“ME/CFS is a serious, chronic, complex, systemic disease that often can profoundly affect the lives of patients.” Institute of Medicine, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness
Myalgic Encephalomyelitis, or as it is more commonly known in the U.S., Chronic Fatigue Syndrome, is a disease that affects all of the major physiological systems in the body. It is typically chronic, lasting years, sometimes decades, and is often preceded by an infection that resembles the flu. In teens the most common trigger is mononucleosis. Patients with this disease are usually healthy before falling ill and can frequently pinpoint exactly when their illness began.
The disease known as chronic fatigue syndrome (CFS) in the United States has historically been called myalgic encephalomyelitis (ME) abroad. Because there are two different terms, the combination ME/CFS, which stands for myalgic encephalomyelitis or chronic fatigue syndrome, is often used. Even though the case definitions of the two illnesses do not match, specialists in the U.S. who treat chronic fatigue syndrome consider ME and CFS to be essentially the same.
The name Chronic Fatigue Syndrome was coined by Dr. Stephen Straus of the NIH to describe an illness that affected the inhabitants of Incline Village Nevada, as well as a spate of similar outbreaks across the country in the 1980s. The name has been hotly contested by the ME/CFS community because it belittles the illness and fosters a dismissive attitude among physicians. The emphasis on “fatigue” also leads to misdiagnoses, as many illnesses present with fatigue. In 2014, the Institute of Medicine agreed that “chronic fatigue syndrome” can result in “trivialization and stigmatization for patients afflicted with this illness.” They proposed a new name: Systemic Exertion Intolerance Disease (SEID). However, this name has also met with considerable criticism, as it, like CFS, reduces the illness to a single symptom.
PRESENTATION: A MULTI-SYSTEM DISEASE
There are numerous symptoms that characterize the illness, but the cardinal symptoms are a profound, unrelenting loss of energy that is not relieved by rest; post-exertional malaise, which is a worsening of all symptoms following mental or physical exertion; unrefreshing sleep; cognitive impairment resulting in slowed processing of information; reduced focus and attention; and pain which may come and go. These symptoms may appear suddenly after a flu-like illness, an infection, surgery, a vaccination, or an injury. Or, less commonly, they may manifest gradually over a period of several months, sometimes years. It is the sudden onset aspect of ME/CFS that distinguishes it from other chronic illnesses with similar symptoms.
Due to the presence, and severity, of so many symptoms, ME/CFS is called a “multi-system disease.” It affects several systems in the body simultaneously – the immune system, the nervous system, and the endocrine system – in ways that profoundly alter normal physiological functions. Because the cells of these three systems share the same receptors, any illness affecting one of these systems will affect the other two. So the question faced by researchers and clinicians, and of primary concern to patients seeking treatment, is which system is the primary driver of the disease?
ABNORMALITIES
IMMUNE SYSTEM
At a glance
- Low Natural Killer Cell function
- Abnormal cytokines
- Autoimmune markers
There have been thousands of research papers on ME/CFS documenting multiple physiological abnormalities in patients with the disease. The most consistent among these abnormalities is immune system dysfunction. Because impaired immune system function lies at the heart of all chronic illnesses, it makes perfect sense that people with ME/CFS would demonstrate problems in this area.
Reduced natural killer cell (NK ) function is one of the most consistent immunological findings among people with ME/CFS. In fact, it is so consistent that the Japanese originally called the disease LINKS, which stood for Low Natural Killer Cell Syndrome.
Natural killer cells are an important part of the innate immune system, which is the oldest part of our immune system. Their function is to destroy tumor cells as well as cells infected with viruses. They are called “natural” because they don’t need previous contact with pathogens in order to form antibodies. NK cells provide a rapid response to viral infections. When NK function is reduced, the immune system is unable to clear new viruses, or to keep latent viruses, such as members of the herpesvirus family, under control.
One of the earliest immune system studies on ME/CFS was performed in 1994 by Barker et al. They found that NK cell dysfunction was a “common manifestation of CFS.” Further studies led by Ogawa, and Ojo Amaize confirmed that NK cells were not properly activated, and, even when they were, had low cytotoxicity. Ojo Amaize’s team concluded that low cytotoxicity of NK cells was consistent with flu-like symptoms, and, perhaps, the reactivation of latent viruses.
Not every study has found a reduction of NK function, which has led to a debate in the research community as to whether ME/CFS should be classified an immune disease. The most recent of the NK studies, conducted by Brenu et al. in Australia cleared up some of the confusion.
The immune system changes minute by minute. As a consequence, studies that take a “snapshot” of immune markers through a single blood draw will have variable results. Brenu’s group looked at immune markers over a period of a year. The study demonstrated that NK cytotoxic activity remained consistently decreased in ME/CFS patients during the course of the disease.
Brenu’s group also found consistent pro-inflammatory cytokines (immune system chemicals that induce inflammation). The persistent upregulation of pro-inflammatory cytokines is an indication of chronic inflammation as well as persistent viral infection. Dr. Nancy Klimas, a physician at Nova Southeastern in Fort Lauderdale, Florida, found a distinct pattern of these cytokines in ME/CFS patients as far back as 1990. More recently, Maes et al. found that inflammatory cytokines and immune markers were not only elevated, but were associated with specific symptoms, including fatigue, sadness, autonomic symptoms, and a flu-like malaise, autonomic symptoms, concentration difficulties, failing memory, and a subjective experience of infection.
A 2015 study spearheaded by Dr. Mady Hornig at Columbia University’s Mailman School of Public Health found that not only were there specific cytokine abnormalities in patients with ME/CFS as compared to healthy controls, but that these abnormalities were distinctly different in short-term as opposed to long-term patients. The findings suggested that patient who had been ill three years or less had immune systems that were stuck in “high gear” while longer-term patients suffered from “immune exhaustion.”
Autoimmunity
Other immune irregularities indicate that an autoimmune process is also involved. A University of Hawaii team led by Yoshitsugi Hokama found antibodies to cardiolipin in ME/CFS patients. Anticardiolipin antibodies (ACA) are found in autoimmune diseases such as lupus, rheumatoid arthritis, autoimmune hepatitis, and scleroderma.
In a further study of autoimmune irregularities in ME/CFS, David Berg, Director of HEMEX Labs, found antiphospholipid antibodies (APLAs) in two groups of patients. APLAs attack the outer surface of cells, causing them to stick together and form clots (hypercoagulability). Once blood cells become “sticky” their passage through capillaries is impeded, leading to a reduced oxygen supply to organs – including the brain. A third indicator that an autoimmune process is underway in ME/CFS is the presence of antinuclear antibodies (ANA), which are found in about one-third of ME/CFS patients.
NERVOUS SYSTEM
At a glance
- Reduced white and gray matter in the brain
- Reduced blood flow to the brain
- Neuroinflammation
There have been many studies documenting nervous system abnormalities in patients with ME/CFS. In the early 1990s, Dr. Jay Goldstein proposed that ME/CFS is the result of an injury to the limbic system, which is an area located deep in the brain just above the brainstem. The limbic system is involved with memory, emotion, and regulation of the autonomic nervous system. The autonomic nervous system regulates homeostasis in the body: appetite, body temperature, blood pressure, blood sugar, sleep, wakefulness, heart rate, digestion, and sex drive. Problems in all of these areas of the autonomic nervous system have been found in ME/CFS patients. Dr. Goldstein’s theory was based on a careful observation of autonomic symptoms, but he also supported it with SPECT scans that showed blood flow was reduced in his patients’ brains.
Other types of brain scans have also been used to documents neurological impairment in ME/CFS. Functional MRIs (fMRI) measure brain responsiveness during the performance of mental tasks. In an international collaboration headed by Caseras at the Institute of Neurosciences at the Autonomous University of Barcelona, fMRI tests showed that people with ME/CFS have slower processing speed, loss of focus, and poor short-term memory. Using a similar technique, a group of Dutch researchers in Holland led by de Lange, mapped structural brain structure and volume in CFS patients and healthy controls. They used high-resolution structural magnetic resonance images using voxel-based morphometry, a form of statistical analysis that measures the shape, size and position of brain structures. The de Lange study found “substantial and consistent” reductions in gray matter volume in two groups of ME/CFS patients as compared with controls.
Since the de Lange study, reductions in both white and gray matter have been confirmed by several other studies. The loss of brain matter is one of the factors that leads to the cognitive problems found in the disease. In 2011, Puri et al. found that “significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness.” Their data also indicated that “subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS/ME.” These findings were confirmed by a Stanford study published in 2014 (Zeineh et al). Using sophisticated imaging techniques, the researchers confirmed that patient with ME/CFS have diminished white matter as well as white matter abnormalities in the right hemisphere.
One of the most significant brain studies in the field of ME/CFS research was published in 2014 by a group of Japanese researchers. Using PET scans, Yasuhito Nakatomi’s team found that neuroinflammation is higher in ME/CFS patients than in healthy controls. They also found that inflammation in certain areas of the brain – the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons – correlated with the symptoms. Patients who reported impaired cognition, for example, showed neuroinflammation in the amygdala, which is known to be involved in memory. This research not only demonstrates the connection between neuroinflammation and cognitive symptoms, it takes us full circle back to Jay Goldstein’s limbic hypothesis, as most of the areas of the brain showing inflammation were located in the limbic system.
ENDOCRINE SYSTEM
At a glance
- HPA Axis dysregulation
- Blunted ACTH and cortisol responses
- Low Growth Hormone
The third major system affected by ME/CFS is the endocrine system. The endocrine system is a collection of glands that secrete hormones directly into the circulatory system. These hormones are then carried to a target organ. The major endocrine glands are the pineal gland, hypothalamus, and pituitary gland in the brain; the pancreas; the sex glands (ovaries, testes); the thyroid and parathyroid glands; the gastrointestinal tract; and the adrenal glands. When glands signal each other in sequence this is referred to as an axis, e.g. the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is responsible for the stress response, also known as the “fight or flight” response.
The HPA axis figures prominently in ME/CFS literature. In 1991 a research team led by Dr. Mark Demitrack published a study demonstrating abnormalities in the HPA axis in patients with ME/CFS. The study showed decreased levels of cortisol, blunted response of the pituitary gland to corticotropin releasing hormone (CRH), and enhanced sensitivity to adrenocorticotropic hormone (ACTH). While the test results ruled out primary adrenal insufficiency (Addison’s disease), they did indicate a dysregulation in the HPA axis, which would lead to excessive fatigue, as well as many other symptoms typical of low adrenal function. The authors concluded that their test results indicated “a mild central adrenal insufficiency” in ME/CFS patients, most likely originating in the hypothalamus.
Subsequent studies by Dinan et al., Maes et al., Cleare et al., and Scott et al. found significant disruptions of the HPA axis, as well as reductions in DHEA (a precursor to sex hormones), and blunted responses to chemical signals sent by the brain (De Becker). Low growth hormone (GH) levels have also been found in ME/CFS patients (Berwaerts at al.) Growth hormone is released during sleep by the pituitary gland. Given that insomnia is one of the primary symptoms of ME/CFS it is not surprising that GH levels would drop. Low GH is associated with a loss of vitality in adults and fatigue.
MITOCHONDRIAL IMPAIRMENT
At a glance
- Ragged red mitochondria
- Cellular fatigue
- Oxidative stress
- Diastolic Dysfunction
The mitochondria are small structures within cells that produce adenosine triphosphate (ATP), the molecule that generates cellular energy. ATP is essential for every function in the body, which means that when the powerhouses of energy production, the mitochondria, are damaged and levels of ATP decline, the body literally runs out of energy. If low levels of ATP are sustained, there can be lasting damage to the heart, which is highly dependent on ATP.
Mitochondrial Disease, an inherited condition found primarily in children, is a mitochondrial disorder that leads to muscle weakness, fatigue, and organ failure. In addition to primary Mitochondrial Disease, mitochondrial dysfunction has been linked to diabetes, Alzheimer’s disease, Huntington’s disease, cancer, and liver disease, all of which produce profound fatigue.
The first doctor to suggest mitochondrial damage in people with ME/CFS was Dr. Melvin Ramsay, the physician who documented the Royal Free Hospital outbreak in the 1950s. In an article written in 1978, Dr. Melvin Ramsay proposed that “abnormal muscular fatigability is the dominant clinical feature and it is suggested that mitochondrial damage may provide an explanation for this phenomenon.”
Not long after Dr. Ramsay’s observation, Drs. Peter and Wilhemina Behan found concrete evidence of damaged mitochondria in muscle biopsies of patients with post-viral syndrome. Out of 50 samples, mitochondrial degeneration was obvious in 40 of the biopsies. Significantly, they also noted the presence of “ragged red mitochondria,” a sign of mitochondrial disease. The authors concluded that their findings provided the first evidence that post-viral syndrome “may be due to a mitochondrial disorder precipitated by a virus infection.”
Since that time, ME/CFS specialists have accepted the fact that ME/CFS produces mitochondrial damage. Dr. Cheney, one of the physicians who documented the Incline Village outbreak in Nevada , has long held that ME/CFS is an acquired mitochondrial disease, a position strongly supported by research showing mitochondrial dysfunction in the muscles of ME/CFS patients.
Because the heart is composed of muscle tissue, cardiac function will be affected by reduced mitochondrial output. A 2003 study performed by Dr. Arnold Peckerman at the VA Medical Center in East Orange, NJ documented cardiac impairment in ME/CFS patients. Test results showed that patients with severe ME/CFS had “significantly lower stroke volume and cardiac output than the controls and less ill patients.” The authors proposed that in patients with ME/CFS, “blood pressure is maintained at the cost of restricted flow, possibly resulting in a low flow circulatory state. Thus, there might be periods in daily activities when demands for blood flow are not adequately met, compromising metabolic processes in at least some vascular compartments.”
Dr. Cheney has proposed that this impairment in diastolic function is what lies at the heart of the majority of ME/CFS symptoms. If cardiac output is low to begin with, standing up would reduce levels to the point that a person would experience dizziness, black-outs, and even fainting. Once cardiac output is sufficiently reduced, all other systems would decline as well. The body, in an effort to supply blood to the heart, would restrict blood flow to other organ systems, such as the gut. As a consequence, digestion would be impaired, with resultant dysbiosis, malabsorption, and a host of GI problems.
Blood flow to the brain would also decline, leading to cognitive problems, depression and anxiety, and impairment of hypothalamic function, resulting in dysautonomia. With reduced blood flow, the immune system, which depends on the vascular system for transport, could not function efficiently; latent viruses and secondary infections would proliferate. The liver, an organ which relies heavily on blood flow, could not detox the body sufficiently, leading to a buildup of toxins. Under these conditions, exercise would not only strain the system, it could be dangerous.
According to Dr. Sarah Myhill, an ME/CFS specialist in the UK, mitochondrial dysfunction is the central mechanism of ME/CFS. Her explanation of mitochondrial damage is that when the body is stressed, the demands placed on ATP production can exceed the supply. In people with ME/CFS, the body is continually stressed by an overworked immune system and secondary infections, resulting in a depletion of overall ATP, which damaged mitochondria cannot regenerate. Once stores are low, the cells begin to convert glucose into lactic acid, which is the reason why ME/CFS patients quickly switch to anaerobic metabolism during exercise. The net result is exhaustion at the metabolic level.
In a study conducted in 2009, Dr. Myhill and two colleagues measured the levels of five biomarkers for mitochondrial function in the sera of ME/CFS patients. The results of the study indicated that when analyzed together, these markers were predictive of illness severity in ME/CFS patients. The researchers concluded that their findings strongly implicated mitochondrial dysfunction as the immediate cause of ME/CFS symptoms. However, they could not determine whether the damage to mitochondrial function was a primary effect, or an effect secondary to lack of cellular oxygen (hypoxia) or oxidative stress.
Oxidative stress is both the product and the cause of mitochondrial dysfunction. That being said, there is also ample evidence that viruses can directly cause extensive damage to mitochondria. The herpes simplex virus causes massive damage to mitochondrial DNA, contributing to cell death and tissue damage. Viruses can also use mitochondrial proteins for replication, induce cell apoptosis (cell death), and increase the production of free radicals.
Mitochondrial Disease shares many common features with ME/CFS. Both illnesses share similar markers – evidence of oxidative stress, high lactate levels, low acyl-carnitine, and low glutathione levels (which has been proposed as a marker for mitochondrial diseases) are common lab findings in both mitochondrial disease and ME/CFS. Both illnesses are heterogeneous, manifesting in different organs and at different rates of severity. Both are difficult to diagnose. And finally, exercise intolerance is a hallmark characteristic of both illnesses, a feature which no doubt led Dr. Ramsay to conclude that ME was a mitochondrial disease. Given the overlap in lab results, symptoms, and treatment, there is every reason to consider ME/CFS as an acquired mitochondrial disease.
ONGOING INFECTIONS
THE GUT
Dr. Kenny De Meirleir has proposed that the translocation of intestinal flora into the bloodstream is what causes the chronic immune activation of ME/CFS. The mechanism through which intestinal bacteria enter the bloodstream is known as “leaky gut” (intestinal permeability), a condition that compromises the protective barrier of the intestinal wall, allowing large molecules and bacteria that would otherwise be trapped in the intestines to pass through into the bloodstream.
In 2012 Dr. Michael Maes, an MD and professor of psychiatry in the Department of Psychiatry at Chulalongkorn University in Bangkok, measured responses to intestinal flora in blood samples from 128 patients with ME/CFS. The researchers found higher levels of IL-1, TNF alpha, neopterin and elastase (an enzyme that destroys bacterial proteins) than in controls, indicating an immune response to bacteria in the bloodstream. Furthermore, IL-1, TNF alpha and neopterin were significantly related to fatigue, flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability. The authors concluded that “increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”
Not only do translocated intestinal flora activate the immune system, their by-products, particularly hydrogen sulfide (the gas that produces the “rotten egg” smell), can exert profound effects on the endocrine system, including a decrease in core body temperature, sleep apnea, reduced heart and respiration rates, and a severe metabolic drop. Excess hydrogen sulfide also can also inhibit mitochondrial oxygen utilization.
In related work, Marian Dix Lemle has proposed that the production of excess hydrogen sulfide is responsible for the mitochondrial dysfunction that lies at the heart of ME/CFS. These three researchers have, between them, established a mechanism that would account for all ME/CFS symptoms. Marian Dix Lemle has identified the chemical component. Dr. De Meirleir has explained the cause for its increase in the gut, and Dr. Maes has identified the mechanism through which it causes symptoms– translocation. All of these components directly reflect the influence of the microbiome on ME/CFS.
The microbiome is the community of bacteria and other micro-organisms that inhabit our bodies. Often, when researchers refer to the microbiome, they are talking about the trillions of bacteria that live in our intestines, and that enable us to digest our food, absorb nutrients, and protect us from pathogens.
Alterations in the microbiome have been found in a number of diseases and conditions, such as autism, diabetes, inflammatory bowel disease, major depression, and ME/CFS. Most promising for patients, altering the microbiome may potentially treat these illnesses.
When a team at Newcastle University in Australia led by Henry L. Butt analyzed the microbiota of patients with ME/CFS, they found that changes in the gastrointestinal microbial ecology were “significantly associated with fatigue symptoms” as well as neurological and cognitive function.
This research led to an obvious solution to the problem: replacing the unhealthy microbes with healthy ones. Dr. Thomas Borody, gastroenterologist and director of the Centre for Digestive Diseases in Australia, treated 60 patients with bacteriotherapy (fecal transplant). The results of the treatment were promising. Of the 60 patients, 42 responded well to the treatment. Most impressive was the fact that after 15 years, 12 of those patients were still symptom free. The authors concluded that “bacteriotherapy achieves initial success rate of 70% in CFS and a 58% sustained response.”
Results like these have prompted Dr. Ian Lipkin, the internationally renowned “virus hunter” at Columbia University, to initiate a million-dollar project to study the microbiome of ME/CFS patients (McGrath). Lipkin believes that “populations of fungi, bacteria and viruses in the colon can have an impact on the immune system and give rise to cytokine activation which could cause the symptom complexes we see in ME/CFS.”
FURTHER READING
List of brain scan research studies: http://www.cfids-cab.org/cfs-inform/Brainscans/brainscans.html
“CFS – The Central Cause: Mitochondrial Failure.” Dr. Sarah Myhill. http://www.drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure
“Mitochondrial Dysfunction, Post-Exertional Malaise and CFS/ME.” Lucy Dechéne http://www.masscfids.org/resource-library/13/302
Ramsay, A. Melvin. “’Epidemic neuromyasthenia’ 1955-1978.” Postgraduate Medical Journal (November 1978) 54, 718-721 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2425324/pdf/postmedj00263-0015.pdf
New Mitochondrial Function Analysis Technique to Be Used in ME/CFS Research at U of Liverpool.” ProHealth. December 21, 2011 http://www.prohealth.com/me-cfs/library/showarticle.cfm?libid=16723
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