Chronic Fatigue

Chronic FatigueChronic Fatigue Syndrome (CFS) affects up to 2.5 million Americans and for most is a very debilitating illness.   It is absolutely one of the most common problems I see in my practice.  Conventional medicine is just now coming around to recognizing CFS as a real syndrome.  Most doctors generally only as a diagnosis of of exclusion, meaning they ruled out other diseases and did not find any reason for the fatigue. Symptoms of CFS can be very broad and vague and often include extreme exhaustion, memory loss, headache, muscle fatigue, weakness, and pain lasting at least six months.  Fatigue can range in severity from mild to severe and be debilitating for some people. It is one of the most common symptoms patients complain about at visits with their doctor and studies show one out of four patients complain of fatigue in visits with their primary doctor.(1)  Conventional medicine’s treatment for CFS is prescription drugs to manage symptoms, including pain medications, stimulants, sleep aids, and antidepressants and in most cases, patients continue to suffer.

“Of the 1159 consecutive patients surveyed in two adult primary-care clinics, 276 (24%) indicated that fatigue was a major problem. After one year of follow-up, only 29 fatigued patients (28%) had improved. The high prevalence, persistence, and functional consequences of fatigue mandate a search for effective therapy.”(2)

 

Known Causes of Fatigue: 

  • Anemias
  • Methylation issues
  • Iron deficiency
  • B12 deficiency
  • Blood Sugar Imbalances
  • Insulin Resistance
  • Reactive Hypoglycemia
  • Cortisol Imbalances
  • Hypothyroidism
  • Neurotransmitter Imbalances
  • Depression
  • Anxiety
  • Intestinal Permeability
  • Detoxification Issues
  • Heavy Metal and Toxic Exposure
  • Chronic Inflammation
  • Stress
  • Mitochondrial dysfunction
  • Cellular energy and ATP deficits
  • Oxidative stress and Inflammation
  • Nutrient deficiencies

Chronic Fatigue

Chronic fatigue, while probably rare decades ago, is now extremely common in modern society. One study published by the American Journal of Public Health found chronic fatigue affected over 11% of the population! It concluded the following:

“Both chronic fatigue and chronic fatigue syndrome are common in primary care patients and represent a considerable public health burden.”(3)

CFS – Chronic Fatigue Syndrome

Chronic fatigue syndrome, or CFS, is a debilitating and complex disorder involving multiple organs characterized by profound fatigue that is not improved by bed rest and that may be worsened by physical or mental activity. Symptoms affect several body systems and may include weakness, muscle pain, impaired memory and/or mental concentration, anxiety and depression and insomnia, which can significantly impact quality of life.(4)

“In addition to fatigue, CFS is associated to a wide spectrum of symptoms, including arthralgias (joint pain), muscle pain, headaches, anxiety, depressive symptoms, cognitive disorders (poor memory, unclear thought, etc.), sleep disorders, or intolerance to physical exertion, among the most frequent.”(5)

How common is CFS?

CFS is quite common. One study found CFS affected 2.6% of the study population.(6) This translates to over 9 million Americans! Another study published in the prestigious JAMA found that 21% of 500 unselected patients, aged 17 to 50 years, seeking primary care for any reason were found to be suffering from a chronic fatigue syndrome consistent with “chronic active Epstein-Barr virus (EBV) infection”.(7)

What Causes CFS?

We still don’t know what causes chronic fatigue syndrome although several hypotheses have been proposed, including chronic infection, immunologic dysfunction, neuroendocrine dysfunction, oxidative stress and mitochondrial dysfunction. There are no reliable diagnostic tests to identify CFS so diagnosis is often based on symptoms, clinical history and exclusion of other conditions.

What-causes-CFS“Given its unknown aetiology (cause of disease), different hypotheses have been considered to explain the origin of the condition (from immunological disorders to the presence of post-traumatic oxidative stress), although there are no conclusive diagnostic tests. Diagnosis is established through the exclusion of other diseases causing fatigue. Currently, no curative treatment exists for patients with chronic fatigue syndrome.”(8)

Some patients present with similar symptoms but are diagnosed with other conditions because fatigue is not the primary symptom. A condition that presents very similarly as CFS but is often given a different diagnosis is fibromyalgia.(9)

What is Fibromyalgia?

Fibromyalgia (FMG) is characterized by widespread pain and tenderness, and is often accompanied by fatigue, memory problems, and sleep and mood disturbances. FMG is even more common than CFS and is present in as much as 2% to 8% of the population!(10) Research including neuroimaging studies show abnormalities in neurotransmitters and an abnormal response to pain.(11)

How is CFS different from Fibromyalgia?

As you can see, there is a significant overlap of symptoms between CFS and FMG. Fatigue is a highly prevalent and persistent symptom affecting 76% of patients with FMG. (12) In addition to fatigue, both conditions often present with memory and cognitive problems, anxiety and depression, sleep disturbances and joint and muscle pain. At the same time, studies show a high frequency of fibromyalgia in patients with chronic fatigue.(13,14) The truth is, these conditions probably share similar pathophysiologic (disease) mechanisms and similar etiology (cause of disease).(15) If a person has all the associated symptoms but their chief complaint is more fatigue than pain, they are usually diagnosed with CFS. If widespread pain and tenderness is the chief complaint along with these other symptoms, they are given a diagnosis of fibromyalgia. Let’s take a look at the prevailing theories on the origins of these conditions.

Theories of Etiology of CFS and FMG:

Infectious theory
Various types of chronic infection have been associated with CFS, including Epstein Barr virus (EBV), Candida albicans, Borrelia burgdorferi (associated with Lyme disease), Enterovirus, Citomegalovirus (CMV), Human Herpes virus (HVS), Espumavirus, Retrovirus, Borna virus, Coxsackie B virus, and hepatitis C virus (HCV) but these infections have not yet been shown to be the causative factor in the development of CFS.(16) Many of these same pathogens have been found in FMG as well, even though a direct causal relationship has not been shown.(17) In particular, viruses such as HCV, HIV, Coxsackie B, and Parvovirus and bacteria like Borrelia could be involved in the development of FMG.(18) Although, multiple infectious agents have been associated with the development of CFS, it is not yet known how these infections are related to the development of CFS or FMG and if they act as triggers for the onset of these diseases.(19) One interesting paper proposed a model wherein vaccinations function as co-triggers for the development of fibromyalgia, in conjunction with additional contributing factors. (20)

Chronic or recurrent viral or bacterial infections seen in many patients with CFS have been shown to induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. This has lead some researchers to focus on autoimmunity as a possible mechanism in CFS. (21)

Although different disorders have been found in the immune system or its function, currently there is no scientific evidence to attribute the cause of CFS syndrome to an immunological disorder such as autoimmune disease. There are a large number of studies on immune disorders observed in CFS, but they frequently yield contradictory results and they do not show the immune system as a causative factor.(22-24) However, there is abundant evidence that many patients with CFS (up to around 60%) may suffer from concurrent autoimmune responses or autoimmune disease. It is also interesting to note that a wide range of abnormalities involved in CFS are conducive to the generation of autoimmunity and autoimmune reactions. The increased levels of pro-inflammatory cytokines, for example, predispose to an autoimmune environment in the body.(25)

Although FMG and CFS are common in patients affected by autoimmune disease, studies showing autoantibodies in fibromyalgia as seen in autoimmune disease have had mixed results. Several authors have investigated the association between FMG and antipolymer antibodies (APAs) but the results are controversial and APAs cannot be used as a marker for diagnosis.(26,27) To make matters more confusing, fatigue is a common symptom of chronic autoimmune and inflammatory disease!(28)

Neuroimmunological theory

A wide range of immunological and neurological abnormalities have been reported in people suffering from CFS. They include abnormalities in proinflammatory cytokines, autoimmune responses, autonomic disturbances and brain pathology.(29) This model proposes that initial infection and immune activation leads to a state of chronic immune activation which leads to progressive damage of self-tissue even when the initial infection has been cleared. Elevated proinflammatory cytokines together with oxidative damage conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and oxidative stress are responsible for the extreme fatigue.(30)

Neuroendocrinological theory

Several disorders in the hypothalamic-pituitary-adrenal (HPA) axis and in the production of related hormones have been found in CFS and FMG, as well as a disorder of the autonomic nervous system. It is known that interactions between different parts of the nervous system are mediated by neurotransmitters and that their disorders lead to unbalanced functioning of certain nervous structures and to the development of other diseases. As discussed, many of the clinical features in CFS are similar to those found in FMG, and it has been postulated that the pathophysiological mechanisms are probably similar in both conditions.(31,32)

As FMG is considered a stress-related disorder, it is easy to understand that the hypothalamic-pituitary-adrenal (HPA) axis is involved.(33,34) Different studies have shown elevated cortisol levels, particularly in the evening, associated with a disrupted circadian (24-hour) rhythm.(35, 36) In addition, FMG patients have shown high levels of adrenocorticotropic hormone (ACTH)(37,38) and a relative adrenal insufficiency.(39)

Mitochondrial theory of fatigue

“Mitochondrial function appears to be directly related to fatigue, and when patients experience fatigue, their mitochondrial function is inevitably impaired.” (40)

Mitochondria are the organelles of the cell that produce the majority of the body’s energy carrier: ATP. Think of the mitochondria as the “energy-producing factories” of the body. This is where ATP is generated, which is then used by the cells to fuel cellular processes.

“The mitochondria, often referred to as “the power house of the cell”, are the source of at least 90% of the energy generated in the cell. The majority of this energy (80%) is produced as ATP by oxidative phosphorylation. A single cell can contain from 200 to 2,000 mitochondria. The number of mitochondria in specific cell types varies considerably, although within a given cell type the number is closely regulated.”(41)

Mitochondrial Impairment Causes Muscle Weakness and Fatigue

“At the biochemical level fatigue is related to the metabolic energy available to tissues and cells. Thus, the integrity of cellular and intracellular membranes, especially in the mitochondria, is critical to cell function and energy metabolism.”(42)

All cells require ATP to function. When the mitochondria become inefficient and are unable to produce sufficient ATP to meet the needs of the cells and surrounding tissue and organs, then muscle weakness or fatigue of these organs can occur. This is well-documented in animal studies.(43) It follows that if a large percentage of cells in the body become inefficient in ATP production, then it may manifest as low energy or muscle weakness in the individual.

Several studies have shown a correlation between mitochondrial dysfunction and CFS. (44,45) Studies have also found a remarkable correlation between the degree of mitochondrial dysfunction and the severity of illness.(46,47)

Paul Cheney, MD, PhD, was a world expert and one of the original researchers on CFS.(48) Some of his research indicated that the most severe CFS patients had very marked oxidative injury to their mitochondria, resulting in the accumulation of 8OHdG, which is a measurement of damaged DNA from oxidative stress. When a certain level of mitochondrial injury was reached (the point at which around 70% of the mitochondrial genome was damaged) he found that it was not possible to bring these patients back to health. They died of many different diagnoses, including cardiomyopathies (heart disease).(49)

Is Mitochondrial Damage Involved in the Development of CFS and FMG?

There is accumulating evidence which suggests that mitochondrial dysfunction is involved in the pathophysiology of both CFS and FMG.(50) Mitochondrial dysfunction has been shown in leukocytes of CFS patients and in muscle cells of FMG patients, which could explain the muscle pain. Additionally, if mitochondrial dysfunction is also present in central neural cells, this could result in lowered ATP pools in neural cells, leading to generalized hypersensitivity and chronic widespread pain.(51) One study which found many physiological similarities but a few differences between CFS and FMG patients, hypothesized that mitochondrial dysfunction-dependent events could be a marker of differentiation between CFS and FMG.(52)

Mitochondria-Related Disorders

Mitochondrial dysfunction causes a lot more problems in the body than just fatigue. It can cause damage to any tissue or organ in the body at any period of life and can result in a wide variety of metabolic, cardiovascular, immunologic, neurologic and psychiatric health disorders.(53-58) For more information on the different diseases associated with mitochondrial dysfunction, see the article below: Conditions Affected by Oxidative Stress and Mitochondrial Dysfunction. It has also been associated with premature and accelerated aging and all the diseases associated with aging.(59-61) For more information on how mitochondrial dysfunction leads to accelerated aging, see Parts 1 and 2 of this website’s Successful Aging series: Delaying the Degenerative Diseases of Aging.

“Mitochondria are therefore vital for normal cellular function, including intracellular metabolic activities and signal transduction of various cellular pathways. Indeed, recent studies have identified a host of common disorders with apparent ties to mitochondria, including metabolic (e.g., type 2 diabetes) and cardiovascular disorders, cancer, neurodegenerative diseases, psychiatric disorders, migraine headache, and the aging process. These mitochondria-related pathologies range from early infancy to senescence.”(62)

Mitochondrial dysfunction has been related to many types of disease, including:

  • Fatigue
  • Weakness
  • Joint and muscle pain
  • Depression
  • Neurodegenerative diseases (Alzheimer’s, Parkinson’s, etc.)
  • Neuropathies (nerve disorders)
  • Liver dysfunction
  • Cardiac dysfunction
  • Pancreatic dysfunction
  • Kidney dysfunction
  • Increased susceptibility to infection, stress or trauma

What Causes Mitochondrial Dysfunction?

Mitochondrial damage can be due to both environmental and genetic causes. There are several causes of mitochondrial dysfunction that have been identified in the literature, including oxidative stress (63-65), pharmaceutical drugs (66), environmental toxins (67,68), nutritional deficiencies (69-71) and genetics.(72) All of these factors have the potential to inhibit mitochondrial production of ATP, resulting in a wide range of disorders, including chronic fatigue. This is very important for the clinician and patient to know because most of these factors are modifiable through diet, nutrition and lifestyle change. For a more complete review of how each of these factors causes mitochondrial dysfunction, read the article below: What Causes Mitochondrial Dysfunction?

Known causes of mitochondrial dysfunction:

  • Oxidative stress and reactive oxygen species (ROS)
  • Medications
  • Environmental toxins
  • Nutrient deficiencies
  • Gluten sensitivity
  • Psychological stress
  • Genetics

How Do We Manage CFS and FMG in the Functional Medicine Model?

As you probably know by now, we always address the underlying mechanisms of any illness in functional medicine while supporting other organs and organ systems. In this case, since increasing studies are showing mitochondrial damage and impairment of ATP production involved in both CFS and FMG, we always provide mitochondrial support and protection when managing these conditions. Protecting the mitochondria from oxidative damage has been shown to have significant potential therapeutic value.(73,74) At the same time, we investigate the function of other organs and organ systems through functional lab testing and provide support for these as well if needed. Some of the organs which are often impacted in CFS and FMG include the adrenal glands, the liver, the immune system, the gastrointestinal system and the brain.

An Individualized Integrative Approach works Best

Evidence shows an individualized integrative approach may help target interventions for subgroups most likely to respond to specific treatments. A recent 2014 review of the literature found a number of avenues for integrative management, including dietary modification, functional nutritional deficiencies, physical fitness, psychological and physical stress, environmental toxicity, gastrointestinal disturbances, immunological aberrations, inflammation, oxidative stress, and mitochondrial dysfunction. It concluded:

“A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research.”(75)

Paleo-diet – A remarkable 2013 study provided 30 CFS patients with an individualized and integrative treatment regime based on 1) following a Paleo diet, 2) ensuring good quality sleep, 3) taking nutritional supplements, and 4) getting the right balance between work and rest. Some modifications were made to the basic regime and were tailored for each patient according to the results of the ATP Profile, nutritional testing and clues from their clinical history. It found that all patients who followed the treatment regime improved in mitochondrial function by on average a factor of 4! In other words, their mitochondria functioned 4 times as efficiently in producing ATP as prior to the regimen!(76) This is a unique study which showed the value of an individualized non-pharmaceutical tailored-approach (similar to the principles of functional medicine) to a complex condition which is often poorly evaluated and poorly managed in the current conventional model.

 

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