An Overview of the Management of Chronic Fatigue and Investigations

There are four principles of environmental medicine and in the management of a chronic environmental illness, these principles must be understood and considered throughout the treatment.

1. Total Load

This is the total load of factors which affect your body in an adverse way. Each factor may be affecting it in varying magnitude and by varying mechanisms, but it is important to consider simultaneously as many mechanisms as possible. 

These factors include:

• sensitivities to foods
• chemicals
• airborne particles
• viruses
• bacteria
• physical trauma
• psychological stress

2. Adaptation

This phenomenon helps the body to cope with chronic and adverse effects of any environmental challenge to the body, such as cigarette smoke, food intolerances, chemicals and so on. The skewed responses can be seen on brainstem testing.

3. Biochemical individuality

This variation arises from the huge range of genetic differences that all individuals have. Our genes code for a vast array of carrier molecules, protein molecules, enzyme functions and so on. These dictate how we react to the environment around us. With newer genetic tests, some of these polymorphisms (differences in a genetic code) can be identified to give an idea of how an individual handles drugs or pollutants, for example.

4. Bipolarity

In human biophysics, an action that occurs is always followed by a reaction, as the body is always trying to maintain homoeostasis. Bipolar reactions are frequently noticed when people are made ill and are environmentally sensitive. We find that low-dose immunotherapy helps to achieve homoeostasis.

Diagram of the biomedical factors to be considered when treating CFS

The two principal requirements for the production of energy are oxygen and food. 

The production of energy from food is by the release of energy through a shuttle between adenosine triphosphate (ATP) and adenosine diphosphate (ADP).  This occurs at every point on the Krebs cycle indicated in the diagram above with an ‘e’.  ATP is converted to ADP and then ADP is reformed into ATP.  This diagrammatic picture of the production of energy from food shows protein and fat being conducted through the citric acid cycle.   A large amount of energy is thus produced and this is our preferred source of energy.

Carbohydrate, on the other hand, largely goes through what is known as the pyruvate pathway, depicted here as bypassing the citric acid cycle.  It is important to recognise that the citric acid cycle is the aerobic cycle requiring oxygen, whereas the bypass, (the alternative pathway), is anaerobic.  In the production of energy from carbohydrates and glucose, the anaerobic pathway can produce lactic acid as a by-product.  Lactic acid can lead to a form of acidosis in the tissues and muscle pain can ensue.  Measurement of ATP and its function is separately described below.  Agents which can block the reconversion of ATP from ADP are also shown.

Measurement of ATP function

In fatigue states, there can also be a problem with the production and use of ATP which occurs in the mitochondria.  Mitochondrial function tests on hundreds of patients with fatigue have shown that the problems are related to:

a) poor ATP availability; reasons include poor magnesium availability with loss of ATP and magnesium.  ATP ↓ Mg ↓

b) defect in hydrolysis of ATP to ADP and phosphate ATP → ADP + phosphate

c) presence of inhibiting chemical preventing cytosolic repletion of ATP from the  mitochondria

d)  translocator problem in the membrane with intracellular acidosis (pH ↓ ) or excess calcium (Ca ↑ )

Examples of substances bound to parts of the mitochondrial membrane, discernible with fluorescence probes:

• Glutathione conjugates
• Organic sulphate conjugates
• Peptide complexes
• Lactic acid and keto-acids
• Chlorinated pesticides
• PCBs (polychlorinated biphenyls)
• PBBs (polybrominated biphenyls)
• Dichlorobenzene
• Organophosphates (including organophosphate pesticides)
• Toxic metal(s)
• DNA/RNA (probably viral)
• Others, e.g. 2,5 dichlorophenol, b-napthol, dyes

Oxygen

We all require oxygen to produce energy.  Oxygen diffuses into tissues from the capillaries and when it is used in the cell tissues by the mitochondria, oxygen will be used in the breakdown of foods.  If the principal use of oxygen is in the citric acid cycle and there is an impediment in the cycle, then the alternative pathway is used.   At each point in the citric acid cycle there are requirements for particular nutrients.

These nutrients are all required for the effective release of energy at each stage in the citric acid cycle.

Respiratory Medicine

Normally oxygen and carbon dioxide are the two gases which are in balance in the respiratory system and controlled by breathing.

Ordinarily, the mechanics of the respiratory tract are not necessarily interrupted by obstructions in the airflow through the nose, pharynx, trachea, bronchi and the alveoli.  Those can be damaged in medical conditions such as rhinitis and nasal polyps.  In the lungs, the alveoli are affected in asthma and can be damaged in emphysema, particularly in people who have been smoking.

However, in general if one assumes that the airways of patients with fatigue states have been examined and these are intact, one is then only concerned with gaseous exchange.  In the lungs gas exchange occurs with an exchange of oxygen from the air into the bloodstream and the release of carbon dioxide from the bloodstream into the lung gases, so that there is an exchange and an exhalation of the carbon dioxide which is produced as a result of metabolism.   This gaseous exchange is critical because there are a number of situations in which there can be abnormalities.

Envisage the conditions in which oxygen can be too low or normal and carbon dioxide too low or too high.  The control of breathing depends upon the correct balance of oxygen and carbon dioxide, because it is not the levels of these in the lungs that are assessed by the body, but the levels of these in the carotid artery in the neck where assessment is undertaken, and the controls for that are in the base of the brain, in the brainstem.

Commentary on the abnormal proportions of oxygen and carbon dioxide

In the tissues oxygen should be at high levels in the arterioles.  There the blood vessels split into a large number of capillary channels which then re-unite to form a venule.   

The oxygenated blood flowing from the arterioles into the capillaries needs to release the oxygen into the tissues before the blood is gathered into the venule.  This exchange of oxygen in the capillaries is a different mechanism from that in the lungs, where there is an exchange of gases.  In the capillaries, the oxygen release depends upon the red blood cells, which contain loosely bound oxygen attached to iron, being squeezed as the red blood cell goes through the capillary bed.   Each capillary might be only four microns in diameter, whereas the red cell will be eight microns in diameter.  Red cells have to be twisted to release the oxygen into the tissues.  Therefore the oxygen saturation, i.e. the amount of oxygen in the blood in the venule, will be very much less than that in the arteriole.  However,  it has been found in people with chronic fatigue that in fact the level of oxygen in the venous blood is too high.

This means either that the oxygen has not diffused into the tissues adequately or that it is not being used up by the Krebs cycle; thus the mitochondria in cells and the alternative pathway for metabolism (by means of glucose and carbohydrates), are being used in the tissues.  This is an anaerobic mechanism.

Therefore in people with chronic fatigue, we need to assess oxygen saturation in the tissues.  In intensive care units it is possible to measure the oxygenation of arterial blood and the oxygenation of venous blood by arterial and venous puncture.  It is not a technique that is commonly used in other practice, but it is available at Breakspear Hospital where we can measure transcutaneous blood gases.  We have been able to discern the tissue oxygenation in patients and therefore can take our investigations to the next stage.

Neurophysiological Assessments of Autonomic Function undertaken by Dr Peter Julu

Coagulation

What is it that causes poor diffusion of oxygen across the capillaries?  Here we look at coagulation factors.

Many different molecules can become stuck in the capillaries because they are so small.  Food complexes which have a piece of antibody and a piece of food together can be big enough to block the capillaries; so can yeast complexes, viruses, bacterial antibodies and complexes in people who have a leaky gut.  Bacteria flood into the bloodstream and can block the capillaries with antibody complexes, organisms such as Borrelia and others which are rickettsial diseases, heavy metals and other pollutants may also affect capillaries.  All of these agents can also be involved in blocking metabolic transfer of information from ATP to ADP and back to ATP.  The translocator proteins can become blocked with any of these agents, so there will be two mechanisms by which these agents can interfere with peripheral metabolism, either inside or outside cells in the capillaries.

Coagulation Studies   

Either anaerobic metabolism producing lactic acid, or high levels of carbon dioxide being retained in the blood, results in what is called metabolic acidosis.  The tissues are acid; they are painful and this can result in fibromyalgia or the pain in the tissues that we see in fatigue syndromes. 

Further neurological testing

At Breakspear we are also able to measure what is known as the neuromuscular unit.  Often muscles are affected in chronic fatigue and are painful.  In any muscle there will be a large number of fibres.  Each fibre can have its own innervation from the spinal cord and a number of these can overlap.  Several neuromuscular units can be present in a tissue the size of a square millimetre, 36 in all.  Therefore measuring whether or not these neuromuscular units are firing in synchrony, so that the muscle contracts in a uniform way, is a means of discerning whether or not a patient has abnormal co-ordination of the neuromuscular system.   One can measure this and thereby find out whether the brain and central nervous system have been affected by, say, a virus or a pollutant, or if the muscle itself is incapable of responding to the brain’s messages through the neuromuscular units.  The asynchronised movement of muscle can be a diagnostic test for chronic fatigue and the ‘jitter’ effect of asynchrony can be discerned.  This can be of great use in ascertaining whether the nervous system has been involved in chronic fatigue.  It can also mean that one can identify whether the agent which is responsible for the fatigue syndrome is a virus or a neurophilic (nerve-loving) toxin that has travelled up the nerves to the brain.

If there is no obstruction to the breathing pathway, an abnormal breathing pattern can be caused by some abnormality of chemical balance in the central nervous system.  This can easily be measured by an electroencephalogram using a thermistor, which is a small device placed near the nose and which will record breathing.  If an EEG changes during sleep and if the thermistor records a very slow breathing pattern, it accounts sometimes for the fatigue that is seen in people with a condition known as sleep apnoea.  Many patients who have fatigue states do have sleep apnoea, which means that they do not breathe smoothly while asleep.  They tend to breathe in a pattern of gasps and pauses.  Again, this can lead to a metabolic acidosis and is yet another reason for fatigue seen in patients with chronic fatigue syndrome.

The integrity of cellular membranes

All of these measurements can be undertaken but the other fundamental item to consider is that the unit of life in the body is a cell.  Each cell has to have its own integrity and at the same time be able to respond to all the other cells in the body, so that unification of performance can be achieved.

The cell is not independent, unless it is a cancer cell which is the only sort that behaves as though it is immortal and unrelated to the rest of the cells in the body.  In a normal cell, which is what we are considering, relationships with other cells have to be conducted through messengers.  The messengers are called cytokines.  These are little protein messengers which are sent in information packets from cell to cell and can guide the body’s responses to foreign matter, to encourage inflammation or to allow scavenging, for example.   The whole process of inter-cell communication is effected by the messengers which are being secreted from cells and are conducting an orchestrated response.

The outer surface of every cell is a membrane made up of two interwoven layers of fat and phospholipids, which are linked by studs all over the cell capsule.  There are also channels allowing the passage of chemicals into and out of the cell. 

The principal ones which gain access are electrolytes: sodium and potassium, calcium and magnesium.  Potassium, magnesium and calcium are all needed inside the cell; sodium is constantly being pumped out of the cell, though it is needed in the cell as well to effect turgidity.   These pump actions take up a huge amount of the energy of the body and therefore it is extremely important that the integrity of the cell capsule is maintained. 

There are four phospholipids: phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine and inositol.  Most phospholipids are guided towards making phosphatidyl choline, which requires a methylation process.  Methylation is a process by which a group of chemicals, known as methyl groups, are used in chemical transfer.  We all need a source of methyl groups and in our facility we use methylcobalamin very regularly because it is a source of methyl groups and also because the cobalamin part is vitamin B12 which is needed for many other functions.

The outer surface of the cell therefore has on it a number of glyconutrients which are protection molecules and also information molecules.  One of their purposes is to prevent bacteria or other foreign proteins from entering the cell and they can also be used in the immune system’s protection. 

In addition, stringing the cells together is the matrix and in the matrix there are long strands of proteins around which are carbohydrate entities.  These strands are known as proteoglycans and they are threaded like a three-dimensional network between cells.  They can act as buffering substances but they also act as information transport, like a primitive nervous system.   Information can pass along them at the speed of sound and therefore one cell can be in communication with others very quickly.

We need to maintain cell wall integrity and stop it being polluted by chemicals which can dissolve in it, but in particular we need phosphatidyl choline.

Replacing some of the glyconutrients can often be helpful and for this we use Ambrotose or Coriolus. 

Low-Dose Immunotherapy

In anyone who has an imbalanced autonomic nervous system, the invasion by any foreign agent can cause a disruption:  it is known, for example, that the pulse rate can increase on challenge in a person who might be sensitive to food.  Therefore dealing with food sensitivities and chemical sensitivities is absolutely imperative to stabilise this aberrant autonomic nervous system.  We use low-dose immunotherapy for this.  Stabilising this system is imperative, whatever else is occurring in the body.