Chapter 4
The Question of a Cause

As researchers look for a disease's cause, one of the first questions they need to answer is whether the disease is contagious, and if so, how it is being spread. For example, epidemiologists will try to determine if the disease can be passed through casual contact or through the exchange of bodily fluids. Since over the years chronic fatigue syndrome (CFS) has appeared to strike clusters of people, there was a strong fear at one point that the disease was contagious. But on closer examination, evidence so far does not support this theory, since many spouses and family members of CFS patients remain healthy, as do others who come into contact with these patients. Instead, some experts suggest that the people infected in these outbreaks were all exposed to a common causative agent, an agent that has yet to be identified.

A Virus?

There are plenty of theories regarding possible causes of CFS. One of the earliest and most widely supported theories holds that CFS is caused by a virus. Viruses are so tiny that they are invisible even under all but the most powerful microscopes, so the most common way to detect them is to test for antibodies that the body develops in response to a viral infection. However, a positive test for a particular antibody does not mean someone has an active infection. A person will test positive for these antibodies after only having been exposed to a virus. Therefore, a positive test for a virus does not necessarily prove that this organism is causing whatever symptoms a patient is showing.

In the case of CFS, Epstein-Barr virus is an excellent example of the difficulty of establishing a causal relationship. It is estimated that nearly every person who reaches adulthood is exposed to Epstein-Barr at some point and will develop the corresponding antibodies. This is why Drs. Daniel Peterson's and Paul Cheney's findings that the majority of their patients in Incline Village had high levels of antibodies to the Epstein-Barr virus were not viewed as meaningful by the Centers for Disease Control and Prevention. In the opinion of many experts, any group of adults could have tested positive for Epstein-Barr, regardless of their state of health.

In fact, even though much of the early focus was on the Epstein-Barr virus as a possible cause of CFS, researchers have considered other viruses as suspects as well. Elevated levels of antibodies for cytomegalovirus, human herpesvirus 6, herpes simplex, rubella, and Coxsackie have all been found in the blood of many CFS patients. And some experts continue to suspect that a different form of the polio virus causes CFS. Still others wonder if CFS will turn out to be caused by an as-yet unidentified virus.

There is also a possibility that a long-dormant virus is somehow reactivated to cause the symptoms of CFS. Of course, if a long-dormant virus suddenly comes to life, the question is: What is causing the renewed activity of the virus in the system?

One expert, Katrina Berne, suggests that this renewed activity could be the result of an impaired immune system that can in turn have a number of causes:

Nonviral triggering factors that interfere with immune functioning may allow viruses to move from dormant to active states so that viral activation is an effect, rather than a cause, of illness. The cause may turn out to be a newly discovered virus, a more virulent strain of a known virus, a recombinant virus, a faulty immune system reacting inappropriately to a "normal" virus, all of the above—or none of the above.³⁵

As Berne's comment suggests, exactly what role viruses play in the cause of CFS remains obscure. But some experts interpret the fact that CFS patients often test positive for numerous viruses as suggesting that a separate factor is leaving the body vulnerable to these viruses, most likely a problem with the body's immune system.

Immune Dysfunction

Strong evidence exists that a malfunction of the immune system plays a large part in this illness, though once again researchers have not been able to pinpoint the reasons for and nature of the malfunction. In fact, scientists have actually seen two opposite problems at once: both an over- and underactivity of the immune system of a CFS patient. Dr. David S. Bell notes that the apparent abnormality of the immune response is what prompts some experts to use the phrase "chronic fatigue immune dysfunction syndrome" as an alternate and preferred name for this disorder.

Some studies have in fact shown lower levels of the immune system's disease-fighting cells, known as natural killer cells, in patients with CFS. However, researchers can only speculate as to what causes the immune system to weaken. Some scientists have explored the possibility that one of a special class of viruses—a retrovirus—is the culprit, but so far they have been unable to find strong evidence to support this theory.

Another theory regarding the cause of the immune suppression in CFS patients is an overgrowth of yeast in the body, a condition called systemic candidiasis. This is one of the more controversial theories, accepted as possible by practitioners of alternative medicine but given little credence by the mainstream medical community. Dr. Jacob Teitelbaum in his book From Fatigued to Fantastic!, a treatment manual for patients, explains the theory: "Yeast are normal members of the body's 'zoo.' They live in balance with bacteria—some of which are helpful and healthy, and some of which are detrimental and unhealthy. The problems begin when this harmonious balance shifts and the yeast begin to overgrow."³⁶ Teitelbaum explains that this yeast overgrowth can be caused by various factors, the most common being frequent antibiotic use. Antibiotics kill both good and bad bacteria in the body, he says. Teitelbaum goes on to argue that many doctors believe yeast overgrowth can cause suppression of the immune system.

The more widely accepted view, however, is that the over-growth of yeast is an effect, not a cause, of immune dysfunction. Bell argues that "the presence of candidiasis is a sign of poor immune functioning, not just infection with yeast."³⁷ Still other experts prefer to withhold judgment. Berne, for example, says that "yeast overgrowth may be a causal contributor or a secondary effect of the illness, or both may be attributable to immune dys-function."³⁸

A related problem that Teitelbaum and practitioners of alternative medicine point to is bowel parasites, which they say can also suppress the immune system. Burton Goldberg, author of Alternative Medicine Guide to Chronic Fatigue, Fibromyalgia and Environmental Illness, notes that both candidiasis and bowel parasites are often present in people with CFS.

Even as many researchers focus on immune system suppression, others are looking at the evidence of overactivity in the immune system of CFS patients. An overactive immune system is one that is hyperaware of every seemingly "foreign" presence in the body, launching multiple attacks on perceived invaders. Some researchers suggest that CFS is the result of the immune system's overreaction to an infection of some kind and that the immune system continues its response even when the "invader" has been subdued. In this scenario, the symptoms of CFS would actually be caused by the body's own prolonged defenses against something that is no longer a threat. Along these lines, some experts wonder if CFS is actually what is known as an autoimmune disease, a class of diseases whereby the immune system treats parts of its own body as foreign and so the body attacks itself. The high ratio of adult women to adult men with CFS lends support to this theory, since a similar disparity between genders is found in most autoimmune diseases. Yet once again, the particular mechanism of how this autoimmune malfunction happens eludes detection, leaving the ideas of both immune suppression and immune system overactivity as possible ties to the cause of CFS, but not the definite answer at this point.

Hormones

Just as various abnormalities have been found with the immune systems of people with CFS, many of these patients also display irregularities in a part of the endocrine system known as the hypothalamic-pituitary-adrenal (HPA) axis, irregularities that might even be linked to the immune disturbances. Together, the hypothalamus and the pituitary and adrenal glands are responsible for a host of functions, such as controlling the body's appetite and temperature, helping the body's metabolism run smoothly, and regulating the body's response to any kind of stress. These functions are accomplished through the various hormones secreted by the glands. Erica F. Verrillo and Lauren M. Gellman explain one possible connection between the endocrine and immune systems, stating that "the continued release of stress hormones leads to depression of the immune system, paving the way for opportunistic infections and increasing susceptibility to a host of transmissible diseases."³⁹

There is certainly no question that when the delicate balance of the HPA axis is disturbed, and either too much or too little of the different hormones are released, the system is easily thrown into chaos; a person's ability to sleep, respond to pain, and even think clearly can all be affected. Because CFS patients often display abnormalities in these areas, researchers have investigated whether disturbances of the HPA axis could be behind the symptoms of CFS.

In fact, studies have shown that CFS patients often have numerous abnormal levels of the hormones produced and regulated by the HPA axis. People with CFS, for example, seem to have low levels of growth hormone, which is necessary for maintaining a person's energy and vitality. Patients also tend to have low levels of the related dehydroepiandrosterone hormone, a building block for the sex hormones estrogen and testosterone and also key to a functioning metabolism; low levels of cortisol, which also provides energy and aids in metabolism and coping with stressful situations; and decreased levels of thyroid hormone, which regulates body temperature and energy levels, among other functions. Some researchers have claimed that hypothyroidism itself could be the cause of CFS. According to Goldberg, "A major and often overlooked cause of chronic fatigue syndrome is … hypothyroidism. Although, according to practitioners of conventional medicine, hypothyroidism is a separate illness from CFS and a diagnosis of one precludes a diagnosis of the other, many people with CFS have not been properly tested for thyroid problems."⁴⁰ Goldberg maintains that hypothyroidism could easily be responsible by itself for many CFS symptoms, including low energy levels, mental sluggishness, memory disturbances, skin problems, and a lower tolerance for pain.

Other researchers attach special significance to the lower levels of cortisol found often in CFS patients. Cortisol, a hormone secreted by the adrenal glands, is responsible for providing energy and mental alertness. Levels of cortisol typically remain at relatively steady levels in healthy individuals, rising slightly higher in the morning hours and dropping at night. These levels rise dramatically, however, in response to physical or emotional stress, and with the dramatic rise comes a surge of energy. This process is called the "fight-or-flight" response, because its biological purpose is to help prepare someone to either deal with or flee immediate, life-threatening danger. However, the modern world is full of non-life-threatening stress that can trigger this response. Some researchers claim to have found that people with CFS tend to overreact to these more minor stimuli, with their bodies producing abnormally high levels of cortisol in response. In turn, the researchers speculate, this leads to depleted levels of cortisol on a daily basis when normal levels of the hormone are needed for energy because the adrenal glands become exhausted from repeated, unnecessary stimulation. "Whereas short bursts of stress hormones can be beneficial and, indeed, may be crucial in circumstances in which running from danger will guarantee survival," Verrillo and Gellman explain, "the long-term results [of frequent short bursts] can be disastrous."⁴¹

While there is evidence to support the theory that hormonal disturbances are important in CFS, once again the underlying question of what causes these disturbances remains unanswered, leaving researchers mystified as to whether endocrine abnormalities are the underlying cause of CFS or merely part of a more complex chain of events that originates outside the body altogether.

Environmental Factors

Some people have latched on to the idea of an overused fight-or-flight response and cited it as support for the theory that CFS is actually a result of the many evils of modern society, of which increased daily stress is just one. Echoing Dr. George M. Beard's concept of neurasthenia, some researchers claim that the pressures and developments of modern civilization are actually causing the breakdowns in people's bodies that lead to the illness of CFS. Other experts point to environmental factors, such as industrial pollutants and pesticides, exposure to which—just as hormonal disturbances can do—can cause impairment to the immune system. Goldberg considers this theory a valid possibility and makes the point that people are exposed to chemicals in far greater concentrations today than in previous generations. He goes on to discuss problems with air and water quality, and all of the chemicals and pesticides allowed in the food supply, offering this evidence as support for the theory that CFS is a modern disease that can be blamed on these factors. Goldberg, however, is in the minority. While some experts acknowledge that chemicals and pollutants may play a role in CFS, most doctors reject chemical exposure as the primary cause of the disease.

Psychosomatic?

The fact that doctors and researchers have so far been unable to uncover the organic cause of CFS has led some observers to maintain that earlier opinions of CFS as being psychosomatic could have been on the mark, or at least close. These people point to the high incidence of depression among CFS patients and suggest that CFS is actually psychological in nature, that the patient's own brain conjures and creates symptoms that feel real. Someone with a psychosomatic illness can be just as sick as someone with a disease that has an organic cause; the key difference is that there is no external causative agent, such as a microbe, at work in a psychosomatic illness.

Although a small contingent of the medical community still believes that CFS is psychosomatic, doctors overwhelmingly believe there is more to CFS than psychology. They maintain that there is far too much evidence suggesting organic agents at work, even if these exact mechanisms have yet to be determined.

Searching for a Trigger

As researchers try to unravel the mystery of what causes CFS, some wonder what role, if any, genetics plays in determining who gets the disease. There is evidence that CFS can run in families, appearing particularly in first-degree relatives—that is, parents and siblings of the patient. However, no genetic marker has been identified, and the history of CFS being found in "clusters" of people who are not related argues strongly against a purely genetic cause. Researchers wonder instead if certain people are genetically predisposed to developing CFS, particularly when circumstances act as a trigger.

The idea is that whatever the underlying cause is, the onset of symptoms is the result of some sort of triggering event. This theory is supported by the fact that although they may later recall experiencing various mild ailments prior to the onset of major symptoms, many CFS patients can identify the precise moment they became ill. Many patients are able to describe a stressful emotional and/or physical experience that occurred right before they became sick, such as a car accident or minor surgery; others report an initial viral infection that ballooned into CFS. "I was hit by a car while riding my bike," one patient recalls. "And I just never recovered from the accident. Instead, I kept getting worse. A year and a half later, when I could barely walk, I was diagnosed with chronic fatigue syndrome."⁴² Beth, another CFS patient, went into the hospital for routine surgery at age thirteen, and spent the next five years homebound and mostly bedridden from her symptoms. Bell lists a number of apparent triggers that he has seen in his patients: "exposure to certain chemicals, bacterial infections, emotional stress, surgical procedures, physical injury, immunizations, and physical stress."⁴³ Bell and others speculate that these trigger events could interact with other organic factors, including perhaps a genetic predisposition, to produce an active case of CFS.

A Combination of Factors

The fact is that no one theory accounts for all cases of CFS, yet all are supported by some evidence. Because of this, many experts are convinced that many factors work together to cause CFS. As Katrina Berne offers, "The many hypotheses [about the cause of CFS] are not mutually exclusive; many of them fit together well. Several factors may be involved: one to set the stage, one to ignite the fuse, and others to perpetuate the process [of getting sick]."⁴⁴

Searching for a multilayered cause to a disease is even more difficult than trying to identify one causative agent, but research is ongoing to uncover any and every important element in what causes patients to become sick with CFS. That may well be the CFS sufferer's best hope, because as long as the question of cause remains unanswered, the approach to treatment will continue to be equally challenging.