Dr.Sarah Myhill - Mitochondria failure - new article

Discussion in 'Fibromyalgia Main Forum' started by happygranny, Sep 2, 2005.

  1. happygranny

    happygranny Member

    I emailed Dr. Myhill about guaifenesin's use for purging the mitochondria of phophate build-up and she responded to me that "have tried guafenisin with poor feedback, so rather gave up!"

    She also attached a new article about the treatment. It is very long (8 pages)and I couldn't find it at her website to make it easier reading.

    so, I will post it here in sections:

    Medical Hypothesis – CFS is a symptom of mitochondrial failure – biochemical and clinical implications
    John McLaren Howard, Biolab Medical Unit, London
    Sarah Myhill GP with Special Interest, Royal Shrewsbury Hospital

    We propose that chronic fatigue syndrome is a symptom of a generalised mitochondrial failure. This results in slow recycling of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and therefore impaired energy supply at a cellular level. Sufferers may have a genetic predisposition to CFS (KERR REF), but the majority of sufferers have an acquired mitochondrial lesion which may be secondary to acquired mitochondrial DNA damage, acquired enzyme inhibition or acquired structural lesions (BEHAN REF). Mitochondrial DNA is particularly susceptible to toxic stresses because it is not separated off in its own “nucleus” but mixes freely inside mitochondria and so is easily damaged by free radicals which are inevitably produced as a part of oxidative phosphorylation. The damage to mitochondria may be through:

    • Immune damage through infection (viruses, bacteria or parasites), autoimmunity or allergy
    • Hormonal imbalances which may be secondary to stress including psychological stress
    • Micronutrient deficiency
    • Endogenous toxic stress from free radicals especially free oxygen species
    • Exogenous toxic stress from pesticides, heavy metals and volatile organic compounds.
    • Other factors

    As cells (or possibly mitochondria) perceive that their energy supply is failing, they stimulate the formation of new mitochondria. However mitochondria, when they replicate, preferentially replicate damaged mitochondria. The mechanism of this is uncertain, but this has the effect amplifying the initial damage. Indeed this is the basis for the normal ageing process – one rarely finds acquired mitochondrial lesions in people under the age of forty – thereafter they increase exponentially (REF SCI. AMER).

    Although the end result is slow recycling of ATP, there are many possible sites at which damage to mitochondria may take place:

    • Inefficient magnesium dependent conversion of ATP to ADP
    • Slow transport of ATP and ADP across mitochondrial membranes by translocator protein
    • Inefficient oxidative phosphorylation either because of damage to protein complexes I, II, III, or IV or because of deficiency of coenzyme Q 10 – the most important shunter of electrons in oxidative phosphorylation (Krebs citric acid cycle).
    • Deficiency of acetyl L carnitine resulting in poor substrate delivery to mitochondria from inefficient movement of acetyl groups across mitchondrial membranes
    • Poor synthesis of de novo ATP from glucose via D-ribose (as a result of poor function of the pentose phosphate shunt) when ATP is converted to ADP and then to AMP which is lost from cells (may result from poor translocator protein function).
    • Poor synthesis of NAD due to vitamin B3 deficiency
    • Other unidentified sites

    Clinical Implications
    Clearly this has huge clinical implications for an explanation as to:

    • why sufferers develop fatigue syndromes
    • the basis of a biochemical and clinical test for chronic fatigue
    • further tests to establish the degree and site of damage
    • tests to establish what is causing the damage at that site
    • what can be done to correct the damage ie the clinical approach to treating CFS

    Why sufferers develop fatigue syndromes
    The Centre for Disease Control defines chronic fatigue syndrome by a number of clinical criteria. However there are only two symptoms which are common to all sufferers namely very poor stamina and delayed fatigue. We believe these two symptoms are directly attributable to poor energy supply at the cellular level, the first being due to slow recycling of ATP. When sufferers overdo things, ATP is converted to ADP faster that the rate at which it can be replenished. This upsets the adenylate energy charge which means ADP is converted to AMP which is very poorly recycled and so leaks out of cells. It then takes days for sufferers to replenish ATP levels because it has to be made de novo via the pentose phosphate shunt. This accounts for the delayed fatigue.

    When oxidative phosphorylation is inefficient, there is increased production of free oxygen species, especially superoxides and these further damage mitochondria and cells through free radical damage.

    As energy supply diminishes, clinically one sees organ failure which manifest initially:
    • in the brain with poor short term memory and defects in motion (clumsiness)
    • in skeletal muscle with poor stamina, switch to anaerobic metabolism with build up of lactic acid with resultant muscle pain. Muscle pain is also caused by free radical damage.
    • in the immune system resulting in poor immunity, tendency to infections, allergies and autoimmunity
    • in hormonal tissues with low normal output of hormones
    • in the liver with impaired ability to detoxify endogenous and exogenous toxins

    All of these failures will result in further damage to mitochondria creating a vicious downward spiral of organ failures, inability to heal and repair, increased free radical production and cell damage.

    Poor energy supply to cardiac muscle results in low output cardiac failure manifesting with low blood pressure, low blood volume and perfusion defects. Sufferers compensate for this by pacing all activities carefully and lying down as much as possible to reduce the work of the heart. The renin-angiotensin system shuts down blood supply to non-essential areas in order to preserve function of essential organs resulting in particularly poor blood supply to the skin, skeletal muscle and joints. This explains some of the very common symptoms experienced by sufferers over and above the physical and mental fatigue such as inability to temperature regulate, cold extremities, gut symptoms, muscle and joint pain.

    The basis of a biochemical and clinical test for chronic fatigue
    Peckerman (REF) has already demonstrated that the level of disability in CFS correlates closely with cardiac out put as measured by impedance cardiography. That is to say the most disabled sufferers have the lowest cardiac output. This we believe is caused by cardiac muscle disease (cardiomyopathy) secondary to mitochondrial failure. However this test does not have direct implications for management, it simply measures levels of disability.

    John McLaren Howard of Biolab medical unit has proposed a test for chronic fatigue syndrome namely the rate at which ATP is recycled through mitochondria (ATP profiles). Early feedback on patients show either low levels of ATP in sufferers or slow recycling or both.


    Is this interesting enough to post the rest of the article?

    happygranny
  2. tansy

    tansy New Member

    Dr Sarah Myhill is one of the most popular UK's ME/CFS specialists, unlike the nationally funded chronic fatigue clinics here she treats her patients.

    John Howard, of Biolab, is pretty amazing too; he has been at the forefront of developing tests relevant to many of us since the 80s.

    love, Tansy
  3. happygranny

    happygranny Member

    Further tests to establish the degree and site of damage
    The above test (ATP profiles) can be broken down further to establish where the defect in ATP recycling takes place. For some this is due to slow hydrogenation of ATP to ADP, a magnesium dependent process, for some this is due to blockage at the translocator protein resulting in ADP being converted to AMP which leaks out of cells. For the rest there is slow conversion of ADP to ATP by oxidative phosphorylation.

    Plasma levels of cell-free DNA in chronic fatigue syndrome is a sign of cell damage. Any disruption to cellular energy supplies will result in cell damage because of damage by free radicals, inadequate or inefficient repair systems, immune damage, poor ability to deal with infectious stress, poor hormonal status and poor ability to detoxify xenobiotic toxins. Cell damage results in DNA spilling over into the blood stream. Levels of cell free DNA in healthy humans is very low but raised in malignancy, infection, stroke and autoimmunity. JMH has found consistently raised levels of cell free DNA in sufferers of CFS.

    Tests to establish what is causing the damage at that site
    The possible candidates for what is going wrong include:

    Substrate deficiency – low levels of blood supply, of oxygen supply, of amino acids (acetyl L-carnitine in particular is required to transport energy substrate across mitochondrial membranes – this is largely available from red meat), B vitamins (especially B3), minerals (especially magnesium) and essential fatty acids (necessary for membrane integrity) may all result in impaired mitochondrial function for obvious reasons. Less obvious is the effect of fluctuating blood sugar levels. If blood sugar levels rise too high, this is damaging to muscle tissue. Raised blood sugar levels are reduced by insulin by causing the periarteriolar cuff of fat to vasoconstrict through release of pro-inflammatory cytokines (REF - LANCET). Effectively this reduces blood supply to muscles and releases cytokines – both of which will cause fatigue. The flip side is that high insulin levels will then cause rebound hypoglycaemia and fatigue will also follow from poor substrate supply. So hyperglycaemia and hypoglycaemia will both cause fatigue, hence the importance of eating a diet of low glycaemic index to stabilise blood sugar levels.

    “Metabolic dyslexia” – that is to say that even with apparently adequate substrate there is an inability to manufacture essential enzymes such as coenzyme Q 10. D-ribose is required to make ATP and there are several rate limiting steps in the pentose phosphate shunt which normally manufactures D-ribose from glucose. Some sufferers require gram doses of vitamin B3 in order to achieve a normal level of red cell nicotinamide adenine dinucleotide (an essential part of oxidative phosphorylation) suggesting a defect in assimilation or synthesis of this essential nutrient. It may well be that hormone deficiencies are secondary to metabolic dyslexias. It is very likely there are many others!

    Poor antioxidant status – resulting in inefficient scavenging of free radicals causing further cellular and mitochondrial damage. Inefficient oxidative phosphorylation results in production of excessive free radicals which require correspondingly high levels of antioxidants to scavenge them. In particular in fatigue syndromes we see low levels of superoxide dismutase (a scavenger of superoxides requiring copper, manganese and zinc), low levels of glutathione peroxidase (requires selenium and amino acids) and low levels of vitamins A, C and E. Indeed niacinamide is also an essential antioxidant particularly in the brain and deficiency may be partly responsible for the cerebral symptoms seen in fatigue sufferers. B12 is an important scavenger of peroxynitrite (another free radical) and is often beneficial in gram doses.

    Damage to mitochondrial DNA from exogenous toxins such as pesticides, heavy metals and volatile organic compounds. These can all be measured either by looking at actual levels of the particular toxin, or by looking for DNA adducts – that is to say whether that particular toxin is stuck onto DNA by the following tests:
    Pesticides – fat biopsy
    VOCs – fat biopsy
    Heavy metals – sweat test and Kelmer test.
    DNA adducts.

    Hormonal imbalances – it is very common to find borderline or low normal levels of hormones in fatigue syndromes. This may be as a result of poor manufacture of hormones because of inadequate energy supply, but that deficiency also has secondary detrimental effects on cellular metabolism. In order of clinical importance we see depression of the hypothalamic-pituitary-adrenal axis with secondary hypothyroidism, poor pineal function with low melatonin output and sleep disturbance, poor adrenal function with low levels of cortisol and DHEA. Teitlebaum has reported low output of growth hormone in fatigue syndromes (REF).

    What can be done to correct the damage ie the clinical approach to treating CFS
    SM has worked full time in private and NHS clinical practice for the last 24 years with a special interest in treating fatigue syndromes. She has developed a chronological structured approach to treating fatigue syndromes which encompasses the above principles and is effective. The various stages are as follows:

    Exclude major pathologies which may present with fatigue such as arteriosclerosis and cancer. Many major pathologies which present with fatigue such as ageing, neurological degenerations, cardiomyopathies and other such organ failures may also be secondary to mitochondrial dysfunctions and will also respond to the following work up.
    Tackle the underlying mitochondrial problem by:

    • Reducing the demands on mitochondria
    • Supplying the raw materials so that mitochondria can function efficiently (which may be micronutrient deficiency or metabolic dyslexia) and repair damage which inevitably accrues.
    • Correcting micronutrient deficiencies and improving antioxidant status
    • Correcting secondary hormonal deficiencies
    • Identifying chronic stresses which may be psychological, emotional, financial or whatever
    • Identifying immune problems (infections, allergy, autoimmunity)
    • Identifying toxic stresses which damage mitochondrial DNA or inhibit enzyme function and doing detoxification regimes

    Clearly the history and tests are vital in determining the priority in which each individual patient is treated but broadly speaking the sufferer needs to do the following:

    Establish the diagnosis by ATP profile.
    This may also give clues as to further management.

    Reducing the demands on mitochondria
    By learning to pace all activity so that the sufferer does not experience delayed fatigue.
    Establishing good quality sleep – sufferers are often deficient in melatonin, which also acts as an antioxidant. Low dose tricyclics antidepressants often improve sleep.

    Supplying the raw materials so that mitochondria can function efficiently (which may be micronutrient deficiency or metabolic dyslexia) and repair damage which inevitably accrues.
    Good quality multivitamin, minerals, essential fatty acids, vitamins A, C, D and E.
    Diet based on foods of low glycaemic index.
    High protein diet – must contain red meat (which is a source of L-carnitine). Vegetarians must supplement with acetyl-L-carnitine 2grams daily.
    Metabolic dyslexia:
    Supplement with D-ribose 5-15 grams daily
    Coenzyme Q 10 must be measured. Experience in treating patients with mitochondrial induced heart failure suggest that plasma levels may have to be 2.5mcgms/ml to see a clinical result (REF – SINATRA).
    Many borderline hormone deficiencies may result from metabolic dyslexia such as melatonin, DHEA, growth hormone, thyroid hormones and probably others. Mitochondria need the right hormonal environment to function optimally.

    Correcting micronutrient deficiencies and improving antioxidant status
    Tests are essential because even given an excellent diet and a good range of micronutrient supplements, deficiencies can still be present. Clinically the most important micronutrients in fatigue syndromes are:

    Magnesium – measure a red cell magnesium – often parenteral magnesium is required to correct a deficiency.
    NAD – a functional test of B3 status – some sufferers need up to 3grams daily to correct a deficiency, (but at doses above 500mgs daily liver function tests should be checked monthly initially, thereafter every 6 months)
    Superoxide dismutase – the most important scavenger of superoxides and free oxygen species. This enzyme is dependent on copper, manganese and zinc for normal function.
    Glutathione peroxidase – a functional test of selenium deficiency.
    B12 by injection 2-4mgs weekly often gives great clinical improvement probably through its ability to scavenge peroxynitrite, a damaging free radical. Serum levels of B12 are rather irrelevant since levels over 2,000 give the best clinical results and one can only guarantee to achieve this by injection. Some sufferers who respond well to B12 can be maintained on high dose oral B12.
    A diet rich in vegetables, nuts, seeds and fruit provides natural antioxidants and free radical scavengers.

    There is one more part to post

    happygranny
  4. happygranny

    happygranny Member

    Correcting secondary hormonal deficiencies
    Fatigue syndromes are characterised by poor pituitary function (REF BEHAN).
    Thyroid function needs assessing by measuring a free T4, free T3 and a TSH because hypothyroidism can result from primary hypothyroidism due to autoimmunity, secondary hypothyroidism because of poor pituitary function or, least commonly, poor conversion of T4 to T3 due to mineral deficiencies.
    Poor adrenal function can be assessed by measuring salivary cortisol and DHEA levels over 24 hours and giving replacement therapy. Physiological doses of hydrocortisone (ie 5-10mgs daily) do not cause adrenal suppression and may give clinical improvement (REF CLEARE). 25mgs of DHEA is sufficient for most sufferers, occasionally 50mgs is required.
    Melatonin levels are often low – again these can be measured but clinically deficiency results in poor sleep. The replacement dose varies greatly from ½ to 9mgs, adjusted according to clinical response.
    Sex hormone replacement therapy is generally contraindicated in fatigue syndromes because of their immuno-disruptive effects and malign effects on nutritional status (REF).
    Teitlebaum reports growth hormone deficiencies in fatigue syndromes but replacement therapy is prohibitively expensive. However endogenous production can be optimised through improving diet and sleep (REF).

    Identifying chronic stresses which may be psychological, emotional, financial or whatever
    Acute severe stress such as overwhelming infection induces a biphasic response. The acute phase is marked by an abrupt rise in the secretions of stress hormones with an associated increase in mitochondrial and metabolic activity. However the combination of severe inflammation and secondary changes in endocrine profiles diminish energy production, metabolic rate and normal cellular processes, leading to multiple organ dysfunction. However not as many patients progress to organ failure as might be expected from the degree of shutdown, suggesting that this decline in organ function is a protective mechanism rather than arising as a result of tissue damage (REF). This is a recognised response to acute overwhelming septic or toxic insult.

    We are suggesting that chronic fatigue syndrome represents a more long term response to overwhelming insults and the clinical syndrome arises partly as a result of protective mechanisms which produce functional rather than structural abnormalities. That is to say a series of insults which may be viral, toxic, allergic, nutritional or hormonal, but also psychological may produce an internal environment which is perceived to be, or actually is, damaging to cells. As a result, cells “shut down” and go into a state of “hibernation” in order to protect themselves from such insults. Identifying and dealing with such psychological stresses will create an internal hormonal environment which is conducive to recovery.

    Identifying immune problems (allergy, infections, autoimmunity)
    Allergy or intolerance can occur to foods, inhalants, chemicals and micro-organisms. These patients often present with a multiplicity of symptoms of which fatigue is just one. Tests for allergy can be very misleading. Only too often patients are led to believe they are not allergic because tests are negative – one example is anti-reticulin, anti-gliaden and anti-gluten antibodies may all be negative but the patient is still intolerant of wheat and grains. All sufferers should do a basic elimination diet which avoids all grains, dairy products, sugar, yeast, alcohol, food additives (preservatives, colourings, flavourings, artificial sweeteners), tea, coffee and citrus fruits since these are the commonest allergens. This diet is based on meat, fish, eggs, nuts, seeds, vegetables, fruit and spring water – ie stoneage foods to which humans have adapted to over thousands of years. This will pick up the majority of sufferers with food allergy although some sufferers are multiply allergic and require desensitisation.

    Allergy to inhalants rarely presents with fatigue. Skin scratch tests and RAST tests are reasonably reliable at diagnosing and the history is usually obvious.

    Allergy to chemicals (multiple chemical sensitivity) can certainly present with fatigue, but sufferers almost invariably have many other symptoms and has worked out for themselves that they are reacting to chemicals. Ideally sufferers should be investigated in an environmentally clean unit but currently there is no such medical unit available in UK.

    Allergy to micro-organisms certainly occurs clinically – the best example being sensitivity to staphlococcus aureus as a cause of eczema. There is no doubt some patients feel well on low dose antibiotics, but these should be used with care because they can cause a gut dysbiosis and other problems arise as a result.

    Chronic low grade infections cause chronic inflammation with resultant immune damage to cells and mitochondria. Some patients will respond favourably to antivirals (REF). Some have low grade infections such as mycoplasma and will respond to antibiotics (REF).
    Some patients have problems with yeast. These can cause clinical problems either because of yeast overgrowth in the gut (which cause simple sugars to be fermented to alcohol which creates a toxic stress), or because the sufferer sensitises to yeast in the gut. Once sensitised to yeast, this may also cause a cross sensitivity to exogenous yeasts and moulds with sufferers typically feeling unwell in damp, humid conditions but well in hot dry or cold dry climates (REF).

    Autoimmune problems can be diagnosed by simple autoantibody screening.

    Identifying toxic stresses which damage mitochondrial DNA or inhibit enzyme function and doing detoxification regimes
    Toxic stresses may be endogenous (free radicals) or
    exogenous environmental pollutants such as:
    • pesticides (organophosphates, synthetic pyrethroids, organochlorines etc),
    • volatile organic compounds (solvents from carpets, paints, building materials, perfumes, fire retardants in soft furnishings, exhaust fumes, cleaning agents, disinfectants etc), cosmetics (VOCs and heavy metals)
    • heavy metals (mercury from dental amalgam and vaccinations, cadmium from smoking, nickel, aluminium from food containers etc)
    • social drugs – smoking (cadmium, carbon monoxide, additives, carcinogens), alcohol, caffeine and other drugs of addiction
    • prescribed medication – statins are particularly problematic in fatigue syndromes because they inhibit endogenous synthesis of co-enzyme Q 10, beta blockers almost invariably worsen fatigue syndromes as do many antidepressants in “normal doses”.
    • silicones used in cosmetic and reconstructive surgery
    • food additives, artificial sweeteners (especially aspartame which is metabolised into formaldehyde), colourings, preservatives
    • oxidised fats from over-cooking foods such as ???????? (high levels in chips, crisps, barbequed meat etc)
    • noxious gases – SOX, NOX, COX from polluting industry and vehicle fumes, or faulty heating devices
    • radioactive contamination from radon, X rays for medical purposes, depleted uranium.
    • Etc

    Endogenous free radicals and exogenous pollutants cause problems in the body for several reasons:

    They act as anti-nutrients partly because they block enzyme reactions which are normally facilitated by micronutrients and partly because they require micronutrients for their detoxification and excretion.
    The increasing total load of toxins mean that detoxification systems in the liver may become overwhelmed and blocked resulting in slow excretion – this is already a well recognised form of drug interaction.

    They adhere to DNA, membranes, proteins etc thereby disrupting normal cellular processes resulting in organ failure and carcinogenesis.
    Many are lipid soluble and so do not present themselves to the liver for detoxification – so they bio-accumulate in fatty tissues such as the brain, bone marrow, breast and testes as well as all cell membranes.

    The overall result of the above effectively causes an acceleration of the normal ageing process which includes mitochondrial damage and resultant fatigue syndromes. The best current test for cellular damage as a result of endogenous and exogenous pollutants is to measure plasma levels of cell-free DNA. The best current test for fat soluble pollutants is fat biopsy for pesticide residues and VOCs. The best current test for heavy metal contamination is sweat testing and Kelmer test (urinary levels before and after a chelating agent).

    The principles of treatment for sufferers of toxic stress therefore are:
    Avoid on-going exposures to exogenous pollutants
    Correct micronutrient deficiencies to improve enzyme levels, facilitate blocked enzyme reactions and improve liver detoxification. To achieve this some micronutrients may be needed in supraphysiological doses.
    Bypass defects of endogenous synthesis (“metabolic dyslexia”) by using supplements such as co-enzyme Q 10, D-ribose, glutathione, physiological doses of hormones, etc.
    Use sweating regimes to mobilise and excrete toxins from fat. The easiest sweating regime is exercise, but this is not possible for fatigue syndromes. Using saunas is equally effective. Sweat essentially is blood but without the protein and cellular content, so most toxins can be excreted through sweat. However beneficial trace minerals are also lost hence the importance of rehydrating with a physiological mix of trace elements.


    And I sure hope some of you reading this (Tansy)who are more knowledgeable about a lot of these medical terms can translate this to a "bottom line" explaination!

    happygranny
  5. happygranny

    happygranny Member

    Bumping for others to see
  6. happygranny

    happygranny Member

  7. mbofov

    mbofov Active Member

    Thank you so much for posting this. I'm going to print it out and send a copy to my doctor. It is long, but very readable - thank you again!

    Mary
  8. pepper

    pepper New Member

    This is interesting. I am too exhausted to get through it all now but am printing it out to read when I am more with-it. This seems to be very valuable info.

    Thank you.
    Pepper
  9. happygranny

    happygranny Member

    Pepper and Ralph,hopefully there is useful information in here once I understand it all.

    Ralph once you have read this over, I will really appreciate your perspective on it.

    I am going to print it out and send to my doctor (GP) with some of my own comments. Hopefully she will read it and be able to discuss it with me at my next appointment.

    happygranny

  10. happygranny

    happygranny Member

    Bumping for more input
  11. happygranny

    happygranny Member

    I appreciate all you had to say, and it makes sense, of course.
    Hopefully my doctor will help me with this.

    A Good Naturopath is what I want to find next.

    Thanks again,

    happygranny