The background on this discovery is that in the course of my normal consulting, I had a cluster of 5 diet coaching clients over roughly one month presenting for a number of different goals, yet similar issues - with a common complaint of daytime fatigue.
Most had joint pains and involuntary muscle contractions. The male and female clients had endocrine, sleeping and neurological disorders, such as acute anxiety. The males and females exhibited signs of alopecia. All had extensive pathology data, spanning more than 10 years and a history of symptoms longer than 15 years. Only one client had ever been officially labelled as a "CFS/ME" patient.
Fatigue is a common and non-specific symptom, with many causes. Solutions that may work for some patients suffering from fatigue may not be generalisable to ME/CFS, which is why strict clinical criteria is necessary. The lack of formal diagnoses make your anecdotes less compelling. Likewise, we are less interested in connections with the vast array of other disorders you listed, we are only interested in patients that meet ME/CFS criteria (even then, there are arguably too many case definitions!).
Specificity is central to science!
ME/CFS is not daytime fatigue, nor exercise intolerance. But a
specific set of symptoms -
the loss of mental stamina/concentration and PEM in particular. Many patients are housebound or bedbound and are unable to work. Patients don't necessarily have "fatigue", but high fatigability of all muscles - from facial muscles to the toes. The symptoms people associate with fatigue - stiffness, soreness aren't fatigue itself, but indicate afferent feedback (and a shift in the balance of gamma motor drive versus muscle spindle activity, hence a sensation of stiffness)
However, I would also like to point out that "involuntary muscle contractions" are not typical for ME/CFS and I personally don't really associate joint pain itself with the condition either, though patients may have joint pain for other reasons. Alopecia likewise is does not have any particular association.
Some patients have GI issues, others do not. Same with sleeping issues. Most patients I know has tried extensive amounts of dietary modifications and supplements, including more than a few that you mention in your manuscript. I agree that ENT type infections seem to be common.
My own case is somewhat unusual - I have the same symptoms as ME/CFS, yet my initial illness was Acute motor axonal neuropathy (a form of Guillain Barre Syndrome) which notably, was not triggered by an infection (I did not have symptoms of an infection and I tested negative to a long list of pathogens). In the first 5 years, I had tested negative many times on every test under the sun for EBV, CMV, HHV6 (and once for HHV7) - both serological testing and PCR, with tests done in America as well as Australia. Therefore I still wonder what commonalities there are that don't involve persistent EBV/CMV/HHV6 infections.
I'd also like to point your attention to the fact that there are specific physiological findings in ME/CFS patients, namely a reduction in the ventilatory threshold (gas exchange threshold) on the 2nd of two CPETs, being repeated after 24 hours. This has been found in over 10 studies and is the most replicated finding so far in the field.
I'd also like to point out that many patients don't necessarily have decreased VO2Max compared to age/sex norms. There is also suggestive evidence of chronotropic incompetence in a minority of patients, but I am sceptical as to whether patients had sufficient encouragement to actually achieved a true VO2Max so this could be a testing artefact.
This finding combined with prior electrophysiological testing and recent studies of healthy individuals (investigating the physiological determinants the VT1/gas exchange threshold ), suggests that the fatigue is primarily central in nature, but is mediated through peripheral afferents that in turn reduce excitability of the motor cortex and possibly other areas of the brain. Notably, studies have not found any consistent evidence of mitochondrial disorders or muscle damage post-exercise, which rules out a lot of hypotheses. Though mitochondrial dysfunction could be a downstream consequence of cellular dysfunction, induced in turn due to extracellular factors. (Also note that ALL perceived fatigue is central in nature - supramaximal twitch interpolation EMG studies have found the same results for ME/CFS, peripheral neuropathies, muscular dystrophies and central neuropathies!)
Of course there are many hypothetical reasons why these afferents are being stimulated, including mitochondrial disorders. But central to all chronic illnesses are feedback loops and particular attention needs to be given to extracellular feedback loops - intracellular metabolic feedback loops are insufficient to explain disease, because it doesn't explain how all of the cells seemed to get into that state in the first place, and secondly, why that state is being maintained throughout the body. Even neoplasms (which necessarily have intracellular metabolic feedback loops) require extracellular mechanisms before they become malignant. "Lifestyle illnesses" likewise, necessarily have characteristic feedback loops - between the biology and behaviour!
All of the clients had exercise intolerance to even the mildest exertion levels, with suboptimal lactate threshold and oxygenation, even beyond my expectations for a sedentary lifestyle.
How do you know what their lactate thresholds or oxygenation levels were? Did they undergo cardiopulmonary testing, with blood lactate testing?
Anyway, with all this in mind, you state several hypotheses relating to the liver. (correct me if I have mischaracterised any of these hypotheses)
The first is that there is latent infection of the liver by EBV or other herpesviruses and this will either create a metabolic burden for those cells. Or antibodies directed against EBV will target hepatic cells, leading to viral hepatitis like symptoms.
My first comment is the virus in the latent phase has very little metabolic burden and probably isn't going to lead to much immune activity either. But that still leaves possibility of more active infection. Or the possibility of residual post-viral effects.
Which begs the question, why don't we see more liver related pathology? For example, there is an absence of signs of hepatitis in most patients. Similarly a lack of other signs such as fibrosis.
No studies have shown defects in hepatic gluconeogenesis leading to problems with glucose homeostasis. Most patients do not have problems on liver function tests, though a surprising number of patients do report high bilirubin. While some patients do appear to generate more lactate than expected (this is a consequence of altered motor unit recruitment patterns as discussed above with regards to the ventilatory threshold findings), patients don't necessarily have a high level of lactate at baseline, and studies haven't yet found a defect in lactate clearance.
I have a friend with autoimmune hepatitis and his symptoms were quite different to that of ME/CFS (and his condition is under control with immunomodulating drugs).
Studies have also not found any unusual hypoxia (multiple studies), despite you stating that it is a "Another CFS/ME feature".
You also discuss a hypothetical α-KGDH deficiency, though signs of this have not yet been found in any studies.
I always like to note what happens in genetic disorders when considering deficiencies of specific proteins (whether human diseases if known, otherwise in murine gene knockout models)
https://rarediseases.info.nih.gov/diseases/617/alpha-ketoglutarate-dehydrogenase-deficiency
Notably, it leads to hypoglycemia, seizures, ataxia and hypertonia, none of which are typical of ME/CFS.
The metabolic signs (besides glucose) are increased creatine kinase levels, elevated alpha-ketoglutaric acid in urine, and a decreased plasma beta-hydroxybutyrate-to-acetoacetate ratio.
No issues with creatine kinase levels before/after exercise have been found. Elevated alpha-ketoglutaric acid was found in the Hanson study you cited, but notably has not been found in the other metabolomics studies (see this 2020 systematic review:
https://link.springer.com/content/pdf/10.1186/s12967-020-02356-2.pdf)
However I note an additional a caveat of these metabolomics studies, namely what goes on in cells in the blood (or spills over into urine) isn't necessarily the same as what goes on in peripheral cells, or in specific organs, given that the microenviroments can be very different.
As far as I know, no study has found (or investigated) α-Ketoglutarate dehydrogenase function or levels in ME/CFS. Metabolomics studies have contrasting findings of Succinic acid (downstream of α-Ketoglutarate dehydrogenase in the citric acid cycle), with one study finding elevated levels, another finding lower levels, others finding no difference, overall suggesting no significance. However
given prior research (and the aforementioned metabolomics studies), I'm not sure this would be something I'd specifically look at.
Also, note that "Complex IV" is Cytochrome c oxidase, not α-ketoglutarate dehydrogenase.
As such, I don't find this evidence particularly compelling. But still, I am open to suggestions of specific testable hypotheses that will show pathology (and hasn't already been ruled out by prior studies).
At this point, although having read perhaps 900 papers, I thought it would probably be best if I studied the literature further, wrote a review and shared it with the community. This presented some new difficulties, as although demonstrated by my recent manuscript, through personal interests my understanding of metabolism, rheumatology, cellular biology, immunology, endocrinology and biological pathways could be considered with some equivalencies to a PhD level education, due to my life choices and preference for self-education, usually by intense reading, I lack the credentials required to present these findings to a wider audience, in the format they would normally be inclined to appreciate and give due consideration.
I'm trying to be polite about this, but your level of education and experience is sufficient to start a post-graduate degree, rather than approaching a PhD standard.
More than a few patient-members of this forum have (individually) read over 10,000 studies and published peer-reviewed (re)analyses and commentaries in mainstream journals, yet this is merely the equivalent of an undergraduate honours thesis at best. (Of course some members already had masters degrees or PhDs and a few have managed to obtain such degrees despite being ill.) It isn't PhD level research unless you publish a systematic review/meta analysis and publish several primary research studies.
