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Chronic Fatigue Syndrome – What You Need To Know

This article provides a complete ‘Chronic Fatigue Syndrome Overview’. View it as a tool that can be used to navigate through our website. As we create more content new links will be embedded in to this article giving you direct access to the information you want to read.

Before reading it you may like to read our short article on functional medicine which can be found here.


While etiological knowledge of chronic fatigue syndrome is still limited, there are numerous mechanisms/systems/theories discussed in the literature which include:

  • Genetic susceptibility
  • Adverse Childhood Events
    • Early life stress
  • Psychosocial stress
  • Immune Dysregulation
    • Immunogenic stress such as a viral/bacterial infection
    • SNPs (variants in genes) related to immune function
    • Inflammation
    • Oxidative stress
    • A Th2 dominant state
    • Autoimmune mechanisms
  • Gender
  • Psychology
    • Self-esteem
    • Personality
    • Illness perceptions and cognitions
  • Digestive Imbalances
    • Dysbiosis
    • Small Intestine Bacterial Overgrowth
    • Leaky gut
  • Hormonal Imbalances
    • Chronically high cortisol
    • Sub-clinical thyroid issues
  • Detoxification issues
  • Mitochondrial dysfunction

It is important to note that it may be impossible to decipher which of these are causes and which of these are consequences of chronic fatigue syndrome.

Immune Deficiency

Patients with CFS have an underlying relative immunodeficiency that prevents effective control of pathogen proliferation, leading to a more severe infection and inflammatory response, which in turn paves the way for the inflammatory pathology of chronic fatigue syndrome. While this difference alone may not be the only determinant of which patients develop CFS and which do not, it is our suspicion that such an immunological difference may be an important deciding factor in the development of chronic fatigue syndrome as a consequence of infection.

So it may be that some individuals have a greater a inflammatory response to a virus, due to their genetics, which ‘tips them over the edge’ in to fatigue.

Hypocortisolemia (low cortisol)

See out in-depth article on cortisol in chronic fatigue syndrome here.

A common finding in chronic fatigue syndrome patients is that of dysregulation of the HPA axis, more often in a hypo-functioning state. Chronic stress may predispose an individual to inflammation and oxidative stress and these pathologies have not only been found in patients with chronic fatigue syndrome but also have been shown to contribute to cortisol resistance and autoimmune mechanisms (both of which have been found in CFS patients).

Cortisol resistance is whereby the cells in the body, or a certain part of the body, become resistant to the effects of cortisol (similar to insulin resistance). This cortisol resistance may cause further inflammation creating a vicious cycle.

Digestive Health in CFS

See our series of articles that discuss digestive health in detail:

Studies have demonstrated that up to 54% of chronic fatigue syndrome participants had SIBO (small intestine bacterial overgrowth) compared to 5% of controls.

Inflammation in CFS

It has been shown (Morris et al., 2014) that up to around 60% of patients with chronic fatigue syndrome have increased levels of pro-inflammatory cytokines.

Recent studies using new technology, called gene expression profiling, have demonstrated a ‘‘transcriptional fingerprint’’ of chronic stress (Miller et al., 2014). Chronic stress has been shown to cause a down regulation of transcriptional activity facilitated by the glucocorticoid (cortisol) receptor and an up-regulation of pro-inflammatory pathways.

The key has to be investigating the underlying cause of inflammation. The most common causes include: food reactivity disorders, bugs (bacteria, yeast, parasites, viruses), oxidative stress and chronic stress.

Oxidative Stress in CFS

Oxidative stress activates a number of transcription factors, such as NF-kappaB and activated protein 1, leading to the production of pro-inflammatory cytokines

Essentially oxidative stress can cause inflammation. Chronic oxidative stress develops in a cellular environment whenever production of reactive nitrogen species (RNS) and reactive oxygen species (ROS) exceeds the clearance ability of the cell’s antioxidant defenses such as the glutathione (GSH) system.

Oxidative stress in frequently found in chronic fatigue syndrome patients (Nijs et al., 2014). The state can be induced by numerous triggers including psychological stress, strenuous exercise, viral infections, inflammation, nutrient deficiencies (Miwa et al., 2010; Maes et al., 2006) and an increased translocation of LPS due to excessive intestinal permeability (leaky gut).

Oxidative stress and inflammation may also lead to mitochondrial dysfunction exacerbating symptoms such as fatigue further (Morris and Berk, 2015; Morris et al., 2014; Morris et al., 2015). Mitochondria are the energy factories of the cell so any dysfunction here will contribute to fatigue.

Mitochondrial Dysfunction in CFS

Mitochondria are the energy factories of the cell so any dysfunction here will contribute to fatigue. See our detailed article on mitochondrial dysfunction in chronic fatigue syndrome here.

Mitochondrial dysfunction may well result from the presence of oxidative stress, as there is now ample evidence implicating oxidative stress as one of the major contributing factors in the development of mitochondrial dysfunction and compromised bioenergetic performance (Morris & Berk, 2015)

Autoimmune Mechanisms in CFS

It has been shown (Morris et al., 2014) that up to around 60% of patients with chronic fatigue syndrome have increased levels of pro-inflammatory cytokines and that, if chronic, this may cause autoimmune mechanisms to be initiated (Morris et al., 2013).

Many of these are interdependent on each other, contributing to a forward feeding loop and meaning that even after the trigger has gone, the pathophysiological state can remain.

Th2 Dominant State

See our article here: CFS – A Th2 Dominant Condition?


Glutathione, acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS).

Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. Glutathione is often found to be low in CFS patents. Read our full article on glutathione here: Glutathione Status in CFS

Light Sensitivity

This is quite a common symptom in people with CFS. I recommend getting a pair of blue light stopping glasses, such as these. They are also excellent for the evenings when seeking improvement in sleep and resetting of our body clock (see our article on circadian rhythm here)


See our Mindset section of articles here. They include topics such as:

Stratification in Chronic Fatigue Syndrome

Based on the causes of chronic fatigue syndrome being multifactorial, as in other conditions, it is likely that the causes and mechanisms contributing to the diverse range of symptoms are different from person to person.

As a result, better client phenotyping may offer a way to understand the multifactorial nature of the disease. Therefore, future work may benefit from stratification – the clustering of patients in to subgroups.

It does appear there are subsets of people with chronic fatigue syndrome based on factors such as the initial trigger and symptomatology (Nater et al. 2008). This may pave the way for a more systematic research approach and thus has implications for clinical practice also. This may help us improve our understanding of the mechanisms involved in different ‘types’ of fatigue.

In fact a paper published in 2016 concluded:

“adults with chronic fatigue syndrome may have one of 6 symptom-based phenotypes associated with sex, duration and severity of illness, and comorbidity. Future research needs to determine whether phenotypes predict treatment outcomes, and require different treatments.” (Colin et al., 2016)

This is why there are so many contradictory findings – some seem to assume that chronic fatigue syndrome is a single entity – that there is one cause of the condition. This seems to be highly unlikely and the first step needs to be investigating what may have contributed to that individuals fatigue, and certainly what’s perpetuating it. .