually my preference is to use the tricyclic antidepressants at night in order to improve the quality of sleep and the length of sleep and this may have a very beneficial effect on the fatigue. If there is secondary depression then this may help address that side as well but at worst one can do little harm with low dose tricyclics. Most patients with fatigue syndromes are intolerant of normal doses of medication and should a tricyclic be tried then it needs to be in much smaller doses than generally considered to be therapeutic. For example with amitriptyline I usually start patients off on 5 to 10 mg at night and it is unusual for them to tolerate more than 25mg. And with Trimiprimine (Surmontil) I suggest 10mgs at night because sometimes this also has a beneficial effect on muscle pain. Having said all that a few patients are improved by small doses of SSRI and I suspect this is because SSRIs also have mild anti-inflammatory actions and downgrade the nitric oxide/peroxynitrite pro-inflammatory cycle and, if relevant, Carlos may feel he would like to discuss these options with you.
Multiple chemical sensitivity
One problem Carlos has identified is a multiple chemical sensitivity – he has to avoid chemicals paints and other chemicals or toxins. Again this is extremely common in patients with fatigue syndromes, especially those who already know they are food allergic. Really MCS is an extension of allergy to drugs and indeed prescription drugs can certainly trigger multiple chemical sensitivity. However sufferers sensitise so they start to react to tiny amounts of chemicals. Treating chemical sensitivity is an absolute nightmare – the single most important thing to do is to avoid chemicals. With chemical sensitivity it is all about total load – this means the total load of chemicals in the diet, prescription medications, hormones, cleaning chemicals, cosmetics and so on may all be a problem. It is essential to do a good clean up of the environment to try to reduce the total load and this will also reduce the allergic burden.
Sometimes there are obvious clues from the history such as being present at the Gulf War, farmers with sheep dip ‘flu, aerotoxic pilots, firemen with 9/11 syndrome, women with silicone implants and so on. In practice, the commonest problems are from mercury dental amalgam, nickel toxicity, fire retardants (dichlorobenzenes from soft furnishings) and wood preservatives (lindane and other organochlorines).
As you can see from the results below we have a very significant problem with toxic stress with Carlos which is most likely to be the cause of his severely impaired translocator protein function (see below). In 2003 Carlos had 7 mercury fillings removed, but this had to be carried out a second time because of errors during the original procedure and so if there was some leakage of mercury, this could be all or part of the problem here.
It is a feature of CFS that standard prescription medications often make patients/sufferers worse. Many sufferers know they are intolerant of alcohol and caffeine which may reflect slow ability to detoxify – this may also be a reason for intolerance of prescription medication. The commonest problems I see are
• Standard doses of medication are not tolerated and the sufferer sees many side effects – this may reflect slow detox or poor micronutrient status.
• Intolerance of medications – may reflect a tendency to allergies and multiple chemical sensitivity
• Antibiotics causing thrush/yeast problems
• Statins making symptoms much worse - possibly because statins inhibit endogenous production of co Q 10 (see below)
• Beta blockers making fatigue much worse – this is because in severe CFS the patient is in a low cardiac output state (secondary to mitochondrial failure) and beta blockers exacerbate this.
People with fatigue syndromes commonly complain of chest pain. The heart is the most physically active organ in the body, but when mitochondrial function in the heart is impaired there is a tendency to switch into anaerobic metabolism with the production of lactic acid. It is this lactic acid build up in the heart which, I believe, causes the chest pain. It can be very persistent because metabolising lactic acid back into glucose (via the Cori cycle) is highly energy requiring. So whilst the chest pain is arguably angina, it is rather atypical because it is more persistent than the angina of blood supply which clears rapidly as soon as the patient rests. My experience is that as the mitochondrial function improves this symptom goes away.
I am increasingly coming to the view that chronic fatigue syndrome is a symptom of mitochondrial failure and I find that mitochondrial function tests are extremely helpful in sorting out what is going wrong, why and where.
Whilst all cells are different, the way in which energy is supplied to cells is the same – all mitochondria are identical and when there is mitochondrial pathology we see widespread symptoms as a result because all cells, metabolically speaking, go slow. The function of mitochondria is to produce ATP and we now have a test, namely ATP profiles, which measures the rate at which ATP is recycled – this I believe will turn out to be the most useful test for diagnosing and managing chronic fatigue syndrome.
When mitochondrial function is impaired, all muscle function is impaired and this includes cardiac muscle. Indeed low cardiac output has already been demonstrated in fatigue syndromes and elegantly explains the symptoms these patients suffer from. For example, they have low blood pressure, marked postural hypotension, low blood volume and perfusion defects. Poor circulation of skin would explain cold hands, cold feet and difficulty with temperature regulation, poor circulation of the brain explains the cerebral symptoms and so on. I have also become interested in the views of a cardiologist in America who believes that many of the cardiomyopathies and congestive cardiac failures are not just due to poor blood supply, but again a mitochondrial induced cardiomyopathy. What is so fascinating is that this cardiologist has come up with a cocktail of micronutrients which reverses the cardiac damage namely, magnesium, co-enzyme Q10, acetyl L-carnitine and D-ribose, to which I would add vitamin B3. By identifying and correcting deficiencies, mitochondrial function can be restored and symptoms such as Carlos’s post exertional malaise improved. This established treatment protocol can be applied directly to patients with fatigue. Thanks to a brilliant biochemist, Dr John McLaren Howard, we now have a test to demonstrate mitochondrial lesions.
Carlos’s symptoms of postural orthostatic tachycardia syndrome and vasovagal syncope is suggestive of poor cardiac output secondary to poor mitochondrial function – we have certainly confirmed this in the tests below.
I am also a co-author of an article that the International Journal of Clinical and Experimental Medicine has published online (Jan 2009) with details of this biochemical test which measures energy supply to cells and therefore fatigue levels in people with chronic fatigues syndrome/myalgicencephalomyelitis (CFS/ME). Ref: www.ijcem.com/files/KJCEM812001 Int J Clin Exp Med (2009) 2, 1-16. What this study shows is that the mitochondrial function test is an accurate and objective way to measure energy levels and the mitochondrial function score is a helpful measure of the level of disability.
So this test can be used to confirm the clinical picture 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. Even if the results are not too bad mitochondrial function could be further improved by taking the supplements suggested. There are three parts to the test: 1. Levels of ATP 2. Oxidative phosphorylation Kreb’s Citric Acid Cycle and ADP to ATP conversion, and 3. Movement of ATP and ADP across mitochondrial membranes.
Interpretation of Mitochondrial Function Test
1. Levels of ATP
The level of ATP in cells is shown by ATP with excess Mg added and with endogenous magnesium only. With excess Mg added the result is 1.37 (1.6-2.9nmol/106). This shows very low levels of ATP, so I recommend supplementing with D-ribose (the body uses this to make brand new ATP – as opposed to recycled ATP) building up to three teaspoonfuls daily (15gms) and adjusting according to response. Indeed, and see below, Carlos has a very high cell free DNA, which may be caused by an inappropriate switch from efficient aerobic mitochondrial metabolism into inefficient anaerobic glycolosis with excessive production of lactic acid which causes secondary cell damage. Indeed this often causes a symptom of fibromyalgia. D-ribose has already been trialled in the treatment of fibromyalgia with excellent results. D-ribose has a very short half life and should be taken in small doses throughout the day in drinks (hot or cold). Interestingly caffeine enhances the effects of D-ribose so I recommend taking it with green tea, coffee, tea or whatever. It is worth supplementing with D-ribose even with low normal results because I have so much happy feedback from patients taking this supplement.
With endogenous Mg only the result is 0.74 (0.9-2.7nmol/106) with a ratio of 0.54 (>0.65). This result shows a low magnesium status. Magnesium is a difficult mineral to replete and some people have to have it by injection. So I recommend taking at least 300mg magnesium daily orally (more if tolerated – up to 600mgs) present in my physiological mix of minerals (MMMs), together with magnesium by subcutaneous injection. I usually use Evans 50% magnesium sulphate. One can give 2mls on a weekly basis, but large volume injections like this can be uncomfortable. I have to say my preference nowadays is to use ½ ml insulin syringes and for patients to inject themselves every day for two months then adjust the frequency of dose according to clinical response Many people end up injecting 2-3 times a week until they are much better. These small volume injections are far better tolerated and less inclined to leave injection lumps. Adding lignocaine often improves matters (0.05ml lignocaine with 0.5ml magnesium). I would be grateful if you could prescribe and demonstrate how to do these injections. Magnesium is a real problem in patients with fatigue syndromes – it is necessary for ATP to release its energy, it is necessary for oxidative phosphorylation and much of resting energy goes to maintain calcium magnesium ion pumps. That is to say low intracellular magnesium is both a cause and a symptom of mitochondrial failure. So there is a very clear indication here to give magnesium by injection.
The main problem can be injection lumps. To avoid these, wait for 2 minutes after the injection to allow capillary bleeding to stop. Then feel the injection site and a small “puddle” of magnesium can easily be felt – then massage the area gently until this “puddle” disperses completely. However if you are still bruising using this technique, try a few injections when you do not massage the site at all.
Epsom salts in the bath (a double handful) will improve magnesium status since magnesium is absorbed through the skin. The bath needs to be as warm as can be tolerated for at least 15 minutes – really the longer the better. Epsom salts can be purchased by the 20kg sack from garden centres or farm supply shops or try www.justasoap.co.uk. who will deliver.
2. Oxidative phosphorylation – Kreb’s Citric Acid Cycle and ADP to ATP conversion
This is going very slow at 38.5% (normal range >60%). In order to assess the efficiency with which ADP is converted to ATP, an inhibitor is added and then removed to see how quickly ATP is reformed. Having added the inhibitor one expects levels of ATP and magnesium to drop below 0.3 – if this does not happen this suggests there is blocking of the active sites. The acceptable percentage is up to 14% and Carlos’s result is 29.9% (up to 14%). This suggests that there is significant blockage of the active sites (i.e. complexes I,II,III,IV and V on inner mitochondrial membranes). The likeliest reason for this is toxic stress and we could explore further by doing microrespirometry studies which look at oxidative phosphorylation in more detail.
We need to explore this result further by looking ata) Vitamin B3 levels. The red cell NAD shows a mild B3 deficiency at 12.7µg/ml (14 – 30). This is an interesting result because NAD is a functional test. Whilst it reflects B3 status, it also reflects function of Kreb’s citric acid cycle. The job of KCA is to take energy from acetyl groups and convert it into NADH, which is then of course converted to NAD in the process of driving oxidative phosphorylation. Therefore to see normal levels of NAD needs not only an adequate supply of B3, but also a functioning Kreb’s citric acid cycle. So a low NAD may (amongst other things) also imply poor acetyl L carnitine levels. Whilst most people can obtain all the NAD they need from a combination of diet and a good B complex vitamin preparation, some people seem to need much higher levels to correct blood levels. I usually start off with 500mgs of niacinamide daily (this is the form of vitamin B3 that is free from side effects - do not use niacin or nicotinamide, which cause unpleasant flushing). Acetyl L carnitine 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. Lamb contains about 5grams per kilo of acetyl L carnitine so one needs to eat quite a lot! A small supplement, geared to meat intake, may be necessary. Indeed acetyl L carnitine has been trialled in the treatment of CFS with positive results.
b) The Co-enzyme Q10 result is back within the normal range but lower than I like it to be at 0.64umol/l (0.55 – 2.0). This is the most important antioxidant inside mitochondria and also a vital molecule in oxidative phosphorylation. Co-Q10 deficiency may also cause oxidative phosphorylation to go slow, but interestingly not invariably. The best results clinically are achieved if levels get up to 2.5 or above. This seems to be necessary to kick start the mitochondria, at which point the dose can probably be reduced according to clinical response. This regime has been worked out by an American cardiologist, Dr Sinatra, who uses Co-Q10 to treat patients with congestive heart failure secondary to mitochondrial failure, which effectively results in a mitochondrial myopathy. The underlying pathology in these cardiomyopathies is the same as that in fatigue syndromes. The problem in heart failure is primarily in the heart muscles, in fatigue syndromes, probably all cells are affected. Co-Q10 is also called ubiquinone, which reflects its presence in all tissues because it is present in all mitochondria. Therefore I suggest starting on 300mg daily of Co-Q10 (the dose should be split into 100mg three times daily) for three months then a maintenance dose of 100mg daily. It is possible for Co-Q10 to be prescribed on an NHS prescription. This is prescribable in capsule form and should you feel able to do this then you would need to prescribe ubidecarenone 100mg capsules.
c) When oxidative phosphorylation goes slow it is often because of free radicals which are produced, in particular nitric oxide and superoxides which combine to form peroxynitrite. These are potentially very damaging but efficiently mopped up by vitamin B12. So often there is very poor antioxidant status in CFS and B12 takes on many of the functions of other antioxidants so effectively giving “instant cover”. So there is a good indication to try B12 subcutaneous injections. Indeed B12 has been shown to be effective in CFS, but in much higher doses than is required to treat pernicious anaemia. Therefore measuring blood levels is irrelevant. Giving B12 with an insulin syringe renders the injection virtually painless so these tiny doses are an excellent way of administering B12. I suggest ½ ml methylcobalamin daily initially for two months and adjust according to clinical response. B12 is a joy to use with no known toxicity. Please would you consider supplying the necessary?
d) Magnesium is also required for oxidative phosphorylation so the magnesium injections will also assist this side of things.
This result simply shows how well oxidative phosphorylation is working at the time the test was taken – it does not predict what will happen if the patient increases exercise levels! So it is important to continue pacing carefully! Indeed as mitochondrial function improves, the first task is for healing and repair of damaged tissues (see cell free DNA result), not to increase activity levels. So it is vital to continue pacing until feeling completely well at rest – only then may a very gentle graded activity programme be considered, and only allowed to continue so long as the patient feels fine – i.e. not at the expense of tissue damage.
3. Movement of ATP and ADP across mitochondrial membranes.
This looks at ability to move ATP and ADP across mitochondrial membranes and this is dependant on translocator protein. Translocator protein ‘out’ is a poor result of 26.6% (normal range >35%). Translocator protein ‘in’ is also a poor result of 21.7% (normal range 55 - 75%). Translocator proteins can be blocked in many different ways. The commonest is toxic stress, which can be chemical or viral or possibly free radical in origin. By chemicals I mean pollutants such as pesticides, volatile organic compounds and heavy metals. One day we may have specific antidotes for specific toxins, but at the present, sweating regimes probably get rid of most toxins. The most physiological way to sweat is to exercise but this is not possible for many sick patients. Therefore I recommend Far Infra Red saunaing at least two sessions a week – more if possible using FIR blanket or sit-in sauna (see enclosed FIR sauna h/o). Using this technique it is only the subcutaneous fat which is warmed, with the idea being to mobilise the chemicals from the subcutaneous fat onto the lipid layer on the surface of the skin, they can then be washed off. Inevitably some chemicals will be mobilised into the bloodstream with the potential to make that person feel ill, but this would be much less than if a traditional sauna was used and the core temperature of the patient raised. So Far Infra Red is as effective as, but less likely to produce initial worsening, as traditional saunas.
There are three key points about saunaing and sweating. The first one is that not only are toxins excreted in sweat, but so are the beneficial minerals. So after a sweat it is vital to re-hydrate with a physiological mix of minerals (such as my mix of MMMs – 1g in a glass of water) containing all essential minerals and take a small supplement of salt (say an eighth of a teaspoon salt on food). Secondly, it is important to shower immediately after a sweat in order to wash away chemicals which may otherwise be reabsorbed back through skin. Thirdly the most excretion of toxins occurs in the first few minutes of sweating as they move onto the surface of the skin – so the best results come from many short sessions (eg one daily just to the point of sweating) rather than protracted sweating which may make the patient feel ill.
Another method of detoxing is to take high dose essential fatty acids and other oils. The idea here is to replace contaminated fats in cell membranes and fatty organs with clean fats. The particular group of oils which are pertinent to fatigue syndromes are made up in the preparation VegEPA and I enclose my handout on this. Interestingly many people who take VegEPA report much improved sleep.
TL protein function is an area where more research is being done, but another possible reason for TL protein blockage is intracellular acidosis. This can occur with hyperventilation, which, I suspect, is much more common in CFS than realised. Hyperventilation causes a respiratory extracellular alkalosis, and intracellular acidosis – these changes can occur within a few abnormal breaths (see hyperventilation in CFS book).
If we are not making progress on this front then we could do more specialised tests of translocator protein function to see exactly what is blocking it. John McLaren Howard has now developed this test that we could do if we wanted to explore this area further.
Mitochondrial Function Score
I am now able to score mitochondrial function tests in order to give an energy score. I have now done several hundred of these tests, and the mitochondrial energy score accords closely with the level of disability. This score takes into account the levels of ATP, how well it releases energy (a magnesium dependent process), how efficiently oxidative phosphorylation works as well as translocator protein function. Carlos’s score is just 0.04 which equates to about 5/100 on my enclosed CFS disability scale (also see CFS book), so it is no wonder that there is a major problem with fatigue.
If the score does not fit clinically, then this may well be because of tissue damage. Many CFS sufferers push themselves to do things at the expense of damaging their tissues. So they can choose between feeling better and doing very little, or having a life and feeling terrible. Most do the latter. So the mitochondrial function score is a measure of how much energy they have got to spend and the cell free DNA a measure of how well they feel.
Note: DNA and ATP disability score do not match my present physical ability.The only thing I could suggest is that the mitochondria in my neutrophils, which are evaluated in the ATP profiles test, are in worse condition than those in my muscle cells. I don't know why this would occur.
Cell free DNA result
When cells are damaged or die, they spill their contents into the blood stream. All DNA should be contained within cell membranes. However, DNA from damaged cells is not – thus this is a good measure of cellular damage. This result shows a highly significant increase in cell degradation at 22.7ug DNA per litre (up to 9.5). To give an idea of the level of severity of this result, people with severe flu or who are on cancer chemotherapy produce cell free DNA levels of 30-40 ug DNA per litre. A high cell free DNA can result from any of the following, all of which need tackling as a separate problem
a) There is poor antioxidant status (see Co Q 10, SODase, glutathione peroxidase),
b) There is ongoing toxic stress (such as from pesticides, volatile organic compounds, heavy metals etc),
c) There is immune activation (as, for example, in acute infection),
d) There is very poor mitochondrial function (see mitochondrial function) score but the patient is forced to do some muscular activity just in order to live.
e) The patient is not pacing well – i.e. pushing too hard and this is resulting in cell damage. However some people who are very disabled have no choice – just the energy required to exist will cause tissue damage. So people with the worst mitochondrial function score often have high cell free DNAs even though they are doing almost nothing.
People who come and see me with chronic fatigue syndrome often complain of the symptom of malaise - that is to say they just feel ill all the time. I suspect this is a symptom that arises from the immune reaction from damaged tissue, in other words a cell free DNA is a marker for this symptom of malaise.
Antioxidant status: Superoxide dismutase
The SODase result is fine at 42% (>40%). The normal level is above 40% inhibition, but the normal range is very narrow and a small deviation from this represents a clinically significant deficiency. Further analysis of this enzyme shows that the Zn/Cu form is 269 (240-410 enzyme units), the Mn form is 158 (125-208) and the EC (extra-cellular) form (another Zn/Cu SODase but not part of the functional SODase test) is 31 (28 – 70).
The gene studies show that the genes for Zn/Cu-SODase, Mn-SODase and EC-SODase are all normal.
Red cell glutathione peroxidase (GSH-PX)
Red cell glutathione (GSH) – 1.31mmol/l (1.7 – 2.6) - normal result
Red cell glutathione peroxidase (GSH-PX) - 48U/gHb (67 – 90) – very poor result
Glutathione peroxidase is made up of glutathione, combined with selenium. There is a particular demand in the body for glutathione. Not only is it required for GSH-Px, which is an important frontline antioxidant, it is also required for the process of detoxification. Glutathione conjugation is a major route for excreting xenobiotics. This means that if there are demands in one department, then there may be depletions in another, so if there is excessive free radical stress, glutathione will be used up and therefore less will be available for detoxification and vice versa. Of course in patients with chemical poisoning or other such xenobiotic stress, there will be problems in both departments, so it is very common to find deficiencies in glutathione.
I recommend that Carlos eat a high protein diet (which contains amino acids for endogenous synthesis of glutathione), and take selenium 200mcg daily (which is present in my physiological mix of minerals MMMs).
For this really poor result I would add in extra selenium, say another 300mcgms at night for four months (total daily dose 500mcgms) to bring Se levels up, then reduce to a maintenance dose of 200mcgms
A summary of the important antioxidants to consider areSuperoxide dismutase (see above)
Glutathione peroxidase (see above) – this requires selenium 200mcgms daily (present in my physiological mix of minerals MMMs) and amino acids for its synthesis (high protein diet).
Co-enzyme Q 10 - is the most important antioxidant inside mitochondria (see above)
B12 – this is an excellent scavenger of the free radical peroxynitrite and may take over some of the function of SODase if this is very deficient
Other antioxidants also important as mentioned above – acetyl L carnitine, NAD (especially in the brain). Also vitamins A, C and E are essential antioxidants.
Natural antioxidants are also present in vegetables, nuts and seeds.
Although the regimes seem complicated, it is simply like getting a car engine to work. It is no good just filling the tank with fuel, or just unblocking the fuel pipe, or doing any one of the necessary jobs such as cleaning the spark plugs, unblocking the air filter, filling the engine with oil, unblocking the exhaust pipe etc on its own – one has to do all these bits in order to make it run. I have to say I have had such happy feedback from patients able to complete the regime that it is really well worth working hard at. The above recommendations have to be done in conjunction with my basic work up of all CFS sufferers with respect to
• MICRONUTRIENTS – multivits, multimins, EFAs, vit C and D (‘Standard for all’ column on enclosed nutritional supplement sheet)
• SLEEP – aim for 9 hours between 9.30pm and 6.30am
• STONEAGE DIET (low glycaemic index diet which avoids the major allergens).
These “cornerstones” of recovery are described in detail in my CFS book. Once they are in place, Carlos should then introduce the other elements of the overall regime i.e.
(a) Correcting mitochondrial function - D-ribose, Mg injections, NAD, acetyl L carnitine, meat, Co Q 10.
(b) Addressing poor antioxidant status - B12, Co Q 10, glutathione peroxidase
(c) Detox regimes where appropriate – i.e. sweating techniques
(d) Identifying chronic infections
(e) Correcting any secondary hormonal lesions in particular secondary hypothyroidism, secondary hypoadrenalism and poor melatonin levels.
I know I am asking for much to be done and it maybe there is insufficient energy to put in place all the interventions required at once. Furthermore some of my very tender flowers do not tolerate all the interventions at once and so one has to progress slowly. I like to see patients get the regime in place and get the regime as tight as possible with respect to all the problems identified. Then I like them to be feeling well at rest. Then, and only then, may they risk trying to do a little more, but this must be on the proviso that any loss of stamina or delayed fatigue and they must pull back again. What many people are tempted to do is to cherry pick – that is to say just put in place the things they can do easily. However often the most difficult lifestyle changes are the most important – especially diet and sleep – and my experience is that the best results are achieved when all these issues are tackled simultaneously.
Carlos has chosen to receive this correspondence from me via email but if he wishes to receive my CFS book (which is too large an attachment to send) which goes into some of the above issues in more detail and contains many of the information sheets alluded to in the text, it is now available as a PDF file to download directly from my website, or a hard copy can be ordered by him postal charge only through my office.
I hope the above is helpful for management, please contact me directly if you have any queries.
Dr Sarah Myhill
Encs: Magnesium by injection, B12 paper, Test results, CFS disability scale, FIR Sauna h/o, Feedback from mito tests h/o, Hypochlorhydria h/o, Supplement h/o, Stoneage Diet h/o, VegEPA h/o, Individual supplement regime, SF h/o, Cc.
Further details available on line at www.drmyhill.co.uk - my CFS book is now available as a PDF file for anybody to download directly from the website. Alternatively a copy of my CFS can be emailed to anyone requesting it from firstname.lastname@example.org.
Unfortunately we are unable to supply supplements to non-UK patients. To help you to source the supplements recommended above you can try the following websites.
www.biocare.co.uk , www.puritan.com , www.igennus.com , www.vrp.com .
Dr Sarah Myhill MB BS, Upper Weston, Llangunllo, Knighton, Powys, Wales, UK LD7 1SL
Tel: 01547550331 Fax: 01547550339 E-mail: email@example.com Website: www.drmyhill.co.uk
CARLOS RODRIGUEZ INDIVIDUAL SUPPLEMENT REGIME MAY 2009
This regime of nutritional supplements comprises my standard supplements that all patients should have regardless of their problems, with the mitochondrial support as a bolt-on extra and the antioxidant support also as an extra as dictated by the tests that have been done. Some supplements have more than one function e.g. Co-Q 10 is essential for mitochondrial function and also an important antioxidant. Supplements in italics go into drinks. Introduce each supplement one at a time and it’s a good idea to keep a supplement diary so that you can pinpoint any that you are intolerant of. These amounts are what you should aim for, but start with tiny amounts and build up gradually.
Standard for all Mitochondrial support Extra Anti-oxidants
In ½ to 1 pint of water/ Acetyl L-Carnitine 1 gram
some fruit juice dissolve: (1 small scoop)
Ascorbic acid 1 g (1 small scoop)
(Or BioCare Vit C 1 g = 2x 500mg caps)
MMM 2 grams (2 small scoops) D-ribose 2.5 grams (½ teaspoon)
Swallow at breakfast with
the above solution:
BioCare Adult multivitamins x 1 capsule
Igennus VegEPA x 4 capsules
Vitamin Research Vit D3 x 2 caps Co-Enzyme Q10 100mg x 2 capsules
Niacinamide 500mg x 1 capsule
By injection Magnesium sulphate ½ ml B12 ½ ml
D-ribose ½ a teaspoon in tea or coffee
Midday – lunchtime
Dissolve in ½ pint of water D-ribose ½ a teaspoon
MMM 1gram 1 scoop
Swallow: Co-enzyme Q10 100mg x 1 capsule
Dissolve D-ribose ½ a teaspoon in tea or coffee
Dissolve in ½ to 1 pint of water/ Acetyl L-carnitine 1 gram
some fruit juice:
Ascorbic acid 1 gram
(Or BioCare Vit C 1 g = 2x 500mg caps)
MMM 2 grams D-ribose ½ a teaspoon
(or adjust to complete your daily dose)
With the above solution swallow
the following caps with food: Co-enzyme Q10 100mg 1 capsule - (after 3 months reduce dose to 100mg daily)
Igennus VegEPA x 4 capsules
After 3 months VegEPA can be reduced to 2-4 capsules daily
Last thing at night in water/fruit juice D-ribose ½ teaspoon
Selenium 300mcg 3 drops
(for 4 months) – GSH-px