Davis speech from Millions Missing. Some new info on metabolic trap hypothesis

[Diwi9]

@JES
Ideally i would like from ME/CFS Researchers to specifically ask for these conditions and then identify whether there is a statistically significant association / comorbidity between ME/CFS and any of the conditions discussed in the Spreadsheet. There are conditions as "benign" as Fatty Liver. But Fatty Liver in combination with other issues may be bringing the Perfect storm we are looking for.

I do not know if this investigative work has been performed on a large scale. To be honest i am really worried because of the fact that not even one paper suggests that a simple test such Total Bile Acids (TBAs) has been performed. Also, note that the only way to rule out a silent Liver Disease is Liver Biopsy from multiple sites. Obviously such testing is not possible. The liver may have very serious problems and despite this, Liver enzymes may be entirely normal (...)

In other words, many things may have been missed.

I'm not up to speed on all of the past research, but I know there was a publication on post mortems of ME patients. I don't remember seeing any conclusion with liver problems? The only finding that seems to crop up again and again is ganglionitis. With the results of you analysis, would you expect findings of liver problems to show up on a post mortem?

 

[mariovitali]

I'm not up to speed on all of the past research, but I know there was a publication on post mortems of ME patients. I don't remember seeing any conclusion with liver problems? The only finding that seems to crop up again and again is ganglionitis. With the results of you analysis, would you expect findings of liver problems to show up on a post mortem?

Makes sense if we assume that during the post-mortem there has been biopsies of the Liver from multiple sites and examination of these samples under the microscope. Has this been performed?

If we assume that this was the case there are some more factors that need to be taken into account : For example we do not know if Liver Fibrosis exists in a sufficient amount in patients having the disease less than 5 years (the number is just an example). F1 which is Level 1 fibrosis is not much of an issue. F2 onwards suggests that there is definitely something wrong.

Second, i am not suggesting that all ME/CFS patients have Liver Fibrosis so i never suggested that Liver fibrosis is a finding that will characterize ME/CFS patients vs Controls. What i am suggesting is that for a -quite possibly- significant percentage of ME/CFS Patients, specific Liver issues may be the cause (along with other factors) or aggravating the condition.

Primarily i would like to focus the interest of Researchers to the Liver and whether previous or current Liver problems (or newly acquired such as Hepatotoxicity from Medication) can set the stage for ME/CFS.

My understanding is that this Task is easy to do, especially since so many Centers are looking for causes right now.

I will be looking very closely to the following work by Prof. Hanson :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365380/

This is a small study but finds metabolites that suggest Liver Disease. More specifically :

Taurine, which has already been found to be present in lower concentrations in the plasma of patients8 , is already used as a nutritional supplement by many ME/CFS patients because of possibility of symptom relief, although no rigorous research has yet proven its effectiveness. Taurine has a number of functions in skeletal muscle, the retina and the central nervous system and its concentrations may be relevant to the altered amounts of lipid metabolism compounds we observed in ME/CFS patients. Taurine conjugates with bile acids to form bile salts, necessary for proper lipid absorption during digestion, and the bile acid biosynthesis pathway was found to be negatively affected in our patient cohort. Primary bile acids such as sulfoglycolithocholate (13) are synthesized in the liver and the major bile salts result from its conjugation with taurine (28) and glycine, forming taurochenodeoxycholate and glycochenodeoxycholate (21), respectively, which are all numbered metabolites found to be significantly reduced in ME/CFS patients. Reduction in these compounds is suggestive of damage to the liver. A study from the FDA National Center for Toxicological Research (NCTR) was able to identify liver injury biomarkers as the result of drug-induced hepatotoxicity in rats25. Strikingly, several other metabolites identical to our findings were also identified in their report, namely 5-guanidino-2- oxopentanoic acid (12, also named 2-oxoarginine), sebacic acid (60), along with energy metabolites from the glyoxylate and dicarboxylate metabolism. These biomarkers could be used to define a serum metabolic signature by creating a panel for hepatotoxicity prediction25. Whether ME/CFS patients actually have liver damage as a result of the disease is not known, as it also could be a consequence of medication toxicity in this patient group, which often uses prescription or over-the-counter pain relievers. Abnormally elevated levels of fatty acids 72, 73 and 74 (Table 2) could be a sign of hyperlipidemia and could also be related to a deficiency in liver activity.

I believe that this kind of Research should be done on a greater scale.

 

[FMMM1]

The way the data splits in many studies is one third to two thirds. This might or might not indicate two separate diseases. There are so many potential confounds that all I am prepared to say is both strictly defined CFS and ME could be mostly one disease (ignoring the massive misdiagnosis rate for CFS right now), all the way to CFS is a massive hodgepodge and ME is a bunch of different disorders. However most of the opinions we have come from a host of different symptoms, which the diversity of the biochemistry might easily explain, to some variations in biochemical markers, to some variations in treatment outcomes.

The reason to insist on quality ME definitions is that is how to advance the science faster. Very weak CFS definitions like Oxford are so bad they are anti-science. Most are just inadequate with lots of potential confounds in any study that uses them.

It is probably too late to use specific outbreak cohorts, as the numbers are too few, and each outbreak should ideally be treated as a separate cohort.

My best guess is that CFS is many conditions, and that ME is at least two. This is however a guess, and as the data becomes available from many of these new studies I predict there will be plenty of surprises for all of us, including our scientists.

If the metabolomic data proves stable across many subgroups over time, and it looks like it might, then it will strongly suggest that ME is one disorder with a great many variations.

Not sure where this reply is going---

I briefly read Cort Johnson's article on a recent conference in Montreal.

Maureen Hanson gave a presentation on her metabolic study; the data is remarkably consistent with Naviaux's (& Armstrong & Japanese researchers - apologies if I missed someone). However, I think someone on this site stated that Davis reckons that there may be a biological system that is common i.e. there's a switch that gets flipped and then you present with ME/CFS. So there may be a bunch of ways to get to a common outcome; and the common outcome may be demonstrated by the relatively consistent metabolic studies.

Cara Tomas gave a presentation in Montreal on her Seahorse studies. Again, from memory, these Seahorse studies are consist, i.e. they demonstrate impaired energy production in cells [has anyone tested muscle cells?]. Here's an extract from Cort's article:
"Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results".
The latter point is interesting since Fluge/Mella [& Ron Davis?] found that for muscle cells the altered energy production tracks with the blood/plasma. I.e. if you use healthy muscle cells and ME/CFS blood/plasma then you get the impaired energy production and vice versa. Possibly the immune system is the master controller in this disease. The muscle cells are simply responding.

Mark Davis presented data showing T-cell clonal expansion (OMF community symposium September 2017). I.e. T-cell activation; possibly T-cell autoimmunity. This was a consistent finding albeit based on a small number of people with ME/CFS.

We don't have large scale studies (e.g. Ron Davis has reported the results from testing 10 people using the nano needle), or validated methods (Davis's team are working on validating the nano needle). However, there appears to be some data showing a consistent picture e.g. metabolomics/seahorse cell respiration studies/T-cell clonal expansion. Possibly the consistent metabolomics/seahorse/nano needle data simply indicates a common outcome (downstream effect); the question may be what is the (upstream) cause. I'm just wondering if we need something new e.g. Mark Davis's T-cell clonal expansion; or a better understanding of virus's [google "Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity" - Cort has written an article on this] to figure out the cause.

I think Ron Davis is right i.e.we need fundamental research to understand the disease.

 

[neweimear]

Any perspectives on how long it will take to figure out.....I just continue to get sicker, there is so much wrong with us, it seems next to impossible to decipher what's causing what..

 

[Murph]

Any perspectives on how long it will take to figure out.....I just continue to get sicker, there is so much wrong with us, it seems next to impossible to decipher what's causing what..

This specific metabolic trap research is supposed to yield results within six months. Presumably somewhat longer for a treatment to become available.

 

[Trillian]

My working theory related to this... Biochemistry texts include information on how the many reactions take place at a specific temp, pH, and other gradients of substrates etc. When conditions change, reactions speed up, slow down or cease to occur. Each variation may effect other reactions or create alternate end products effecting all other reactions around them.

Luckily, there are many ways to maintain or recover homeostasis... such as the usual aerobic metabolism is supplemented by anaerobic which creates lactic acid which in turn can be shunted and used by inactive muscle cells easily when there is too much. We breath more - exhale excess CO2, increase O2 and then the aerobic system can take care of energy needs again. (Simplistic version to illustrate only) During this pH changes can alter how easily oxygen is held or released from hemoglobin, to help prevent overloads. Highly complex.

My theory is that an insult pushes us past the usual methods of recovering homeostatis and impairs ATP production which then impacts everything. The myriad of symptoms come from varied ways our bodies are trying to get back to normal.

This might be the metabolic switch you refer to. Recovery does happen, although not often enough. Pacing, nutrition, and avoiding mental/physical stress, the most recommended pathways to improvements, all are ways to give the body system of balances a chance to equilibrate, then slowly, the systems can begin to optimize themselves.

If so, is this enough for recovery, or do one or more reactions get stuck in an adaptive/reactive mode which prevents return to normal? Would this be the metabolic switch?

 

[Eastman]

Any perspectives on how long it will take to figure out.....I just continue to get sicker, there is so much wrong with us, it seems next to impossible to decipher what's causing what..

Maybe in the meantime, you could follow @mariovitali's thread. He claims to have seen some patients recover e.g. see here.

 

[mariovitali]

Maybe in the meantime, you could follow @mariovitali's thread. He claims to have seen some patients recover e.g. see here.

I will have to add that I”ve been trying since 2015 to have Researchers evaluate this claim under strictly controlled conditions.

 

[ljimbo423]

If so, is this enough for recovery, or do one or more reactions get stuck in an adaptive/reactive mode which prevents return to normal? Would this be the metabolic switch?

I think Morris and Maes have a good theory in this paper.

Where they explain how oxidative and nitrosative stress (O&NS) and an activated immune system, create "self-sustaining and self-amplifying pathological processes". Which includes mitochondrial dysfunction.

The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS.

Jim

 

[Snow Leopard]

Perhaps the third disease is Liver Disease

Liver disease is not the cause, but I think liver issues are a key risk factor.

I like many other people have Gilbert's Syndrome (and so do much of my healthy family). The only "high" metal I have when tested is copper - but that is common in the local population here due to the water and soil.

 

[mariovitali]

Liver disease is not the cause, but I think liver issues are a key risk factor.

I think it is better to say that we do not know if Liver is the cause or is a risk factor, correct? All i can say is that i see a pattern of Liver / Gallbladder issues among ME/CFS Patients (and other syndromes such as Post-Accutane, Post-Finasteride, etc) which has to be further explored by Medical Professionals.

I like many other people have Gilbert's Syndrome (and so do much of my healthy family). The only "high" metal I have when tested is copper - but that is common in the local population here due to the water and soil.

So you have two "Liver Stressors" both shown in the Google sheet i provided. Of course many people can have these but if they also have impaired Bile Acid Metabolism and some additional problems to RCT (Reverse Cholesterol Transport) and/or Vitamin K absorption then i hypothesise that these people may get ME/CFS .

But again, there are so many other issues that i believe that Researchers haven't looked at. In my cohort, 17% has pathogenic alleles for SERPINA1 (Alpha-1 Antitrypsin Deficiency). I do not believe that this is a coincidence but this hypothesis must be further explored.

Interestingly , Alpha-1 Antitrypsin Deficiency affects the Liver (hence the entry on the spreadsheet) :

https://en.wikipedia.org/wiki/Alpha_1-antitrypsin_deficiency

I wonder what is the cost of not exploring this hypothesis vs the cost of exploring it.

EDIT : I think "Dr Blanco" may be right :

http://forums.phoenixrising.me/inde...ast-cell-treatments.19045/page-15#post-319084

and

3. Fibromyalgia
Up to date three cases have been reported by Blanco et al. (Hospital Valle del Nalón, Principality of Asturias, Spain) [68,69].

Cases 1 and 2 were reported in 2004 [68]. In the early nineties two PI*ZZ Spanish sisters with severe fibromyalgia started AAT replacement therapy. During the next 3 and 5 years, respectively, they both experienced a rapid, progressive and constant control of fibromyalgia symptoms. However, a commercial shortage of AAT by 1998 led to the annual interruption of infusions for 4-6 consecutive months during 5 years. As a result, fibromyalgia symptoms recurred during infusion interruption and disappeared completely whenever infusions were resumed. Currently, both patients are regularly treated with Prolastin®, and do not have fibromyalgia symptoms anymore (Figure (Figure33).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094201/

and some more

http://forums.phoenixrising.me/inde...a-1-antitrypsin-deficiency.51189/#post-845802

 

[adambeyoncelowe]

Hyde and Ramsay found some patients had swollen livers that could be felt by palpation. I'm sure it's involved in ME in many cases, but agree it's probably not causative. It's too easy a thing to notice.

 

[valentinelynx]

I don't think we have a name for anything (as far as I know!) but IMO, one group has to be immune deficient and the other autoimmune. I don't mean the disease name, I mean the mechanism or characteristics.

I would assume one group constantly gets sick, fevers, flus, chills, swollen lymph nodes and is immune deficient on tests vs. the other group literally never gets sick, is autoimmune on tests, and is skewed toward allergic reactions. But I am just guessing. And I have no idea what the third group might be!

Hmm. Where would that put me, I wonder? I have both immune deficiency (low IgG, low B cells, low NK cell # and function) and 8/9 high titers of the CellTrend autoantibodies (plus the GAD65 antibody). I should get sick a lot based on my low immune function, but don't (except a severe case of gastroenteritis once or twice a year).

LOL! Now I see I wasn't the only one with this sort of issue...

 

[Gingergrrl]

Hmm. Where would that put me, I wonder? I have both immune deficiency (low IgG, low B cells, low NK cell # and function) and 8/9 high titers of the CellTrend autoantibodies (plus the GAD65 antibody). I should get sick a lot based on my low immune function, but don't (except a severe case of gastroenteritis once or twice a year).

I have no idea but I know that there are many people who have low immune functioning on tests AND autoimmunity. Maybe this is a whole other sub-group? I really have no idea! I have had very low NK cell functioning since first tested (in 2014) but it doesn't seem to play any active role since I have not had any traditional illness in 5+ years, including the past year with zero B-cells from Rituximab. I was at the hospital almost every day for three months while my mom was dying and every single member of my family got sick except for me. Weird.

 

[mariovitali]

I have no idea but I know that there are many people who have low immune functioning on tests AND autoimmunity. Maybe this is a whole other sub-group? I really have no idea! I have had very low NK cell functioning since first tested (in 2014) but it doesn't seem to play any active role since I have not had any traditional illness in 5+ years, including the past year with zero B-cells from Rituximab. I was at the hospital almost every day for three months while my mom was dying and every single member of my family got sick except for me. Weird.

I believe that the reason behind you not getting sick is the fact that your N-Linked Glycosylation is not working properly (hypothesis). Because this is not working right, viruses simply do not find the necessary "material" to replicate.

This hypothesis has been mentioned to a couple of ME/CFS Researchers. The interesting thing is that this Hypothesis can be tested out quite easily by taking a specific supplement.

 

[Gingergrrl]

I believe that the reason behind you not getting sick is the fact that your N-Linked Glycosylation is not working properly (hypothesis).

What does this mean?

Because this is not working right, viruses simply do not find the necessary "material" to replicate.

In my case, the viruses were definitely replicating b/c I remained IgM+, Early Antigen (EA)+, etc, for EBV for about 3-4 years post Mono. But I have not had a traditional illness (cold, flu, etc) since Jan 2013 which is now over five years. I have been exposed to family members and friends with colds, flu, strep, etc, but have never caught it. Yet as a child up until 2013, I was constantly getting tonsillitis and traditional illnesses. But once I got the final virus in Jan 2013 (which caused POTS), I never got "sick" again.

The interesting thing is that this Hypothesis can be tested out quite easily by taking a specific supplement.

What is the supplement? I doubt that I would ever try it but am just curious for my own knowledge!

 

[mariovitali]

What does this mean?



In my case, the viruses were definitely replicating b/c I remained IgM+, Early Antigen (EA)+, etc, for EBV for about 3-4 years post Mono. But I have not had a traditional illness (cold, flu, etc) since Jan 2013 which is now over five years. I have been exposed to family members and friends with colds, flu, strep, etc, but have never caught it. Yet as a child up until 2013, I was constantly getting tonsillitis and traditional illnesses. But once I got the final virus in Jan 2013 (which caused POTS), I never got "sick" again.



What is the supplement? I doubt that I would ever try it but am just curious for my own knowledge!

I should have made this clear. I meant the traditional influenza virus which goes away in most cases within 3 days. Something that could be answered by an expert is whether ME/CFS patients do not get infections from enveloped viruses in general.

I will PM you the name of the supplement

 

[ljimbo423]

But I have not had a traditional illness (cold, flu, etc) since Jan 2013 which is now over five years. I have been exposed to family members and friends with colds, flu, strep, etc, but have never caught it. Yet as a child up until 2013, I was constantly getting tonsillitis and traditional illnesses. But once I got the final virus in Jan 2013 (which caused POTS), I never got "sick" again.

This is my experience as well. I use to get bronchitis, after a cold or a flu, once or twice a year for years and many, many illnesses as a child.

It's been years now since I've had a real cold, flu or bronchitis. I haven't had a true fever in probably 15 years or longer! This seems to say that my innate immunity is high, preventing colds and flus.

What other dysfunctions I have in my immune system is anybody's guess!

Jim

 

[FMMM1]

Any perspectives on how long it will take to figure out.....I just continue to get sicker, there is so much wrong with us, it seems next to impossible to decipher what's causing what..

Check out the OMF site; they've just announced the opening of a new ME/CFS Research Centre at Harvard. I suppose we have to hope that researchers will make progress in the near future. Here's an extract from the OMF site [https://www.omf.ngo/science-wednesday/]:

"OMF creates new Harvard ME/CFS Collaborative Research Center and expands Stanford Data Center
BIG NEWS on this #OMFScienceWednesday: OMF creates new Harvard ME/CFS Collaborative Research Center and expands Stanford Data Center ME/CFS Collaborative Research Center at the Harvard: We are proud to announce that OMF has funded $1.8 million for the establishment of a new ME/CFS Collaborative Research Center at the Harvard Medical School affiliated hospitals, which includes Massachusetts…"

 

[pibee]

Hmm. Where would that put me, I wonder? I have both immune deficiency (low IgG, low B cells, low NK cell # and function) and 8/9 high titers of the CellTrend autoantibodies (plus the GAD65 antibody). I should get sick a lot based on my low immune function, but don't (except a severe case of gastroenteritis once or twice a year).

LOL! Now I see I wasn't the only one with this sort of issue...

I have 8/9 on CellTrend too,quite high with M4 highest at 48,5.
no low IgGs (other things never measured). Only low IgG4 which is least important think.

with positive anti-GAD65 you should get some serious treatment I think? do you have any symptoms of encephalitis other than ME ?