CARLSBAD, CA—Chronic fatigue syndrome (CFS), one of the most vexing conditions for patients and doctors alike, reflects a state of oxygen toxicity. Management of oxidative stress appears to be a key to reversing the fatigue, pain, and neuropsychological complaints associated with this disorder, according to Paul R. Cheney, MD, PhD, a pioneer in the clinical research of CFS.

Dr. Cheney, director of the Cheney Clinic, Asheville, NC, began studying the condition now called CFS in 1985. Since then, he has published more than 30 articles in peer-reviewed journals. He contends that oxygen toxicity, while not a “cause” of CFS, is a final common pathologic pathway, one that to a large extent determines patient outcomes. He discussed his nearly 25 years of research leading to the oxidation toxicity hypothesis at the 15th International Symposium on Functional Medicine, presented by the Institute for Functional Medicine (IFM).

The hypothesis has its roots in the observation that people with CFS have a distinctive pattern of low oxygen utilization. At peak activity levels, people with this syndrome show markedly reduced oxygen uptake compared with non-CFS control subjects (De Becker P, et al. Arch Intern Med. 2000; 160: 3270–3277).

Dr. Cheney found that his own patients with CFS had a much higher incidence of diastolic dysfunction (Cheney PR, Lucki NC. Presented at International Association for Chronic Fatigue Syndrome (IACFS) meeting, Jan. 2007), which is highly suggestive of an underlying myocardial energy deficit (Morgan JP. N Engl J Med. 1991; 325: 625–632). In addition, diastolic dysfunction is known to lower cardiac output, which is also common in CFS patients and may be related to their post-exertional fatigue (Peckerman A, et al. Am J Med Sci. 2003; 326: 55–60). Dr. Cheney set out to determine how this constellation of factors figures into the symptoms of CFS patients.

Cardiomyopathy and CFS

A major development in his thinking was the Everest III study, in which healthy subjects were put in a hypobaric oxygen chamber for 3 months, mimicking a climb to the top of Mt. Everest. Echocardiography showed that the resulting oxygen-deficient state caused significant diastolic dysfunction, including decreased stroke volume and increased isovolumetric relaxation time (IVRT), an indicator of free energy (Boussuges A. Am J Respir Crit Care Med. 2000; 161: 264–270).

Interestingly, these findings were very similar to what Dr. Cheney saw in his CFS patients. But when the Everest III subjects went back to normal atmospheric conditions, the diastolic dysfunction normalized. Dr. Cheney wondered if it would be possible to normalize diastolic dysfunction in CFS patients by giving them oxygen. His findings were surprising.

He administered oxygen to both CFS patients and controls, and found that the relative cardiac cellular energetic response was significantly different in CFS. Instead of getting better on oxygen, CFS patients got worse. This suggests that CFS patients do not have a heart problem, per se, but rather an oxygen utilization problem that manifests as diastolic dysfunction.

In this context, the definition of toxicity is not a clinical one; the patients did not necessarily feel sick when receiving oxygen, but the free energy of the system shifts in a negative direction. Dr. Cheney used the example of blowing on a fire: Normally, this makes the fire brighter, but in CFS, increased oxygen makes the fire smaller. Sometimes the fire even goes out.

CFS and Fetal Physiology

A key finding from Everest III was that high-altitude, low-oxygen states cause left atrial cavitation, another common finding in Dr. Cheney’s CFS patients. When an oxygen deficit creates an energy deficit and thus diastolic dysfunction, the heart compensates by squeezing the left ventricle more vigorously. If the ventricle squeezes hard enough, it rebounds and sucks blood out of the left atrium, collapsing the atrial cavity.

Dr. Cheney hypothesized that in some cases, the resulting pressure differential in the heart may be enough to blow a hole where there used to be one—the prenatal patent foramen ovale (PFO). Using saline bubble tests, Dr. Cheney found PFOs in a shocking 90% of his CFS patients (Cheney PR, Lucki NC. Presented at IACFS meeting, Jan. 2007).

According to Dr. Cheney, the cardiac physiology of CFS is related to that of the fetus in utero, which has a PFO and is highly susceptible to oxygen toxicity. The oxygen tension in the womb means that the fetus develops in an environment effectively mimicking an altitude of 29,000 feet. As a result fetal hemoglobin binds oxygen significantly more tightly than adult hemoglobin does. Dr. Cheney explained that fetuses must be protected from oxygen because they have not yet begun producing glutathione peroxidase, catalase, and superoxide dismutase, and other enzymes that provide protection from damaging oxygen metabolites.

CFS patients, like fetuses, bind oxygen more tightly than non-CFS adults, and probably for the same reason—they cannot handle oxygen correctly because they do not have adequate defense against oxidative stress. The excess oxygen metabolites damage the red cell membrane, as evidenced in a recent study showing that people with CFS have rigid red blood cells caused by membrane lipid peroxidation (Richards et al. Arch Med Res. 2007; 38: 94–98). This results in even less oxygen to be delivered to the tissues, creating a devastating feedback loop.

CFS Symptoms as Compensatory Mechanisms

Dr. Cheney explained that his thinking on this CFS is centered on an adaptation model rather than a disease model. He believes CFS symptoms reflect the way a patient’s physiology compensates for oxygen toxicity. The specific adaptation mechanisms at work in a given patient will determine how the disorder manifests. For example:

• Microcirculatory Left Shift: Oxidative stress causes red cell membranes to become rigid, preventing oxygen delivery to the tissues, and resulting in small vessel disease, a common finding in CFS patients. Oxidative stress also damages the mitochondria, which may shut down in order to prevent even further stress. The result is reduced ATP, ADP, and AMP—in other words, an energy deficit—and a feedback mechanism that further lowers oxygen transfer.
• HPA Axis Abnormalities: Normal activity of the Hypothalamic-Pituitary-Adrenal axis serves to protect against oxidative stress, but in CFS, the axis function is in a reversed mode. When CFS patients are stressed, they collapse (the “push-crash” phenomenon), and when this happens, the HPA axis can no longer protect against the effects of oxygen metabolites.
• Methylation Block: Methylation pathways normally conserve methionine to make S-adenosyl-methionine (SAMe), which is important in the regulation of neurotransmitters and in gene expression (through methylation of the histone molecules). However, in oxidative stress, SAMe is rapidly oxidized to increase production of cysteine, the rate-limiting step for glutathione production. This defense mechanism burns SAMe, affecting both cognitive function and sleep.
• P450 Buffering: Free radical production by the P450 enzyme system is a strong inducer of defense mechanisms against these very free radicals. But if these mechanisms are down, any kind of xenobiotic induction of the system will produce environmental illness.

While CFS is still a disorder of unknown cause, Dr. Cheney’s findings appear to narrow the range of potential causes: Whatever pathophysiology is put forth must explain the oxidative stress and resultant oxygen toxicity in these patients.

Though there are several different case definitions of CFS, the symptoms that Dr. Cheney sees most often in his clinic are a triad of energy disturbance, brain problems such as cognitive and mood disturbances, and pain. Interestingly, however, 5% of his CFS patients do not have pain, which means they do not meet the CDC case definition though Dr. Cheney believes they have CFS.

CFS often evolves from symptom dysfunction to dynamic dysfunction. The illness starts out with a heavy symptom burden, but over time, symptoms lessen as patients reduce the scope of their lives, often becoming homebound. As the condition progresses, patients complain less about symptoms and more about the problem of not being able to do anything.

New Directions in Treatment

An emerging treatment for CFS makes use of low-molecular-weight peptides from cell-associated, mammalian tissue homogenates. Dr. Cheney proposes that these factors signal cells to increase production of superoxide dismutase and glutathione peroxidase (from heart) and catalase (from liver). This would strengthen a CFS patient’s defense mechanisms against oxidative stress, thus lessening oxygen toxicity. He presented the results of his research, showing a significant improvement in daily function of CFS patients following the use of bison and porcine cell-signaling factors delivered transdermally.

Dr. Cheney has also used extracts of Hawthorne (Crataegus oxycantha), a botanical with a known ability to induce both superoxide dismutase, and human growth hormone, which he has found effective in low doses (0.2 mg, subcutaneously, once weekly).

Because more than 95% of patients diagnosed with CFS present with pain, Dr. Cheney’s presentation served as an elegant lead-in to IFM’s 15th Symposium, entitled, “The Many Faces of Pain: Functional Models for Assessment and Treatment.” Recordings of Dr. Cheney’s talk, as well as all 28 presentations given during the 15th Symposium can be purchased at IFM’s booth during the American Academy of Family Practice Scientific Assembly in San Diego (Booth #4930) or from the IFM website, www.functionalmedicine.org.