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Etiology and Pathophysiology

While the cause or causes of ME/CFS are still unknown, evidence supports a combination of factors that are thought to contribute to the development of this illness. These may include:

  • Infection – some, but not all, patients develop ME/CFS following an acute viral-like illness. It is possible that in some people an infection may lead to changes in the immune system that contribute to the development of ME/CFS. Post-infectious fatigue is recognized to occur in about one in ten people infected with Epstein-Barr virus, Ross River virus, or Coxiella burnetti (the causative agent of Q fever). People with these infections who had severe symptoms during the acute illness were more likely than those with mild symptoms to later develop an ME/CFS-like illness. Other infections that have been studied in connection with ME/CFS include human herpesviruses, enterovirus, rubella, Candida albicans, bornaviruses, mycoplasma, and retroviruses. However, in ME/CFS, no causal role has been established for a specific infectious agent.
  • Physical or emotional trauma – some patients report experiencing an accident, trauma, immobilization, surgery, or significant emotional stress prior to onset of symptoms.
  • Genetics – ME/CFS has been observed within some families. This suggests either a possible genetic link or a common environmental exposure (infectious or toxic). Twin studies show higher rates of ME/CFS in identical than fraternal twins. However, specific genetic associations have not been established.
  • Environmental factors – exposure to mold or toxins has been suspected as a trigger for ME/CFS. However, associations of specific environmental factors with ME/CFS have not been established.

ME/CFS is a biological illness, not a psychologic disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have multiple pathophysiological changes that affect multiple systems. It is not known whether these changes occur prior to the onset of the illness or as its consequence. These changes include:

  • Immune system abnormalities – some people with ME/CFS have impaired natural killer cell function and/or T cell function, chronic higher production of inflammatory cytokines, and in some cases slight increase in some autoantibodies (rheumatic factor, anti-thyroid antibodies, anti-gliadin, anti-smooth muscle antibodies, and cold agglutinins).
  • Cellular metabolism abnormalities – some people with ME/CFS also appear to have impaired ability to produce energy from the usual “fuel” that cells use to produce energy: oxygen, glucose, fatty acids, and amino acids. Exercise studies in adults have revealed impaired oxygen consumption and activation of anaerobic metabolic pathways in the early stages of exercise.
  • Neuroendocrine disturbances – some people with ME/CFS report physical or emotional stress before they become ill, which can lead to dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis). Some patients with ME/CFS have flattened diurnal cortisol profiles compared to healthy people, but their cortisol levels are still within the normal range.
  • Blood pressure or heart rate regulation abnormalities – some people with ME/CFS, particularly adolescents, experience symptoms of orthostatic intolerance. Patients with orthostatic intolerance develop a worsening of symptoms with quiet upright posture and improvement (though not necessarily full resolution) of symptoms with recumbency. Two common forms of orthostatic intolerance experienced by patients with ME/CFS are:
    • Neurally-mediated hypotension (NMH): an abnormality in the regulation of blood pressure during upright posture. NMH is sometimes also referred to as neurocardiogenic syncope, vasodepressor syncope, vaso-vagal syncope, “the fainting reflex”, and delayed orthostatic hypotension.
    • Postural orthostatic tachycardia syndrome (POTS): an abnormality in the regulation of heart rate in which a change from lying to standing causes an abnormal increase in heart rate; the heart is usually structurally normal.

These two conditions can occur together. Notably, not all patients with NMH or POTS have ME/CFS, and not all patients with ME/CFS have NMH or POTS.

Disclaimer: The content of this ME/CFS website is for informational purposes only and does not represent a federal guideline or recommendation for the treatment of ME/CFS. The information provided on this website is not intended to be a substitute for the medical judgment of the healthcare provider and does not indicate an exclusive course of action or treatment.

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