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 (1). This is a recognised response to acute overwhelming septic or toxic insult.
I am suggesting that chronic fatigue syndrome represents a more long term response to overwhelming insults and the clinical syndrome arises 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 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. The mechanism by which this occurs is mediated by a decrease in mitochondrial activity and a reduction in oxidative phosphorylation leading to reduced cellular metabolism.
This proposed mechanism accords well with my clinical observations made over the course of 20 years during which time I estimate I have seen over 3,000 patients with CFS. Most of them have been substantially improved by attention to the predisposing factors and correction of the metabolic abnormalities which develop secondarily.
Hans Selye was the first to identify physiological responses to stress. During the acute stress response there is adrenal hypertrophy associated with raised levels of stress hormones. This allows the organism to cope with the acutely stressful event. Once this insult or stress is removed, the adrenal gland reverts to its normal size. However if the stress or insult is on-going and unremitting with no time for recovery, this leads to adrenal atrophy and ultimately death of the organism. I suspect that CFS represents the stage of adrenal atrophy as the hormonal picture in CFS is one of general suppression of the hypothalamic-pituitary-adrenal axis.
The metabolic changes which accompany CFS are remarkably similar to those which accompany the endocrine changes in response to acute illness and it is instructive to review these now:
The Hormonal Changes Recognised In the Acute Phase of Acute illness and Immediate Aftermath (1). Following an acute stress (such as sepsis), during the first few hours, there is a massive release of stress hormones including ACTH and cortisol, catecholamines, vasopressin, glucagon and growth hormone resulting in improved circulation, increased levels of glucose, fatty acids and amino acids for action and repair with a resulting increase in total energy consumption. Intracellular metabolism may be boosted by up to 200%.
After a few days, this is then followed by a completely different hormonal profile with inappropriately low levels of vasopressin (resulting in low blood pressure), onset of the sick euthyroid syndrome (functional hypothyroidism in the presence of normal levels of thyroid hormones) and reduced adrenal responsiveness to ACTH. The magnitude of these changes has major prognostic implications. The mechanism of this action appears to be through the effect of cytokines and nitrous oxide at hypothalamic, pituitary and end-organ levels.
The effect of corticosteroids depends on the duration of exposure – in acute stress there is increased activity of mitochondrial enzymes, but in chronic stress, there is reduced mitochondrial function.
In laboratory models, mitochondrial respiration is increased during the early phase (up to 16 hours) but consistently falls with protracted inflammation. This decline in energy production is probably triggered by nitric oxide and cytokines which are produced in large amounts during the acute phase of acute illness. Nitrous oxide and cytokines have a large inhibitory effect on mitochondrial respiratory enzymes. Mitochondria also have receptors for glucocorticoids and thyroid hormones and thyroid status is a key modulator of mitochondrial function. Availability of ATP is the rate-limiting step of all cellular metabolism.
This shut down in energy availability is induced by high levels of cytokines and nitrous oxide and is thought to be a secondary protective effect to try to reduce toxic effects on cells during the recovery phase. Insulin resistance and inadequate levels of thyroid hormone, especially T3, are felt to be particularly important in poor mitochondrial function (1).
The Symptoms of CFS
I believe Chronic Fatigue Syndrome is a symptom of inadequate mitochondrial function which can be arrived at via many possible mechanisms. Clinically there are only two symptoms which I am looking for to make a diagnosis of CFS:
The first is very poor stamina – initial strength is satisfactory (maybe low because of disuse atrophy) but cannot be sustained – this I suspect is due to poor mitochondrial function (and reflected by muscle lactate levels).
The second is the symptom of delayed fatigue – that is to say if the patient overdoes it one day (either physically or mentally) he “pays” for it the next day and perhaps for several days. I believe this represents mitochondrial structural damage which is quickly arrived at when the function is down – it then takes days to repair or make new mitochondria or new enzyme systems.
Unless one starts to address the underlying causes of CFS then the patient’s general health deteriorates progressively in terms of energy levels and increasingly a plethora of other symptoms which simply reflect impaired energy supply to the affected organ. Poor energy supply to muscle cells results in myalgia (possibly mediated through an early switch to anaerobic metabolism and build up of lactic acid), in brain cells results in cognitive dysfunction and so on. Different organs in different individuals may be affected to a greater or lesser extent and this explains the wide range of symptoms seen in these patients.
Possible Implications for CFS
The majority of patients with CFS have their illness triggered either by viral infection (such as glandular fever, influenza, vaccination etc) or by toxic insult (such as pesticide poisoning, carbon-monoxide poisoning, poisoning by volatile organic compounds, silicones or whatever) but some are triggered by psychological or physical stresses. Most people who get a viral infection or who are poisoned have a period of illness lasting a few days or weeks but then go on to recover normally. However I find that for those who do not recover and evolve into a CFS almost invariably there are predisposing factors which pre-date the viral or toxic trigger. Therefore I am suggesting that the trigger event causes the acute inflammatory reaction followed by the inevitable abreaction but sufferers are kept in this abreaction state by a protective mechanism against the ongoing underlying predisposing factors.
This protective mechanism is characterised by high levels of cytokines and high levels of nitrous oxide resulting in hypofunctioning mitochondria with low levels of ATP. Thus the energy supply to all cells and therefore organs is restricted. This results in the multiple symptoms of CFS and the severe fatigue. Delayed fatigue is the characteristic of this illness because as sufferers attempt to do things when there is no ATP to fuel activity this results in structural or enzymatic damage to mitochondria which may take days to repair. Because the cells are in a state of “hibernation” there is no overt damage to organs which means that standard investigations such as haematology and biochemistry are normal as are X-rays and scans.
The damage is at a subcellular levels with impaired energy supply to all cells in the body due to hypofunctioning mitochondria thus explaining the plethora of symptoms that these patients present with.
Implications for Treatments
I know from clinical experience the sort of treatment interventions which improve patients clinically. However I believe that the above hypothesis provides a logical framework into which these treatment approaches can be placed
Rest, pacing and sleep
This aspect of management relates to maximising whatever mitochondrial function is available and not damaging mitochondria further.
The level of rest and pacing depends on two important symptoms namely poor stamina and delayed fatigue. These symptoms are extremely helpful with regard to management and allow patients to monitor activity. They should not exercise (physically or mentally) to the point at which they start to become weak, furthermore if patients get delayed fatigue then they are over-doing things and need to reduce activity further. Good quality sleep is essential and patients must take whatever hypnotics are necessary such as melatonin to re-establish a normal pattern of sleep.
Graded exercise and cognitive behaviour therapy are positively contraindicated until the symptoms of poor stamina and delayed fatigue are gone. If patients exercise despite these symptoms then they will make themselves very much worse and seriously retard or damage their prospects for recovery.
Identify underlying causes
This aspect of management addresses the underlying causes of CFS which often pre-date the trigger and onset of the illness:
• Correct poor micronutrient status with appropriate tests and high dose nutritional supplements.
• High dose magnesium supplements orally and/or by injection – magnesium is essential for mitochondrial function and energy production. It is also the commonest cation deficiency.
• Identify allergies to foods through elimination dieting. The foods which most commonly cause allergy problems are the grains, dairy products and yeast but any food can cause allergy. Desensitise where appropriate. Allergies to aero-allergens (including moulds), chemicals and micro-organisms may also play a part.
• Eat a low carbohydrate diet – carbohydrates, especially those of high glycaemic index, induce insulin resistance and therefore poor mitochondrial function. A low carbohydrate diet restores insulin sensitivity but withdrawal reactions can be severe with the patient going through a phase of chronic hypoglycaemia. A high protein diet supplies amino acids necessary for stage II detoxification conjugation reactions. It also helps to stabilise blood sugar levels.
• Eliminate or reduce toxic stress by avoiding on-going exposures and detoxifying if possible and where appropriate. Detoxification regimes include high dose micronutrients and sweating regimes (spa therapies, saunas, Turkish baths etc) to increase excretion of toxins through sweat. The patient needs to rehydrate using a physiological mix of minerals since sweating gets rid of essential minerals as well as toxins.
• Some patients develop allergic like reactions to chemicals and this is called multiple chemical sensitivity. This necessitates a clean up of the patient’s environment to reduce such exposures.
• Stop immunodysruptive hormones such as the Pill and HRT.
• Identify any chronic low grade infection which may be causing on-going inflammation such as gut dysbiosis (parasites, yeast overgrowth or bacterial overgrowth), chronic dental sepsis, chronic mycoplasma infections and so on.
• Reduce the burden of xenobiotics (often prescription medications) which compete with other toxins requiring detoxification in the liver. Most patients quickly discover they are intolerant of alcohol, antidepressants, beta blockers, statins, caffeine and other drugs and this may be a symptom of slow detoxification mechanisms.
Treat the Secondary “Protective” Effects
This must be done with care because these secondary effects may be part of the above protective mechanism.
• Correct the sick euthyroid syndrome. This may require supplements of T4 and/or T3 so that the levels of these hormones are running at the top end of the normal range and the TSH is suppressed (the TSH is inevitably low since pituitary function is suppressed). Supplements must be given in low doses initially and increased slowly and be commensurate with clinical improvement. If there is clinical worsening then they should be stopped.
• Correct low levels of cortisol and/or DHEA. Again the patient needs to be carefully monitored as low levels of these hormones may be part of a protective reflex.
• High dose B12 – B12 is a powerful scavenger of nitrous oxide and this helps to break the vicious cycle of inflammation producing tissue damage producing more nitrous oxide which generates further inflammation. (2) Most patients need 2-6mgs weekly of parenteral B12 – most learn to inject themselves and space injections according to clinical response. Response to B12 is independent of serum levels. Some patients can be maintained on high dose sublingual B12 (5mgs daily).
• High dose vitamin D (either as sunshine or cholecalciferol 4,000iu daily) has an immune modulating effect and often affords substantial improvements.
• High dose essential fatty acids help a small proportion of patients.
Allow time for these interventions to work!
A Test For Chronic Fatigue Syndrome
If indeed CFS is the clinical picture produced by mitochondrial failure then a test of maximal mitochondrial production of ATP would be diagnostic. To develop such a test is extremely important for the following reasons:
It would get rid of the controversy over whether or not CFS is psychological in origin
Patients could be staged accurately and this would help with management
It would identify those patients who are fatigued for other reasons and who may benefit from graded exercise and cognitive behaviour therapy.
It would help hugely with establishing which patients qualify for benefits so that assessments could be made objectively on tests results rather than the very unsatisfactory current system of subjective opinion.
1. Multiorgan failure is an adaptive endocrine-mediated metabolic response to overwhelming systemic inflammation. Singer M, De Santis V, Vitale D Jeffcoate W. Lancet vol 34 Aug 7th 2004.
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