What Causes Chronic Fatigue Syndrome?

Clues as to Causes for CFS

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What causes chronic fatigue syndrome? Tough question! Despite lots of research, experts haven't been able to pin it on any single cause. Some believe chronic fatigue syndrome (ME/CFS) could result from multiple factors coming together under the right conditions. These factors may include:

  • Genetic factors
  • Central nervous system and hormone abnormalities
  • A virus or other infection
  • Immune system abnormalities
  • Stressful conditions
  • Exposure to toxins

Not everyone with ME/CFS has all of these factors going on. They likely have a combination of them that, for some reason, has led to the condition. Because different combinations of factors can cause different symptoms and changes in the body, experts are identifying categories or subgroups of ME/CFS. Eventually, subgrouping may help you and your doctor figure out the best way to treat you.

Genetic Factors and Chronic Fatigue Syndrome

Research links ME/CFS with genes involved in the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The HPA axis controls your sleep, response to stress, and depression.

In a 2006 study published in Pharmacogenetics, researchers looked at DNA that controls how your body reacts to trauma, injury and stress, and they found a common variation that could predict ME/CFS with 76% accuracy. The CDC called this "the first credible evidence of a biological basis for chronic fatigue syndrome." Still, researchers weren't able to pinpoint genetic markers or determine how variations influenced symptoms.

Other studies show genetic abnormalities in people with ME/CFS that influence immune function, cellular communication, and the ways your cells get energy.

All of this suggests that some people may be genetically predisposed to ME/CFS -- in other words, they're likely to get it if enough triggers come together.

For example, if someone who's predisposed is going through a stressful time and is then exposed to a particular virus or toxin, they'll develop ME/CFS. Someone with a different genetic make-up, however, would come through the same scenario and be fine.

Central Nervous System and Hormone Abnormalities

As mentioned above, some people with ME/CFS have abnormalities in the HPA axis. Researchers are especially interested in some of the central-nervous-system chemicals and hormones controlled by the HPA axis:

  • Neurotransmitter changes
    Neurotransmitters are chemicals that communicate messages in your brain. Research has shown that some people with ME/CFS have abnormal levels of certain important neurotransmitters (serotonin and dopamine). Researchers are working to explain the role these abnormalities play in ME/CFS.
  • Stress hormone deficiencies
    Experts know levels of the stress hormone cortisol are low in ME/CFS patients, and they believe this could be what makes it hard to deal with stress -- either physical (such as infection or exertion) or mental. Cortisol replacement helps some, but not all, ME/CFS patients. In a 2008 study, women with ME/CFS had low morning cortisol levels while men with ME/CFS did not, which could help explain why the condition is far more common in women.
  • Disturbed circadian rhythms
    Your circadian clock (part of the HPA axis) regulates your sleep-wake cycle. Evidence suggests that in some people with ME/CFS this clock is thrown off, possibly by a mentally or physically stressful event, and the body isn't able to get the proper rhythm reestablished. People with this problem appear to spend more time in the rapid-eye movement (REM) phase of sleep, which is when you're dreaming. People in this subgroup of ME/CFS get more help from sleep medications than people in other subgroups, according to experts.


Many of the signs and symptoms of ME/CFS are similar to those of a lingering viral illness, so a lot of research has focused on the possibility of a viral or infectious cause. Researchers have examined three infection-related theories, though none has been proven:

  1. A virus or bacteria infects the body and damages the immune system. The damage then continues to cause flu-like symptoms even after the virus or bacteria is gone.
  2. After an infection, an abnormal action by the immune system triggers a virus that had become inactive to reactivate.
  3. A physiological response to viral infections occurs in people who are susceptible.

While not everyone with ME/CFS shows signs of infection, many do. Several pieces of evidence support a theory that some ME/CFS is caused at least in part by a virus:

  • Enterovirus connection
    In a 2007 study, people with ME/CFS were four times more likely than healthy people to have evidence of enteroviruses in their stomach tissues. Enteroviruses cause stomach infections, and symptoms of ME/CFS frequently start after that kind of illness.
  • Rnase L
    Your body uses the enzyme Rnase L to kill viruses that are attacking your cells, and ME/CFS patients frequently have high Rnase L activity.
  • Natural Killer (NK) Cells and T Cells
    NK & T cells in your immune system attack virus-infected cells, and people with ME/CFS frequently have impaired NK and T cell functions and numbers, suggesting chronic immune activity may be exhausting and depleting them.
  • Antibodies
    People with ME/CFS typically have high levels of antibodies to many infection-causing organisms that cause fatigue and other ME/CFS symptoms. These organisms include those that cause candida (yeast), human herpesvirus type 6 (HHV-6), measles, parvovirus, and Epstein-Barr. Researchers have not been able to show that any of these is a significant cause of ME/CFS.
  • Post-illness onset
    Up to 80 percent of ME/CFS cases start suddenly after a flu-like condition.
  • Cluster outbreaks
    While the CDC has not confirmed most cluster outbreaks, reports of multiple people in the same household, workplace, and community developing ME/CFS at the same time are not unheard of.

Some researchers suggest that changes in normally harmless bacteria in the intestine may play a role in the development of ME/CFS.

However, some evidence seems to run counter to the viral-cause theory. ME/CFS doesn't appear to spread through direct content, people with it don't appear contagious, and -- in spite of well-designed studies -- researchers have not been able to link ME/CFS with any specific infections.

A Note on XMRV

In 2009, researchers from the Whittemore Peterson Institute (WPI) published a study in the journal Science that suggested a link between XMRV, a newly discovered retrovirus, and ME/CFS. They found XMRV in about 67% of blood samples from ME/CFS patients. They also detected it in 3% of healthy controls.

However, subsequent studies failed to confirm the link, including a large study involving the WPI's primary researcher. Other studies suggested means by which contamination may have created false positives in the original study. By late 2011, the XMRV theory had been all-but abandoned.

Immune System Abnormalities

Several studies have shown irregularities in the immune systems of people with ME/CFS, but researchers have not found a consistent pattern of abnormalities. Among the most common are allergies and an overactive immune system.

Some studies have reported that a majority of ME/CFS patients are allergic to things including pollen, foods and metals such as nickel and mercury. That's led to a theory that allergens may trigger a series of immune abnormalities which then lead to ME/CFS.

One theory is that allergies, stress and infection may combine to deplete a chemical called adenosine triphosphate (ATP), which stores energy in cells. Some ME/CFS patients show evidence of decreased ATP production.

Some ME/CFS patients have high levels of a substance called cytokines, which scientists theorize could cause symptoms of ME/CFS, including fatigue and muscle aches. Various studies have reported T cell imbalances in people with ME/CFS, but other studies have not confirmed the T cell and cytokine abnormalities.

Chronic fatigue syndrome appears to have a few features in common with autoimmune diseases such as lupus or multiple sclerosis, in which the immune system mistakenly attacks healthy parts of the body. A growing body of research suggests ME/CFS may be autoimmune.

Stressful Conditions

Researchers believe your psychological makeup, personality and social situation can impact whether you'll develop ME/CFS, but they don't yet fully understand the complex relationship between them.

While these factors are probably not a primary cause of ME/CFS, they're likely to play a role in making you susceptible.

Note: ME/CFS is not considered a primary psychological illness, nor does having ME/CFS mean someone is psychologically weak or unable to cope with things. While it is sometimes linked to clinical depression, ME/CFS is a distinct condition.

Chemicals and Environmental Toxins

In one subgroup, chronic fatigue and pain are associated with exposure to various chemicals and environmental toxins. These can include solvents, pesticides or heavy metals. However, because most of us have been exposed to these types of chemicals at some point, it's difficult to track down which ones might be causing problems. A condition called multiple chemical sensitivity (MCS) causes many of the same symptoms as ME/CFS, and the two are believed to be overlapping conditions.


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Lombardi VC, et al. Science. 2009 Oct 23;326(5952):585-9. Detection of an infectious retrovirus, XMRV, in blood cells of people with chronic fatigue syndrome

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Simmons G, et. al. Science. 2011 Nov 11;334(6057):814-7. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study.

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