Fatigue is a very common symptom. The difficulty in evaluating it is that it can be caused by several different problems. Most who have fatigue and present to medical care have lab tests done to investigate causes such as thyroid disease and anemia. This testing often fails to provide the cause or help guide a solution.

There are other common causes of fatigue that are often not investigated in the medical setting such as adrenal fatigue and cell energy production deficits.

Adrenal Fatigue

The adrenal glands make a family of steroid hormones including cortisol. Cortisol is a multi-tasking hormone involved in energy production, inflammatory control, stress activation of the brain and blood sugar regulation. Any chronic stress to the adrenal glands can eventually cause cortisol imbalance.

Often with chronic adrenal stress the cortisol response will become excessive. This can cause difficulty getting to sleep at night, some anxiety and an abundance of energy. However, it will eventually transition to the development of fatigue as the adrenal glands begin to fail to keep up with the demand for cortisol. Other signs of adrenal fatigue include sleep maintenance difficulty, poor inflammatory control and brain fog or lack of mental clarity.

Sleep maintenance difficulty is a pattern where it is usually easy to fall asleep but then the individual wakes up 2-5 hours later and has difficulty going back to sleep. Cortisol is expressed in small amounts at night to help prevent low blood sugar during the 8-10 hours without eating. In adrenal fatigue the inadequate cortisol response is compensated by another hormone, epinephrine which causes the brain to become alert, but also causes the individual to feel somewhat agitated and the heart rate to elevate some.

Cortisol is our main anti-inflammatory hormone. In adrenal fatigue we produce inadequate levels magnifying symptoms such as muscle and joint pains, allergies and other inflammatory responses.

Cortisol also is a stress hormone intensifying brain alertness in response to danger or stress. Inadequate cortisol while awake will often dull perception with individuals typically referring to it as brain fog or poor concentration.

Adrenal fatigue is diagnosed by a combination of questionnaires regarding symptom patterns, 16-hour cortisol analysis and Biomeridian Testing. Cortisol levels vary considerably with the time of day in a circadian rhythm. For example, cortisol should be 2-2.5 times higher the first hour after awakening than it is late morning. This is why a single point blood test may be highly misleading reporting only morning or afternoon cortisol.

The report below shows the normal values are much higher first thing in the morning, moderate mid-day and much lower at bedtime. Both the values at each interval and this circadian pattern are important. Saliva samples are used for home collection to make this 16-hour test practical.

The test below shows a pattern of significant adrenal fatigue. This pattern will often correspond with a symptom pattern of strong fatigue throughout the day with improved energy in the later evening. It is important to correlate the time of the low cortisol readings with the timing of fatigue to improve diagnostic accuracy.

Occasionally, an added specimen is used if the patient wakes up during the night and has difficulty getting back to sleep to differentiate spiking of cortisol or excessive low cortisol response both of which disrupt sleep.

An additional pattern of adrenal fatigue is called dysregulation. In this pattern cortisol is very low in the morning and often mid-day but gets high in the evening and night. This pattern seen below is often associated with daytime fatigue and high energy in the evening making it difficult to get to sleep.

This pattern often requires early morning treatment with activating herbs and evening treatment with calming herbs. As with all other fatiguing patterns, the triggering cause of the adrenal fatigue must be found and resolved.

Resolving adrenal fatigue involves identifying the causative factors (stress, blood sugar imbalances, food sensitivities) and adrenal restoration with the appropriate nutrients and reparative herbs.

Atypical Thyroid Syndromes

Some patients with fatigue have had thyroid testing which proved to be normal. The fatigue may, however, be caused by reverse T3 (rT3) thyroid syndrome which is different from simple hypothyroidism, or under functioning of the thyroid. The presence of high amounts of rT3 will suppress cell thyroid signal even in the presence of normal amounts of thyroid hormone. The TSH which is used to determine thyroid hormone function will often be normal in the presence of rT3 syndrome as the production of TSH only indicates the presence of adequate normal thyroid hormone. The fatigue is caused by the lack of effect of the thyroid hormone at the cell level because too many of the cell thyroid hormone receptors are being taken up by the inactive rT3 present.

The cause of high rT3 production is the presence of high cortisol. Both the thyroid hormones and adrenal hormones (cortisol) activate cell energy production. If both thyroid hormone and cortisol were very active at the same time, it would be too stimulating. This is prevented when cortisol is too high by its inactivation of thyroid hormone by the conversion of much of it to rT3.

Because both cortisol and thyroid hormones activate cell energy, cells are carefully regulated to protect cells from too much activation from intense cortisol and thyroid hormone activation at the same time. The thyroid gland makes hormone predominantly as T4. As shown above this is a molecule with an iodine on each of four corners hence the name T4. This circulating form has lower cell activating properties, and most T4 once it enters a cell will have an iodine removed from one corner by an enzyme called a deiodinase making it a more active hormone, T3. The T3 fits into a receptor triggering cell activation.

When cortisol levels are high, cells protect themselves from overstimulating by both cortisol and thyroid hormone. The high cortisol causes the cell to produce another enzyme called a reverse deiodinase, or type II deiodinase.

The type II deiodinase enzyme knocks an iodine off the wrong corner making an inactive molecule rT3. Reverse T3 will fit into the hormone receptors but will not trigger cell activation. It also prevents active T3 from doing so, hence the “hypothyroid effect”.

Standard testing for thyroid related fatigue typically only looks at “how much” and not “why”. How much testing is done simply to judge the need for thyroid hormone replacement therapy. Some thyroid dysfunction results from autoimmune attack on the thyroid triggered by things such as food sensitivities. The answer in this case is often isolating the cause and removing it allowing the thyroid to normalize its own function. Many patients have had limited thyroid testing and been told that is not the problem when it may be. Comprehensive testing should involve looking at the pituitary signal to the thyroid (TSH), thyroid antibodies, as well as free thyroid hormones.

Cell Energy Production Deficits

Fatigue may also be caused by impaired energy processing through cells. This may result from a number of causes, but they all have a common mechanism. This mechanism is inhibition of the cell mitochondria. The mitochondria are small “engines” within the cell that generate the molecule responsible for energy, ATP.

The generation of ATP is done taking potential energy molecules that the cell has processed such as sugar and fats and transitioning them through several enzymes that result in the final production of ATP. Nutrient deficiencies, inflammation, oxidative stress, and genetic mediated enzyme variations can all slow these enzymes making it difficult to produce adequate ATP to keep up with energy demand. This results in generalized fatigue often accompanied by low grade aches and pains.

Each enzyme is produced by a specific gene each time it is needed. However, when it is produced, it is inactive and has to be combined with “cofactor” to be fully active. Cofactors are typically micronutrients such as vitamins and minerals with each enzyme requiring a different combination.

Each human gene can have multiple variations called polymorphisms. These gene variations tend to cause the resulting enzyme to be underactive. One of the interesting findings has been that in these genetically underactive enzymes, their activity can often be raised to normal with much higher amounts of the nutrients that are co-factor for that enzyme normalizing energy production.

There are hundreds of different enzymes in humans, and the unique ones that are underactive in each person is unique. Testing is now available looking at the gene polymorphism in the common enzymes in the energy production process. This allows for individualized nutritional recommendations to correct energy deficits.

Another type of testing called metabolomic analysis is also available. This testing looks at intermediates called organic acids in the enzyme pathways in the urine. For example if a metabolic pathway converts “A” with enzyme A into “B” and then enzyme B converts “B” into ATP and enzyme A does not work very well because of genetic variation; or if it is being suppressed by inflammation, “A” will build up and spill excessively in the urine as shown below.

Normal enzyme resulting in high conversion of “A” to “B” and very little urinary spilling of “A”

Weak enzyme resulting in poor conversion of “A” to “B” and high urinary spilling of “A”

While each individual may have a unique group of factors producing their cell energy deficits, identification of these factors, correction of modifiable factors (inflammation, oxidative stress, etc) and an individualized nutritional program will often produce pronounced symptomatic relief.

Currently, relatively cost effective genetic testing is available for some of the common gene variations that cause imbalances in energy metabolism and ultimately, fatigue. In appropriate patients it can allow specifically tailored treatment.

As you can see, fatigue can be from several factors. It is one of the most important symptoms to approach with this understanding. The solution always revolves around knowing the cause in the first place.

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