Causes of Chronic Fatigue Syndrome

The causes of Chronic Fatigue Syndrome are as yet undetermined, but studies have shown that multiple nutrient deficiencies, food intolerance, or extreme physical or mental stress may trigger chronic fatigue. Studies have also indicated that Chronic Fatigue Syndrome may be activated by the immune system, various abnormalities of the hypothalamic-pituitary axes, or by the reactivation of certain infectious agents in the body. Some Chronic Fatigue Syndrome patients were found to have low levels of PBMC beta-endorphin and other neurotransmitters. Thyroid deficiency may also be a contributing factor in Chronic Fatigue Syndrome (refer to the Thyroid Deficiency protocol to find out how to determine if you are deficient in thyroid hormone production). A number of the triggers that may cause or exacerbate Chronic Fatigue Syndrome are discussed below

Chronic Viral Infections and Chronic Fatigue Syndrome

      Symptoms of Chronic Fatigue Syndrome resemble a postviral state and for this reason chronic viral conditions have been thought to contribute to Chronic Fatigue Syndrome in some patients. Several viruses have been associated with Chronic Fatigue Syndrome, including:

      • Herpes virus, particularly human herpes virus 6 (HHV-6)
      • Epstein-Barr virus (a herpes virus which causes infectious mononucleosis)
      • Cytomegalovirus (a herpes virus)
      • Coxsackie viruses B1 and B4

If you are infected with a chronic, energy-depleting virus, there are conventional and alternative therapies that may be of help. It should be noted that most individuals have been exposed to pathogenic viruses that can be reactivated by adverse environmental conditions and cause chronic fatigue and other diseases.

Studies indicate that the Epstein-Barr virus may be suppressed with bilberry extract (anthocyanins), curcumin, carotenoids, and chlorophylls. The exact doses of these natural plant extracts that might be effective against Epstein-Barr have yet to be determined.

Immune Response to Bacterial and Viral Antigens and Chronic Fatigue Syndrome

      There are two different types of T-helper cells that defend against different organisms:

      • T-helper 1 cells target organisms that invade cells, such as viruses. Interleukin-12 (IL-12) stimulates Th1 activation.
      • T-helper 2 cells (Th2) target organisms that are found outside of cells. Th2 cells are involved in humoral or antibody-mediated immunity and are triggered by interleukin-10 (IL-10), which is stimulated by bacteria, parasites, toxins, and allergens.

Each of the T-helper cells are activated by different cytokines (see following table). In a healthy condition, there is a balance between Th1 and Th2 activity. When presented with an acute infection, the Th1 system predominates (and Th2 is suppressed). In chronic infections, the Th2 system predominates, leading to antibody production.

Cytokine Profiles and Functions of T-Helper Cells

T-helper 1Interferon-gammaActivates cytotoxic cells
Interleukin-2Inhibits Th2 cells
T-helper 2Interleukin-4, -5, -6, and -10Activation and maturation of B cells
Inhibits Th1 cells

Viruses, especially herpes viruses (such as Epstein-Barr virus, cytomegalovirus, and human herpes virus 6), make proteins that mimic IL-10, which activates the immune system and remains untouched by the body’s natural defenses.

Addressing the two different types of T-helper cells has been the focus of work by Paul Cheney, M.D. His protocols are designed to stimulate Th1 and inhibit Th2.

According to Dr. Cheney, chronic fatigue patients have activation of T-helper 2 cells (Th2). Th2 activation suppresses T-helper 1 (Th1) activity, particularly cytotoxic T-cells and natural killer (NK) cells, which are the main defense against viruses. In this way the viruses are able to “fool” the immune system.

Several mechanisms can be used to stop the process of Th2 activation:

      • Enhance natural killer (NK) cell function.
      • Lower interleukin-10 (IL-10) levels, which will reduce Th2 activation.
      • Raise interleukin-12 (IL-12) levels, which stimulate Th1 activation.

An article in the Journal of Clinical Infectious Disease measured NK cell activity in 50 healthy individuals and 20 patients with clinically defined chronic fatigue immune dysfunction syndrome (CFIDS). The patients were divided into three groups based on severity of clinical status. NK cell activity decreased with the increasing severity of the clinical condition (Ojo-Amaize et al. 1994).

Several nutritional supplements, including essential fatty acids, vitamin A, vitamin E, DHEA, and melatonin, have been found to have beneficial effects on the Th1:Th2 ratio (see the Natural Therapies section).

For more information about Dr. Cheney’s work, see


Infection and Inflammation, and Chronic Fatigue Syndrome

A theory was published by Dr. Martin L. Pall, a professor of biochemistry and basic medical sciences at Washington State University. The theory starts with the observation that infections that precede and may therefore induce Chronic Fatigue Syndrome and related conditions act to induce excessive production of inflammatory cytokines. This initial step activates a series of reactions:

      • Inflammatory cytokines induce, in turn, nitric oxide synthase (iNOS), which synthesizes excessive amounts of nitric oxide.
      • Nitric oxide reacts with superoxide to produce the potent oxidant peroxynitrite.
      • Peroxynitrite acts via six known biochemical mechanisms to increase the levels of both nitric oxide and superoxide, which react to produce more peroxynitrite.

In this way, once peroxynitrite levels are elevated, they may act to continue the elevation, thus producing a self-sustaining vicious cycle. According to the theory, it is this cycle that maintains the chronic symptoms of Chronic Fatigue Syndrome, and it is this cycle, therefore, that must be interrupted to effectively treat this condition.

Breaking the chain of inflammation caused by chronic viral infections would require a three-part protocol:

      • First, the underlying viral infection should be addressed with antiviral supplements (such as ginseng, echinacea, and lactoferrin) and those that shift the Th1:Th2 ratio (such as essential fatty acids and vitamin E).
      • Second, inflammation should be reduced with anti-inflammatory agents (such as essential fatty acids and curcumin).
      • Third, the nitric oxide system should be supported with supplements (such as arginine, vitamin B2 [riboflavin], vitamin B3 [niacin], and folate).


Multiple Chemical Sensitivity and Chronic Fatigue Syndrome

Multiple chemical sensitivity (MCS) is a controversial term. Synonyms for MCS are twentieth century disease, Environmental Illness, Total Allergy syndrome, Chemical AIDS, and Idiopathic Environmental Illness. It is believed by some that exposure to a chemical (or many chemicals) can trigger a complex of symptoms called MCS. It appears to affect young women at a higher rate than men. There has not been a consensus on the specific definition for MCS. The disorder is characterized by recurring symptoms affecting multiple organ systems. The individual demonstrates symptoms of MCS when exposed to many unrelated chemicals, in doses that are far below those recognized to cause harm in the general population. No single, widely accepted test of physiologic function can be correlated with the symptoms.

The theories for MCS include, but are not limited to, dysfunction of the immune system and neurological abnormalities–specifically, chemical sensitization of the limbic system–and various psychological theories. To date, no studies have validated any theory. One study points out that MCS, fibromyalgia, Chronic Fatigue Syndrome, and post-traumatic stress disorder are overlapping diseases, sharing common symptoms. Very often, each disorder seems to be induced by a relatively short-term stress, which is followed by a chronic pathology, suggesting that the stress may act by inducing a self-perpetuating vicious cycle.

Pall et al. believe that the vicious cycle mechanism is the explanation for the etiology of Chronic Fatigue Syndrome and MCS, based on the elevated levels of nitric oxide and its potent oxidant product, peroxynitrite, found in both conditions.

Beckman et al. reported that peroxynitrite reacts with and inactivates several important mitochondrial enzymes leading to metabolic energy dysfunction.


Metal Sensitivity and Chronic Fatigue Syndrome

The effect of dental metal (amalgam) removal was studied in 111 patients with metal hypersensitivity and symptoms resembling Chronic Fatigue Syndrome. After consultation with a dentist, the patients decided to replace their metal restorations with nonmetallic materials. A significant number of patients had metal-specific lymphocytes in the blood. Nickel was the most common, followed by inorganic mercury, gold, phenyl-mercury, cadmium, and palladium. As compared to lymphocyte responses in healthy subjects, the Chronic Fatigue Syndrome group had significantly increased responses to several metals, especially to inorganic mercury, phenyl-mercury, and gold. Following dental metal removal, 83 patients (76%) reported long-term health improvement; 24 patients (22%) reported unchanged health; and two patients (2%) reported worsening of symptoms. Following dental metal replacement, the lymphocyte reactivity to metals decreased as well.


Oxidative Stress and Chronic Fatigue Syndrome

Studies have shown that oxidative stress plays a role in the development of Chronic Fatigue Syndrome. Oxidative stress is a term used to describe the body’s prolonged exposure to oxidative factors that cause more free radicals than the body can neutralize. Free radicals are produced as a byproduct of normal metabolic functions. When there are enough free radical scavengers present, such as glutathione and vitamins C, E, and A, along with zinc and other nutrients, through normal metabolic functioning, the body will “mop up” or neutralize the free radicals. When free radicals are not neutralized, the body can become vulnerable to cellular destruction.

A relationship between abnormal oxidative stress and Chronic Fatigue Syndrome can be found in the literature. An article in the journal Life Science described a study that showed that patients with Chronic Fatigue Syndrome had lower serum transferrin levels and higher lipoprotein peroxidation. These results indicate that patients with Chronic Fatigue Syndrome have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidizing effects of Chronic Fatigue Syndrome.

Exercise has been shown to increase the production of oxidants. Fortunately, regular endurance exercise results in adaptations in the skeletal muscle antioxidant capacity, which protects myocytes (muscle cells) against the deleterious effects of oxidants and prevents extensive cellular damage.

A study of the oxygen delivery to muscles in patients with Chronic Fatigue Syndrome found that oxygen delivery and oxidative metabolism was significantly reduced in Chronic Fatigue Syndrome patients after exercise (compared with sedentary controls).

Possible Related Side Effects of Chronic Fatigue Syndrome

Orthostatic Hypotension
Orthostatic hypotension is defined as an excessive fall in blood pressure on standing, usually greater than 20/10 mmHg. It is considered to be a manifestation of abnormal blood pressure regulation due to a variety of causes.

Hypotension, particularly orthostatic hypotension, is a common symptom in chronic fatigue patients. Many people with Chronic Fatigue Syndrome have chronic low blood pressure (the normal is 120/80 mmHg), which is made even worse on standing. This may be a particular problem in the morning, when standing can cause dizziness. Exercise or a heavy meal may exacerbate the symptoms. Syncope is a loss of consciousness and postural tone caused by diminished cerebral blood flow. Syncope often occurs during the morning shower, perhaps due to the vasodilating effect of hot water.

There are several mechanisms that govern blood pressure. Upon standing, a large amount of blood pools in the veins of the legs and trunk. The transient decrease in venous return to the heart results in a low blood pressure. The body responds with a sympathetic-mediated release of catacholamines that increase heart rate contraction and vasoconstrict the arteries. With continued standing, antidiuretic hormone (ADH) is secreted which activates the renin-angiotensin-aldosterone system, subsequently causing sodium and water retention and an expansion of the circulating blood volume.

There are many causes of orthostatic hypotension, including:

      • Hypovolemia (low blood volume) induced by excessive use of diuretic agents (e.g., loop diuretics, such as furosemide, bumetanide, and ethacrynic acid) and relative hypovolemia due to vasodilator therapy with nitrate preparations and calcium antagonists (verapamil, nifedipine, or diltiazem) or with angiotensin converting enzyme (ACE) inhibitors.
      • Histamine, a key player in allergic reactions, induces vasodilation and hypotension.
      • Potassium deficiency (hypokalemia) impairs the reactivity of vascular smooth muscle and may limit the increase in peripheral vascular resistance on standing
      • The adrenocortical hypofunction of Addison’s disease may lead to orthostatic hypotension in the absence of adequate salt intake.
      • Several classes of drugs reversibly impair autonomic reflexes and reduce blood pressure on standing as an important adverse effect. These include many drugs used to treat psychiatric disorders such as the monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, and tranylcypromine) used to treat depression; the tricyclic antidepressants (nortriptyline, amitriptyline, desipramine, imipramine, and protriptyline) or tetracyclic antidepressants; and the phenothiazine antipsychotic drugs (chlorpromazine, promazine, and thioridazine). Other drugs that may produce orthostatic hypotension are quinidine, L-dopa, barbiturates, and alcohol.

Elevated Homocysteine Levels
Homocysteine is a sulfur-containing amino acid that is produced as a byproduct of methionine metabolism. When the body has an adequate supply of cofactors, such as vitamins B6, B12, and folic acid, homocysteine is detoxified, rendering compounds useful for other functions. Currently, homocysteine levels are in the forefront as a cardiovascular risk because of the damage that can occur to blood vessels and arteries when homocysteine levels are high.

A study of 12 women who fulfilled the criteria for both fibromyalgia and Chronic Fatigue Syndrome found that, in all the patients, the homocysteine levels were increased in the cerebrospinal fluid (CSF). There was a significant positive correlation between CSF homocysteine and B12 levels and fatigue-ability, as rated on the Comprehensive Psychopathological Rating Scale. The authors concluded that “increased homocysteine levels in the central nervous system characterize patients fulfilling the criteria for both fibromyalgia and chronic fatigue syndrome.” They also noted that B12 deficiency caused a deficient remethylation of homocysteine. Therefore, a vitamin B12 deficiency can be considered a contributing factor to the higher homocysteine elevations found in these patient groups.

Glutathione Deficiency
Glutathione is a tripeptide made up of three amino acids: glycine, cysteine, and gamma-glutamic acid. Glutathione functions as a modulator of cellular homeostasis, including detoxification of oxyradicals and metals. It also acts as a potent free radical scavenger that can help prevent damage to DNA and RNA, detoxify heavy metals, boost immune function, and assist the liver in detoxification through its various enzymes. Levels of intracellular glutathione decrease with age, lowering the body’s ability to detoxify free radicals and the many important enzymes glutathione makes.

An article in the journal Medical Hypothesis proposed that glutathione, an antioxidant essential for lymphocyte function, may be depleted in Chronic Fatigue Syndrome patients. Glutathione is needed for both the immune system and for aerobic muscular contraction. The authors proposed that glutathione depletion by an activated immune system also causes the muscular fatigue and myalgia associated with Chronic Fatigue Syndrome.

Cysteine is a precursor to glutathione. It has been hypothesized that glutathione and cysteine metabolism may play a role in skeletal muscle wasting and muscle fatigue. The combination of abnormally low plasma cysteine and glutathione levels, low natural killer (NK) cell activity (with a resulting susceptibility to viral infection), skeletal muscle wasting or muscle fatigue, and increased rates of urea production define a complex of abnormalities that is tentatively called “low CG syndrome.” These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn’s disease, ulcerative colitis, Chronic Fatigue Syndrome, and to some extent in overtrained athletes.


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