Chronic Fatigue Syndrome: Oxidative Stress and Dietary Modifications

Chronic Fatigue Syndrome:
Oxidative Stress and Dietary Modifications

This section is compiled by Frank M. Painter, D.C.
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FROM:   Alternative Medicine Review 2001 (Oct); 6 (5): 450459 ~ FULL TEXT

Alan C. Logan, ND, Cathy Wong, ND (Cand.)


Chronic fatigue syndrome (CFS) is a relatively common disorder, particularly in women, affecting 522 women and 291 men per 100,000. [1] In addition to the characteristic persistent fatigue, CFS patients often complain of a number of symptoms including headache, joint pain, gastrointestinal (GI) disturbance, cognitive dysfunction, visual disturbance, and paresthesia. [2, 3]

Pathological changes have been observed in CFS patients, including white matter lesions in the CNS [46] and cerebral hypoperfusion. [79] Other findings that suggest CNS involvement include vestibular dysfunction [10, 11] and gait abnormalities. [12, 13] Immune response also appears to be impaired; specifically, elevated levels of interferon alpha, transforming growth factor beta, interleukin-4, interleukin-6, interleukin-1 alpha, and tumor necrosis factor alpha (TNF-a) have been observed. [1419]

The purpose of this paper is to integrate various branches of current research in an effort to highlight the importance of antioxidant capacity and food intolerance in CFS. First, recent studies will be reviewed that indicate oxidative stress is involved in the pathogenesis of CFS. This suggests antioxidants may be beneficial in the management of CFS. Glutathione (GSH), N-acetylcysteine (NAC), a-lipoic acid, oligomeric proanthocyanidins (OPCs), Ginkgo biloba, and Vaccinium myrtillus (bilberry) would therefore be dietary supplements with potential therapeutic benefit. Second, the literature will be reviewed that suggests food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction.

Although food intolerance can be an important consideration in the presentation of this heterogeneous disorder, evidence also suggests celiac disease should be included in the differential diagnosis of CFS. Celiac disease may present primarily with neurological symptoms in the absence of gastrointestinal symptoms.

Current Research on Oxidative Stress in CFS

The role of oxidative stress in CFS is an emerging focus of research. Although it is uncertain whether oxidative stress is a cause or a result of this illness, recent studies have demonstrated that oxidative stress contributes to the pathology and clinical symptoms of CFS. Theoretically, oxidative stress can be caused by an increase in the generation of reactive oxygen species, of which mitochondrial dysfunction is believed to be a main source, or it can be caused by a decline in the efficiency of antioxidant enzyme systems. [20] Recent studies have examined both of these possibilities by looking for markers of oxidative stress and protective antioxidant systems.

Fulle et al observed evidence of oxidative damage to the DNA and lipids of biopsy samples from the vastus lateralis muscles of CFS patients. [20] In addition, they found an increase in the activity of antioxidant enzyme systems, including glutathione peroxidase, an increase they suggest is a compensatory measure in response to oxidative stress. The researchers noted a similarity between increased oxidative damage in CFS patients and age-related changes in healthy individuals, concluding that antioxidants have therapeutic potential to reduce oxidative damage.

Pall suggests the level of the oxidant peroxynitrite is important in CFS patients. [21] He contends elevated peroxynitrite causes mitochondrial dysfunction, lipid peroxidation, and, by way of positive feedback, elevated cytokine levels. The cytokines, in turn, cause the formation of nitric oxide that combines with superoxide to form the potent oxidant peroxynitrite, thus continuing the cycle. Peroxynitrite targets the mitochondria and Pall notes this may help explain mitochondrial dysfunction in CFS. As support for the peroxynitrite theory, Pall cites evidence that the mitochondrial enzymes succinic dehydrogenase and cis-aconitase are inactivated by peroxynitrite. [22, 23] This makes for an interesting finding because decreased succinic dehydrogenase activity has been found in CFS patients [24, 25] and urine levels of the intermediates metabolized by these enzymes have been found to be elevated in CFS patients. [26, 27] Pall proposes a number of nutritional and botanical interventions that may reduce peroxynitrite and cytokine levels; among them, the soy isoflavone genistein, epigallocatechin-3-gallate from green tea, and vitamins C and E.

Keenoy et al found impaired antioxidant capacity in a sample of CFS patients with "subclinical" or moderate magnesium deficiency. [28] The impaired capacity involved both the total antioxidative capacity of plasma, as measured by Trolox Equivalents Antioxidant Capacity (TEAC), and the antioxidant component dependent on albumin. While no improvement was observed in these parameters after oral or intravenous magnesium supplementation, some patients demonstrated increased serum vitamin E and an associated decrease in lipid peroxidation. This finding, according to the authors, is likely due to the sparing effect of magnesium on vitamin E by preventing its in vivo oxidation. In addition, the researchers postulated that an elevated concentration of inflammatory cytokines might indirectly cause diminished antioxidant capacity by inhibiting albumin transcription in the liver.

A subset of patients whose magnesium body stores did not improve after supplementation also had lower blood glutathione levels, suggesting a relationship might exist between intractable magnesium deficiency and low glutathione. [28] Interestingly, RBC magnesium levels have previously been reported to be decreased in CFS patients, some of whom had adequate dietary intake of magnesium. [29]

Some of these same researchers further examined the role of oxidative stress in CFS. They found an increased susceptibility of LDL and VLDL to copper-induced peroxidation in CFS patients. [30] They conclude this might indicate the impaired lipoprotein antioxidant capacity in CFS, causing accelerated lipid peroxidation.

Richards et al found CFS patients had elevated levels of methemoglobin (MetHb), a marker of oxidative stress. [31] Formation of MetHb, a product of iron oxidation, is regulated by NADH-MetHb reductase. Consequently, levels of MetHb may increase when there is an alteration in this reducing system within the erythrocyte. The researchers reported the increase in MetHb correlates with the presence and severity of several CFS symptoms, including photophobia, irritability, and GI complaints. MetHb also requires glutathione and cysteine to be reduced in normal cells. It is interesting to note that both glutathione [28] and cysteine [32] levels have been found in decreased levels in CFS patients.

Additional evidence supporting the role of free radical damage in CFS patients and the efficacy of antioxidant treatment comes from a recent study. [33] In a three-month, double-blind, placebo-controlled crossover study, 22 CFS patients were given a Swedish pollen extract high in antioxidant polyphenols. Statistically significant improvement was observed in the treatment group, notably in fatigue, sleep disturbance, GI complaints, and hypersensitivity. In addition, there was a highly significant improvement in erythrocyte fragility, a marker of oxidative damage. The researcher acknowledged the synergistic effect of antioxidants, as in the Swedish pollen extract, and suggests future research using antioxidant combinations.

Implications for Antioxidant Treatment

The above findings on oxidative stress suggest that supplementing with certain antioxidants, in addition to vitamins C and E, may be valuable in a CFS treatment protocol (Table 1). A number of supplements should be considered for potential therapeutic intervention, including selenium (necessary to support glutathione peroxidase activity), [34] GSH, NAC, and a-lipoic acid. Although there is conflicting evidence, a number of studies have shown oral administration of GSH can directly increase plasma and tissue GSH concentration. [3537] Alternately, NAC and a-lipoic acid can increase GSH concentration indirectly; [38,39] NAC provides cysteine for GSH synthesis, and a-lipoic acid is believed to increase intracellular GSH levels by reducing extracellular cystine to cysteine, bypassing the cystine transporter. [40] GSH is neuroprotective and may play a role in preventing additional CNS lesions. [41] a-Lipoic acid is also neuroprotective, scavenges nitric oxide and peroxynitrite, and may be especially promising as an antioxidant against mitochondrial dysfunction.40 The supplement coenzyme Q10 has similar neuroprotective qualities and has the ability to improve mitochondrial function. [42]

The botanical antioxidants OPCs and Ginkgo biloba should also be considered. Bagchi et al found that OPCs are highly bioavailable and provide significantly greater protection against free radical damage than beta carotene and vitamins C and E. [43] These authors also reported the ability of OPCs to provide protection from radical-induced lipid peroxidation and DNA damage, which is of particular importance to CFS patients.

Ginkgo biloba is a powerful antioxidant, [44] demonstrating strong neuroprotective properties in animals. It has been shown to reduce mitochondrial reactive oxygen species, in particular peroxynitrite. [45] The capacity of Ginkgo to increase cerebral blood flow [46] and improve memory and cognition associated with cerebral insufficiency [47] suggests it may be useful for CFS symptoms related to hypoperfusion.

Plant-based antioxidant support should be maximized through dietary intake. Cao et al found that a diet high in fruits and vegetables can increase plasma antioxidant capacity in humans, as measured by oxygen radical absorbance capacity (ORAC) assay. [48] Blueberries have the highest ORAC scores among thirty fruits and vegetables tested, [49,50] and may be of significant benefit due to their high potential antioxidant activity, [51] neuroprotective properties, [52] and specific ability to protect red blood cells from in vivo oxidative damage. [53] Of the blueberry species, Vaccinium myrtillus has the highest combined anthocyanidin, phenol, and ORAC scores. [51]

In a recent double-blind, placebo-controlled, crossover study, administration of pure anthocyanidins (80 mg daily) showed a small but statistically significant benefit in a group of patients with the related disorder of fibromyalgia. [54] The trial was three months in duration for active treatment and involved an anthocyanidin combination derived from grape seed, bilberry, and cranberry. Improvements were observed in sleep quality and fatigue. Based on these findings a similar trial is warranted in CFS patients.

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