The Non-Mystery of Chronic Fatigue Syndrome

The-Mystery-of-Chronic-Fatigue-Hadassah-Magazine-Chronic-UNREST-Jennifer-BreaThe Non-Mystery of Chronic Fatigue Syndrome

My wife gave me an article from Hadassah Magazine entitled “The Mystery of Chronic Fatigue Syndrome”, by Carol Saline, about the 2017 documentary on Jennifer Brea called “Unrest”.  The film documents her experience with severe chronic fatigue.(1-3)  Jennifer Brea was a previously healthy robust young women until the onset of immune dysfunction with six different infections, followed by debilitating fatigue and brain fog.  The article goes on to state there is no known cause and no known cure for “chronic fatigue syndrome” also called “ME/CFS”.  This has changed. The mystery has been unraveled by a group from Stanford.  Above image courtesy of Jennifer Brea Unrest Movie.

Gut bacteria dysbiosis clostridiaLeaky Gut – Incriminating the GUT Microbiome

Dr Montoya’s group at Stanford found elevated pro-inflammatory cytokines in chronic fatigue patients, implicating chronic inflammatory up regulation. (4-5)   In an accompanying editorial in PNAS, Dr Anthony Komaroff  explains it nicely with this quote:(5)

“Another way of incriminating infection in CFS (Chronic Fatigue Syndrome) involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain.”

Notice Jennifer Brea’s story includes six different infections, yet the story says nothing about the antibiotics used to treat these infections.  Many of these patients have history of multiple long term antibiotic use implicating gut dysbiosis and leaky gut.   The use of NSAIDS for fibromyalgia pain worsens the leaky gut pathology as discussed in my previous article.

Leaky gut causes low grade endotoxemia which then upregulates inflammatory cytokines which travel to the brain causing upregulated microglia, depression and HPA (hypothalamic pituitary axis) dysfunction, which then causes adrenal, thyroid and gonadal hormone dysfunction leading to severe fatigue and fibromyalgia.  On top of this there is usually a variable element of mitochondrial dysfunction.

Pre-Existing Genetic Defects and Aggravating Conditions

Symptoms are worse in patients with pre-existing genetic defects in methylation pathways such as MTHFR, or COMT (catechol -o-methl-tranferase), or B12 transport protein defects (detected with elevated MMA levels)   Symptoms are worse if there is an aggravating medical condition such as low thyroid, menopausal transition, gluten sensitivity, stressful workplace or home life etc.

The Mystery Becomes Unraveled

The reason why this disease is a mystery is because the mainstream conventional physician does not bother to test for any of these abnormalities.  Nor do they treat them. We do, and most of our patients eventually get better. That is why Chronic Fatigue/Fibromyalgia is a non-mystery.

Jeffrey Dach MD
7450 Griffin Road Suite 180-190
Davie, Florida 33314

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Articles with Related Interest

Low Level Endotoxemia, Depression and Endocrinopathy

NSAIDS, Small Bowel Damage and Leaky GUT

Links and References

1)  The Mystery of Chronic Fatigue Syndrome By Carol Saline February 2018

2)  Jennifer Brea’s Sundance award-winning documentary, Unrest, is a personal journey from patient to advocate to storyteller. Jennifer is twenty-eight years-old, working on her PhD at Harvard, and months away from marrying the love of her life when a mysterious fever leaves her bedridden. When doctors tell her it’s “all in her head,” she picks up her camera as an act of defiance and brings us into a hidden world of millions that medicine abandoned.
In this story of love and loss, newlyweds Jennifer and Omar search for answers as they face unexpected obstacles with great heart. Often confined by her illness to the private space of her bed, Jennifer connects with others around the globe. Like a modern-day Odysseus, she travels by Skype into a forgotten community, crafting intimate portraits of four other families suffering similarly. Jennifer Brea’s wonderfully honest and humane portrayal asks us to rethink the stigma around an illness that affects millions. Unrest is a vulnerable and eloquent personal documentary that is sure to hit closer to home than many could imagine.
Myalgic Encephalomyelitis (ME), commonly known as Chronic Fatigue Syndrome (CFS) or ME/CFS, is a devastating multi-system disease that causes dysfunction of the neurological, immune, endocrine and energy metabolism systems.
It often follows an infection and leaves 75% of those affected unable to work and 25% homebound are bedridden. An estimated 15-30 million people worldwide have ME.

3)  Psychology Today: Why is Chronic Fatigue Syndrome Still a Mystery?


4)  Montoya, Jose G., et al. “Cytokine signature associated with disease severity in chronic fatigue syndrome patients.” Proceedings of the National Academy of Sciences (2017): 201710519.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis. Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.


Another way of incriminating infection in CFS involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain (5, 16⇓–18).

5)  Komaroff, Anthony L. “Inflammation correlates with symptoms in chronic fatigue syndrome.” Proceedings of the National Academy of Sciences 114.34 (2017): 8914-8916.

Neuroendocrine studies demonstrate abnormalities of the hypothalamic–pituitary–adrenal axis, of growth hormone secretion, and of adrenergic metabolism in CFS patients that are distinct from those seen in healthy control subjects and in patients with major depression.

Increased lactate levels in cerebrospinal fluid may indicate impaired oxidative phosphorylation, with a consequent shift to anaerobic metabolism. Possible causes of acquired mitochondrial dysfunction in the CNS include infection and cerebral hypoperfusion.

Many studies have found evidence of oxidative stress in CFS patients:

For 17 of the 51 cytokines there was a statistically significant upward linear correlation between the level of the molecule and the severity of the illness, suggesting that the cytokine levels are, indeed, causally associated with the symptoms.

Patients with severe symptoms and increased production of proinflammatory cytokines during the initial illness were the most likely to develop CFS.

Another way of incriminating infection in CFS involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain (5, 16⇓–18).

6)  Blomberg, Jonas, et al. “infection elicited autoimmunity and Myalgic encephalomyelitis/Chronic Fatigue syndrome: an explanatory Model.” Frontiers in Immunology 9 (2018): 229.

7)  Researchers identify biomarkers associated with chronic fatigue syndrome severity
Stanford investigators used high-throughput analysis to link inflammation to chronic fatigue syndrome, a difficult-to-diagnose disease with no known cure. Jul 31 2017  Jose Montoya and his colleagues have found evidence inflammation may be the culprit behind chronic fatigue syndrome, a disease with no known cure. Steve Fisch
Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
“Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”

8)  Scientists zoom closer towards understanding chronic fatigue
Last updated on August 1st, 2017 at 6:43 pm by Mihai Andrei E-mail author
Montoya and colleagues found levels of 17 cytokines dramatically higher than normal in patients suffering from CFS. Out of these 17, no less than 13 were associated with promoting inflammation.

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314

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The Non-Mystery of Chronic Fatigue Syndrome
Article Name
The Non-Mystery of Chronic Fatigue Syndrome
Chronic Fatigue is a Mystery to Mainstream Medicine, but not to us.
jeffrey dach md
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