Chronic Fatigue Syndrome

Chronic Fatigue Syndrome

The information listed below is on a slightly more technical level, those who suffer from CFS will gain very inportant information from the below. For help with your specific concerns, please contact Kirsten Taylor at the New Zealand Health Shop on (09) 378-0444 or email: kirsten@nzhealthshop.co.nz

Chronic fatigue syndrome (CFS) is defined as debilitating fatigue with associated symptoms lasting for at least 6 months. CFS primarily affects women ages 25-45. In the United States alone, as many as 800,000 people may be affected by CFS. Although there are no FDA-approved treatments for CFS, through the management and treatment of symptoms, the prognosis for patients is usually good.

Even though the CFS was officially recognized CFS in 1988, it remains a controversial issue. Some physicians believe the illness to be psychosomatic, although others remain open-minded. Fortunately, most physicians are determined to help their patients who experience the debilitating symptoms of this illness.

Some experts believe CFS to be closely related to another chronic condition, fibromyalgia (FMS). For many individuals whose chronic fatigue does not significantly improve after a 5-year duration, the most prominent symptom changes from fatigue to muscle pain. This muscle pain is the prominent symptom of fibromyalgia.

DIAGNOSTIC CRITERIA

The criteria for diagnosing CFS were officially defined by the  Council for Diagnostic Criteria (CDC) in 1988 and revised in 2001 (CDC 2001). The Oxford criteria differ slightly. The British criteria insist upon the presence of mental fatigue, although the American criteria include a requirement for several physical symptoms, reflecting the belief that CFS has an underlying immune or infectious pathology (Fauci et al. 1998; Reid et al. 2000).

Centers for Disease Control's Criteria for Chronic Fatigue Syndrome
Clinically evaluated, unexplained, persistent, or relapsing fatigue that is

• Of new or definite onset
• Not a result of ongoing exertion
• Not alleviated by rest
• Results in a substantial reduction in previous levels of occupational, social, or personal activity

Four or more of the following symptoms that persist or recur during 6 or more consecutive months of illness and that do not predate the fatigue.

• Self-reported impairment of short-term memory or concentration
• Sore throat
• Tender lymph nodes
• Muscle pain
• Multijoint pain without swelling or redness
• Headaches of a new type, pattern, or severity
• Unrefreshing and/or interrupted sleep
• Postexertion malaise (a feeling of general discomfort or uneasiness) lasting more than 24 hours

Exclusion criteria.

• Active, unresolved or suspected disease that is likely to cause fatigue
• Psychotic, melancholic, or bipolar depression (but not uncomplicated major depression)
• Psychotic disorders
• Dementia
• Anorexia or bulimia nervosa
• Alcohol or other substance misuse
• Severe obesity

Additional Symptoms
Although the symptoms heretofore listed are the official diagnostic criteria, many patients with CFS present a variety of other symptoms, including:

• Pain (almost universal in chronic fatigue)
• Allergies
• Chemical sensitivities
• Secondary infections, including Candida and viral infections
• Cognitive impairment, including short-term memory loss, difficulty concentrating and doing word searches and math problems
• Digestive disturbances, such as chronic constipation or diarrhea
• Night sweats or spontaneous daytime sweats, unaccompanied by fever
• Headaches, migraines
• Weakness (paresis), muscle fatigue, and pain (fibromyalgia)
• Premenstrual syndrome (PMS)
• Sleep disorders, including excessive sleep (hypersomnia), light sleep, or an inability to sleep for more than an hour (hyposomnia), disturbing nightmares
• A period of 1-3 hours after awakening during which patients are too exhausted to get out of bed (dysania)
• Cystitis (inflammation of the urinary bladder), particularly interstitial cystitis in which urine cultures are negative
• Vision and eye problems, including sensitivity to light (photophobia), dry eyes, tunnel vision, night blindness, and difficulty focusing

An initial office examination may also find the following signs:

• Low blood pressure, particularly on standing (orthostatic hypotension)
• Low oral temperatures (less than 97°F)
• Slightly elevated oral temperatures (but less than 100°F) which are part of persistent flulike symptoms
• Increased heart rate (tachycardia)
• A positive Romberg test (unsteadiness when standing with eyes closed)

Novel and Conventional Laboratory Tests
Doctors usually perform the following laboratory tests, when attempting to diagnose a patient with CFS:

• Complete blood count (CBC) with differential
• Chem 20 panel
• Erythrocyte sedimentation rate (ESR), a marker of inflammation
• Urinalysis

Optional tests include:

• Antinuclear antibodies (ANA) and rheumatoid factor (RF). (These are tests for rheumatoid arthritis and SLE, systemic lupus erythematous.)
• Thyroid tests (T3, T4, TSH)
• Adrenal tests (a.m. and p.m. cortisol levels)
• Lyme titers and HIV serology

Specific tests that support (but do not necessarily confirm) a diagnosis of chronic fatigue include (Verillo et al. 1997):

• Tests for viral infections, such as cytomegalovirus, Epstein-Barr virus, human herpes virus 6, and coxsackievirus
• Immune system tests, including low natural killer (NK) cell counts, elevated interferon alpha, tumor necrosis-alpha, interleukins 1 and 2, T-cell activation, altered T4/T8 cell ratios, low T-cell suppressor cell (T8) count, fluctuating B- and T-cell counts, antinuclear antibodies, immunoglobin deficiency, antithyroid antibodies
• Exercise testing may show decreased cortisol levels after exercise, decreased cerebral blood flow after exercise, inefficient glucose utilization, and erratic breathing patterns

POSSIBLE CAUSES

The causes of CFS 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 CFS 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 CFS patients were found to have low levels of PBMC beta-endorphin and other neurotransmitters. Thyroid deficiency may also be a contributing factor in CFS.

Virus and CFS
Symptoms of CFS resemble a postviral state and for this reason chronic viral conditions have been thought to contribute to CFS in some patients. Several viruses have been associated with CFS, including (Manian 1994):

• 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

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

• T-helper 1 cells (Th1) target intracellular pathogens (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.

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

For more information about Dr. Cheney's work, see www.sonic.net/cnds .

Infection and Inflammation
A theory was published by Dr. Martin L. Pall, a professor of biochemistry and basic medical sciences at Washington State University, in 2001. The theory starts with the observation that infections that precede and may therefore induce CFS 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 CFS, and it is this cycle, therefore, that must be interrupted to effectively treat this condition (Pall 2001a).

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).

Role of the Endocrine System
Reduced Cortisol Levels
The HPA axis refers to the hypothalamus, pituitary, and adrenal glands, which are part of the endocrine system. The hypothalamus secretes several hormones that control the pituitary gland. The pituitary gland is considered the "master gland" of the endocrine system because it secretes hormones that control other glands (including the ovaries, testes, adrenals, and thyroid glands).

Researchers are exploring the relationship between cortisol and central neurotransmitter function, in particular, the relationship between cortisol and 5-HT (serotonin).

A review of the CFS database at King's College (London) found that one-third of the studies that reported baseline cortisol found it to be significantly low, usually in a third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function and enhanced serotonin (5-HT) function on neuroendocrine challenge tests (Parker et al. 2001).

An article in the Journal of Affective Disorders described a study in which cortisol levels were measured in 10 patients with CFS, 15 patients with major depression, and 25 healthy controls. Baseline circulating cortisol levels were highest in the depressed patients; lowest in the CFS patients; and intermediate between the two in the control group of 25 healthy individuals. Prolactin responses to the selective serotonin-releasing agent d-fenfluramine were lowest in the depressed patients, highest in the CFS patients, and intermediate between both in the healthy group. The authors concluded that depression is associated with hypercortisolemia and reduced central serotonin neurotransmission and suggest that CFS may be associated with hypocortisolemia and increased 5-HT function (Cleare et al. 1995).

Addison's disease results from hyposecretion of cortisol and is characterized by weakness, fatigue, and dizziness upon standing. As described below, CFS may be a mild form of Addison's disease. Blood tests can determine serum cortisol levels. Blood must be drawn in the morning and afternoon because cortisol levels are higher during the day and lower at night. Total normal cortisol levels (morning and evening) in adults are:

• 8 a.m.: 5-23 mcg/dL (138-635 nmol/L)
• 4 p.m.: 3-16 mcg/dL (83-441 nmol/L)
• 8 p.m.: less than 50% of 8 a.m. levels

Adrenal Fatigue
As noted, it has been proposed that CFS is a mild form of Addison's disease (referred to as adrenal insufficiency or hypoadrenalism). The following evidence has been presented (Jefferies 1994; Baschetti 1999; Jeffcoate 1999; Baschetti 2000):

• Many of the symptoms of CFS overlap those of Addison's disease (adrenal failure).
• Improvement in CFS patients has occurred after supplementation with mineralocorticoids (fludrocortisone), low-dose hydrocortisone (cortisol), and licorice (an old herbal remedy for Addison's disease).

Multiple Chemical Sensitivity
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 (Cullen 1987a; 1987b).

Metal Sensitivity
The effect of dental metal (amalgam) removal was studied in 111 patients with metal hypersensitivity and symptoms resembling CFS. 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 CFS 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.

Oxidative Stress
Studies have shown that oxidative stress plays a role in the development of CFS (Fulle et al. 2000; Richards et al. 2000; Logan et al. 2001). 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 CFS can be found in the literature. An article in the journal Life Science described a study that showed that patients with CFS had lower serum transferrin levels and higher lipoprotein peroxidation. These results indicate that patients with CFS 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 CFS (Manuel y Keenoy et al. 2001).

A study of the oxygen delivery to muscles in patients with CFS found that oxygen delivery and oxidative metabolism was significantly reduced in CFS patients after exercise (compared with sedentary controls) (McCully et al. 1999).

Possible Related Side Effects of CFS
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 CFS have chronic low blood pressure (the normal is 120/80 mmHg), which is made even worse on standing.

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

A study of 12 women who fulfilled the criteria for both fibromyalgia and CFS 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 (Regland et al. 1997).

Glutathione Deficiency
Glutathione is a tripeptide made up of three amino acids: glycine, cysteine, and gamma-glutamic acid.

An article in the journal Medical Hypothesis proposed that glutathione, an antioxidant essential for lymphocyte function, may be depleted in CFS 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 CFS (Bounous et al. 1999).

NATURAL THERAPIES

A report in the Annual Review of Medicine stated that CFS "is an illness characterized by activation of the immune system, various abnormalities of several hypothalamic-pituitary axes, and reactivation of certain infectious agents" (Komaroff et al. 1998). This suggests that an individual with CFS should follow a regimen that involves protecting and enhancing the immune system with proper nutritional supplements, proteins, and hormones. Free radicals play a role in causing damage to the immune system.

A comprehensive approach to CFS would address several key areas, based on the results of laboratory tests, including:

• Immune support (antiviral): ginseng, echinacea, essential fatty acids
• Supplements involved in energy metabolism: CoQ10, NADH, L-carnitine, and magnesium
• Adrenal support: DHEA, licorice, and sodium
• Stress: glutamine and Adapton
• Brain hormones and neurotransmitters: tyrosine
• Homocysteine metabolism: B6, B12, folic acid, and SAMe
• Antioxidants: glutathione, N-acetyl-cysteine, and alpha-lipoic acid
• Fatigue: ginseng and Maté
• Digestive support: digestive enzymes

Ginseng and Echinacea
Commission E, the group of scientists that advises the German government about herbs, endorses ginseng "as a tonic to combat feelings of lassitude and debility, lack of energy and ability to concentrate, and during convalescence" (Bahrke et al. 2000).

Ginseng is highly prized in China as an herb that increases energy. The higher grades are extremely expensive.

Echinacea has become very popular in the United States as "the herb" to take for colds and flus. It is known for its ability to stimulate the immune system and suppress infection-causing microbes.

Essential Fatty Acids
The use of essential fatty acids in CFS is controversial. It has been proposed that essential fatty acids play a role in CFS. One possible mechanism is that viruses, as part of their attack strategy, may reduce the ability of the cells to make 6-desaturated essential fatty acids (Horrobin 1990; Gray et al. 1994).

The use of essential fatty acids for postviral fatigue syndrome was examined in a double-blind, placebo-controlled study of 63 adults (Behan et al. 1990). The patients had been ill for 1-3 years after an apparent viral infection and had severe fatigue, myalgia, and a variety of psychiatric symptoms. The patients received either placebo or a preparation containing linoleic, gamma-linolenic, eicosapentaenoic, and docosahexaenoic acids (8 500-mg capsules daily) over a 3-month period. Participants were asked to assess their improvement at months 1 and 3. The treatment group showed continual improvement, whereas many in the placebo group reverted toward baseline.

The essential fatty acid composition of the subjects' red cell membrane phospholipids was analyzed at the first and last visits. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. The authors concluded that essential fatty acids provide a rational, safe, and effective treatment for patients with postviral fatigue syndrome (Behan et al. 1990).

Coenzyme Q10
Coenzyme Q10 has long been prescribed for CFS patients. CoQ10 is a potent antioxidant that aids in metabolic reactions including the process of forming ATP, the molecule the body uses for energy. Virtually every cell in the body contains CoQ10. It is concentrated in the mitochondria, the area of the cells where energy is produced.

Judy (1996) presented a study of 20 female patients with CFS who required bed rest following mild exercise and 20 healthy controls: 80% of the CFS patients were found to be deficient in CoQ10, which further decreased following mild exercise or over the course of normal daytime activity. After 3 months of CoQ10 supplementation (100 mg/day), the exercise tolerance (400 kg-meters of work) of the CFS patients more than doubled. All patients had improved: 90% had reduction and/or disappearance of clinical symptoms, and 85% had decreased postexercise fatigue (Judy 1996).

NADH
NADH (reduced B-nicotanimide dinucleotide) is a coenzyme molecule formed from vitamin B3 (niacin). NADH (along with CoQ10) is essential for the production of energy (ATP) in a process called oxidative phosphorylation.

A randomized, double-blind, placebo-controlled crossover study examined the use of NADH in CFS: 26 eligible patients diagnosed with CFS received either 10 mg of NADH or placebo for a 4-week period. Eight of 26 (31%) responded favorably to NADH in contrast to two of 26 (8%) to placebo. Based upon these encouraging results, the authors decided to conduct a larger study to establish the efficacy of NADH in CFS (Forsyth et al. 1999).

NADH (5-10 mg/day) is most effective when taken in the morning, 30 minutes before breakfast.

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