Chronic Fatigue Syndrome
Myalgic encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic illness characterized by extreme fatigue that lasts for more than six months. This fatigue cannot be explained away by an underlying medical condition. Common symptoms include joint pain that moves around in the body, muscle pain, poor concentration, headaches, night sweats and constant fatigue. Many patients will also have digestive issues as well such as IBS. Many also have depression and anxiety as well. More than 1 million Americas suffer from ME/CFS, and 75% are women. The presence of ongoing or fluctuating flu-like symptoms, arthralgias, myalgias, autonomic disturbances, and a striking hypersensitivity to stimuli in many patients with this illness has led to the suspicion that ME/CFS is an inflammatory or immunological disorder. There are different theories to what causes ME/CFS. One theory is that allergies, stress, and infection may combine to deplete ATP levels in the cells, since ME/CFS patients show evidence of decreased ATP production.
Because the symptoms are ME/CFS are characterized as “sickness behavior” induced by pro-inflammatory cytokines, the cytokines I felt were associated with ME/CFS include IL-1, IL-6 and TNF-a. In particular decreased motor activity, altered food and water intake, sleep and cognition have been linked to increases in the levels of IL-1b, IL-6 and TNFα in the brain (Broderick et al., 2010).
Rationale: Pro-inflammatory cytokine associated with sickness behavior-malaise, fatigue, and depression
Rationale: Pro-inflammatory cytokine
Rationale: Pro-inflammatory cytokine associated with onset of fragility, poor physical performance, loss of muscle strength, and cognitive decline.
Rationale: Proinflammatory cytokine that is associated with fragility, decrease in muscle strength, and aging.
Stanford immunologist Jose Montoya and their teams analyzed the blood of 192 people who had met one of the established criteria for CFS/ME diagnosis and 392 healthy individuals, the team found that the levels of 17 cytokines, most of them which were pro-inflammatory. What was interesting from my research was the consistent presence of TGF-B that was elevated in 63% of the patients in the study. “TGF-β is a 112-amino acid protein that provides cells with the pleiotropic capacity to affect cell-developmental programs and behavior, including cell proliferation, differentiation, morphogenesis, tissue homeostasis, and regeneration” (Montoya et al., 2017). TGF- β is often viewed as an anti-inflammatory cytokine. It is produced by many cell types, such as macrophages and helps regulate T cell function. TGF- β is also involved in glucose regulation and energy balance. However according to Montaya, the presence of this cytokine may represent down-regulatory activity by the patient’s immune systems against constant inflammation. TGF- C is often thought of as anti-inflammatory but it can also be a pro-inflammatory cytokine in various cancers. In fact, TGF- β can suppress inflammation on a systemic level but can stimulate immunity and inflammation at a local level. Interestingly, ME/CFS patients have a higher than normal incidence of lymphoma as well, which could be due to TGF- β. According to Montaya et.al, TGF- β does not always function to counteract inflammation, and in the case of ME/CFS its effect may depend on the target tissues and the overall level of the cytokine (ME Association, 2017). “Thus, elevated levels of TGF-β in ME/CFS patients may actually be detrimental and may be a major factor in promoting relentless inflammation and a “fibrotic” milieu resistant to therapeutic interventions in some ME/CFS patients” (Montoya et al., 2017).
Other cytokines that was found in research include TNF-a (Moss, Mercandetti, & Vojdani, 1999), IL-6 (Grygiel-Gorniak & Puszczewicz, 2015), and IL-1 (Roerink, van der Schaaf, Dinarello, Knoop, & van der Meer, 2017). Interesting to mention circulating levels of IL-1 (particularly IL-1B) were higher in the acute phase, but dropped as the disease progressed (Roerink et al., 2017). “The perpetuation of fatigue symptoms in the absence of peripherally increased cytokine concentrations suggest that other, most likely central mechanisms, may be involved in persistent fatigue after an acute infection” (Roerink et al., 2017).
Additionally, “highly attenuated” TH1 and T17 within a strong TH2 environment are often seen in patients with ME/CFS as well. In fact, many people with ME/CFS also have allergies. Changes in TH1/TH2 responses aligns to the theory that ME/CFS can be triggered by viruses such as Epstein Barr (EBV) and cytomegalovirus (HCMV). Chronic stress can also reactivate viruses that downregulate TH1 immune responses, which can also contribute to chronic fatigue.
A study lead by Begona Ruiz-Nunez discovered a link to thyroid conditions and ME/CFS. What they found was that CFS patients had lower serum levels of T3 and T3 but normal TSH levels (Dockrill, 2018). What they also found was that CFS patients often demonstrated higher levels of reverse T3 (rT3), which may contribute to lowering levels of free T3 (fT3) and total T3. Additionally, people with ME/CFS also have abnormal levels of serotonin and dopamine (Dellwo, 2018). Cortisol levels are also on the low end of the range for ME/CFS patients, which can be due the chronic stress or from adrenal dysfunction caused by viral or bacterial burden.
Diet and Lifestyle
The diet and lifestyle plan should consist of an anti-inflammatory diet with elimination of reactive food antigens, high in vitamins and minerals that support mitochondrial function. It may be a good idea to run a comprehensive food sensitivity test for these patients to “cut to the chase” and help them identify their triggers early. The diet should initially be a strict Elimination diet that eliminates the common triggers (gluten, dairy, nuts, soy, shellfish). Interesting, many people with ME/CFS also have chronic intestinal candidiasis, which may be leading to immune depression in many CFS patients (Cater, 1995). Therefore, it would be a good idea to investigate if there is overgrowth and implement an anti-Candida diet and rotate in some natural antifungals within the diet and supplement protocols. A micronutrient test would also be helpful to determine deficiencies associated with the fatigue. Common deficiencies include Vitamin B6, B12, magnesium, and potassium.
The diet should be supportive of the immune system, and include dark green leafy vegetables (kale, spinach, lettuce, romaine), dark fruits such as blueberries, pomegranates, spices and herbs such as garlic, ginger, curcumin, onions, shallots and cruciferous vegetables. Certain flavonoids, such as quercetin, can have strong antioxidant and anti-inflammatory properties which can diminish the sensation and intensity of fatigue. “It (quercetin) inhibits mast cell degranulation and decreases the secretion of TNF-α, IL-6 and IL-8” (Roerink et al., 2017). Minimal processed foods and foods high in saturated fats should be consumed since they can increase TH1 response. Also, a diet high in fat is associated with elevated levels of IL-6 (Roerink et al., 2017), perhaps due to increased LPS levels. Fat sources should be from polyunsaturated omega-3’s which contain compounds that can inhibit the activation of NF-kB, which stimulates a gene encoding IL-6 (Roerink et al., 2017). EPA and DHA can promote an antioxidative effect that may also help explain the suppressive effect on IL-6. Omega-6 fats, on the other hand, should be limited as they can activate NF-KB and in consequence increase IL-6 levels.
The focus should be on whole and natural foods. Prebiotic rich foods and foods high in fiber would greatly support the microbiome. Healthy fats such as fish oil and olive oil may address some of the inflammatory markers. Probiotics such as Bifidobacteria strains can help regulate Treg cells to improve TH1/TH2 balance. Prebiotic rich foods can also support the bifidobacterial strains to upregulate the Treg cells. Strategies can focus on improving TH1/TH2 balance through increasing Treg cells. However, experimental trials of increasing TH1 can also help drive down some of the TH2 response using adaptogens such as Reiki or Maitake mushrooms.
Below is a chart of some interventions to address ME/CFS
Broderick, G., Fuite, J., Kreitz, A., Vernon, S. D., Klimas, N., & Fletcher, M. A. (2010). A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun, 24(7), 1209-1217. doi:10.1016/j.bbi.2010.04.012
Cater, R. E., 2nd. (1995). Chronic intestinal candidiasis as a possible etiological factor in the chronic fatigue syndrome. Med Hypotheses, 44(6), 507-515.
Dellwo, A. (2018). Causes and Risk Factors of Chronic Fatigue Syndrome. Retrieved (2018, July 27) from https://www.verywellhealth.com/what-causes-chronic-fatigue-syndrome-716100
Dockrill, P. (2018). Chronic Fatigue Syndrome Might Have a Crucial Hormonal Link. Retrieved (2018, July 27) from https://www.sciencealert.com/we-just-discovered-a-crucial-hormonal-link-to-chronic-fatigue-syndrome-thyroid-myalgic-encephalomyelitis
Grygiel-Gorniak, B., & Puszczewicz, M. (2015). Fatigue and interleukin-6 – a multi-faceted relationship. Reumatologia, 53(4), 207-212. doi:10.5114/reum.2015.53998
Montoya, J. G., Holmes, T. H., Anderson, J. N., Maecker, H. T., Rosenberg-Hasson, Y., Valencia, I. J., . . . Davis, M. M. (2017). Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A, 114(34), E7150-e7158. doi:10.1073/pnas.1710519114
ME Association (2017). MEA Summary Review: Cytokine signature associated with disease severity in ME/CFS. Retrieved (2018, July 27) from http://www.meassociation.org.uk/2017/08/mea-summary-review-cytokine-signature-associated-with-disease-severity-in-mecfs-18-august-2017/
Moss, R. B., Mercandetti, A., & Vojdani, A. (1999). TNF-alpha and chronic fatigue syndrome. J Clin Immunol, 19(5), 314-316.
Roerink, M. E., van der Schaaf, M. E., Dinarello, C. A., Knoop, H., & van der Meer, J. W. (2017). Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation, 14(1), 16. doi:10.1186/s12974-017-0796-7
Stanford Medicine. (2017). Researchers identify biomarkers associated with chronic fatigue syndrome severity. Retrieved (2018, July 26) from https://med.stanford.edu/news/all-news/2017/07/researchers-id-biomarkers-associated-with-chronic-fatigue-syndrome.html