Machine Learning-assisted Research on ME/CFS

[NelliePledge]

I ended up not being able to have a single piece of food, it was not a good feeling at all. Upon looking to what may have happened I linked that incident with having too much acetylcholine.

I was getting warning signs for a couple of months before where I would see my appetite very slowly diminishing but I foolishly kept taking it.

I was taking Choline for a good 9 months non stop

Maybe I will try a low dose of choline for a few weeks to see if it helps reduce appetite?? What supplement were you taking.

 

[mariovitali]

Maybe I will try a low dose of choline for a few weeks to see if it helps reduce appetite?? What supplement were you taking.

It was standard Choline (not Phosphatidylcholine or some other special supplement mix containing also Choline).

 

[arewenearlythereyet]

Might be of interest but eggs are a source of choline ..I eat 3 a day ....gives about 400mg

 

[mariovitali]

@Ravn

Perhaps someone knowledgeable could step in but i look for the expression of IDO1 in several tissues. According to the following there is not much involvement of IDO1 in the Liver :

https://www.proteinatlas.org/ENSG00000131203-IDO1/tissue

Your way of thinking is very important : Does this hypothesis answer the multitude of symptoms and issues we are facing? One very important latest finding is that by Jonas Berquist regarding Pregnenolone. Does "Metabolic Trap" explains this finding or are we looking for other "Metabolic traps" involving pregnenolone as well?

I feel as we do not have important pieces of information (if this info exists please let us know). As an example of questions regarding hypothyroidism :

a) What is the prevalence of Hypothyroidism among ME/CFS Patients vs controls?
b) What is the percentage of women with ME/CFS becoming Symptom-free / Worse / not affected while being pregnant?
c) Among women becoming symptom-free during pregnancy is there some other common characteristic ? (e.g most of them are also hypothyroid)

These questions may help us identifying why the things we see are happening.

Of course we could definitely rule out the Liver by looking at a greater scale the metabolites suggesting Hepatotoxicity/ impaired Liver function identified by Maureen Hanson and performing several Fibroscans / Liver Biopsies. Unfortunately to this day, nothing has progressed in this area.

 

[Ravn]

Perhaps someone knowledgeable could step in but i look for the expression of IDO1 in several tissues. According to the following there is not much involvement of IDO1 in the Liver :

@mariovitali
What about TDO, do you know? That's in the liver I understand but the question is could it be downregulated by any of the typical ME triggers like EBV? Or could it be generally downregulated if there were the sort of liver problems you talk about?

Edit: typo - corrected TPO to TDO

 

[mariovitali]

@mariovitali
What about TPO, do you know? That's in the liver I understand but the question is could it be downregulated by any of the typical ME triggers like EBV? Or could it be generally downregulated if there were the sort of liver problems you talk about?

My understanding is that given a Liver Injury (through a virus, medication, toxic chemical) can disrupt many processes of metabolism since Liver is the main metabolic organ.

EDIT : I see TPO expressed in the Thyroid gland mostly

 

[Milo]

My understanding is that given a Liver Injury (through a virus, medication, toxic chemical) can disrupt many processes of metabolism since Liver is the main metabolic organ.

EDIT : I see TPO expressed in the Thyroid gland mostly

Hi @mariovitali, since the mid 1980’s we know that about half of the patients with ME have needed to have their gallbladder removed (from Osler’s Web by Hilary Johnson, p 28???)

in my case i had lab-confirmed EBV onset with liver involvement (elevated liver enzymes and lots of pain, ultrasound showed sludge in gallbladder but no stone. 5 months after onset i had the mother of all gallbladder attacks, and it was removed, the surgeon found no stone, still sludge, and it was necrotic. I also developped GERD very early into my illness.

The problem we are facing and i will speak of Canadian patients is that the doctors learn early on to not offer testing, and specialized scans would only be ordered by a specialist authorized to perform these scans, under specific criterias. This is to reduce costs to our socialized health care system. They also become very suspicious when the patients start asking for further tests. And really we are suffering from the ‘no testing, no problem’ kind of attitude. Same goes on with brain scans and other specialized testing which would inform a specialist seeing the same population of patients, which would help in looking for similarities and generating research questions. The system is truly broken for us.

Edit to add: @mariovitali the other peculiar symptoms that patients with ME have is sensitivity to epinephrine. (Like when going to the dentist and getting anesthesia which contains epinephrine causes a prolonged crash to many of us) this has not been investigated much. It would be interesting to understand this mechanism, as it is not understood well and patients have trouble convincing dentists not to use epinephrine.

 

[mariovitali]

Hi @mariovitali
specialized scans would only be ordered by a specialist authorized to perform these scans, under specific criterias.

That's the point, right there. Is it possible that given the lack of elevated Liver enzymes , researchers assume that there is nothing wrong with the Liver? I -honestly- begin to feel at loss here but i cannot do anything on my own. What we need is to have a group of patients asking that more Research goes towards Liver function .

Imagine what would happen if Jen Brea and/or Jamison Hill decided to put this question forward (ie "have Researchers looked at Liver function close enough?"). Despite my repeated attempts they just won't.

Thank you also for the source you mentioned regarding gallbladder and ME/CFS, i will have a look.

 

[Milo]

That's the point, right there. Is it possible that given the lack of elevated Liver enzymes , researchers assume that there is nothing wrong with the Liver? I -honestly- begin to feel at loss here but i cannot do anything on my own. What we need is to have a group of patients asking that more Research goes towards Liver function .

Imagine what would happen if Jen Brea and/or Jamison Hill decided to put this question forward (ie "have Researchers looked at Liver function close enough?"). Despite my repeated attempts they just won't.

Thank you also for the source you mentioned regarding gallbladders, i will have a look.

In case you missed it I added something at the bottom of my post above

 

[mariovitali]

@Milo

Spot on regarding epinephrine, although i am trying to understand why. Here is slide 25 from my presentation, Machine Learning ranks epinephrine quite high :






In any case i am trying to find any unknown connections regarding the metabolic trap and ME/CFS and i will post them here

 

[Milo]

@Milo

Spot on regarding epinephrine, although i am trying to understand why. Here is slide 25 from my presentation, Machine Learning ranks epinephrine quite high :


View attachment 4363



In any case i am trying to find any unknown connections regarding the metabolic trap and ME/CFS and i will post them here

I have not followed too precisely your tables and such and not too sure how to interpret, but one question I wonder is whether there is a relationship between epinephrine sensitivity and the presence of adenergic receptor antibodies (from the Sheibenbogen paper).

 

[mariovitali]

@Ravn

TDO is highly expressed in the Liver :

https://www.proteinatlas.org/ENSG00000151790-TDO2/tissue

 

[mariovitali]

I have not followed too precisely your tables and such and not too sure how to interpret, but one question I wonder is whether there is a relationship between epinephrine sensitivity and 5e presence of adenergic receptor antibodies (from the Sheibenbogen paper).

Given epinephrine = Adrenaline = Catecholamines

From a study in mice :

Psychological or physical stress stimulates the adrenal medulla to secrete the two catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine), which initiate the “fight or flight” response. Many researchers have found that catecholamins and adrenoceptors are implicated in modulation of cytotoxicity and tissues injury including liver.

and

It has been shown that various types of stress are associated with enhanced free radical generation, a cause of oxidative stress, particularly in the liver [13], [30]. Moreover, oxidative stress has recently been shown to play an important role in various liver diseases[31]. The exacerbation in oxidative stress can be the result of not only an increase in reactive oxygen species (ROS), but also a decrease in antioxidant capacity. Glutathione (GSH) is an important tripeptide thiol antioxidant and its intracellular concentration is an indicator of oxidative stress. Within the cells, GSH exists in two different forms: the reduced (GSH) and oxidized (GSSG) forms. Oxidative stress has a profound effect on the cellular thiol balance and can lead to an increase in the GSSG: GSH ratios in the liver [32].

In summary, our data demonstrate that restraint stress can increase serum transaminase levels, disrupt the balance between oxidants and antioxidants in the liver and promote hepatocytes apoptosis. In addition, we find for the first time that catecholamines are responsible for restraint-induced liver injury, and α-1 and α-2 adrenoceptors mediate the hepatocyte apoptosis induced by restraint through caspase-9 and Bcl-2 family of apoptotic regulatory proteins. Future studies should be undertaken to investigate the effect of stress on subjects with hepatic disease, for a better understanding of the impact of stress on the liver will help deal with issues of the kind in clinical settings.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092125



It appears that too much Epinephrine (and catecholamines in general?) is not good for the Liver. Perhaps this is why we have cases of ME/CFS after "prolonged periods of stress". Therefore we could add Prolonged stress as potential causes of Liver injury in susceptible individuals

 

[Milo]

Given epinephrine = Adrenaline = Catecholamines

It appears that too much Epinephrine (and catecholamines in general?) is not good for the Liver. Perhaps this is why we have cases of ME/CFS after "prolonged periods of stress". Therefore we could add Prolonged stress as potential causes of Liver injury in susceptible individuals

I believe many of us PWME have a low cortisol finding and blunted diurnal cortisol curve.

 

[Inara]

@mariovitali, would the vagus nerve hypothesis by van Elzekker fit into your findings? Or, if there were vagus nerve issues, how would that influence the liver?
I think there are so many possible reasons for liver dysfunction though...

 

[Inara]

Is it possible that given the lack of elevated Liver enzymes , researchers assume that there is nothing wrong with the Liver?

Even if liver enzymes are increased, doctors (that I met) don't care. They only care if those enzymes are sky high.

Interestingly, I share @Milo's experience regarding EBV and the gallbladder, nearly 1:1, only that my gallbladder wasn't removed (lucky me).

Edit: Ok, not 1:1 exactly I re-read your post @Milo. But it was EBV and gallbladder attack with slightly elevated liver enzymes.

 

[Milo]

Even if liver enzymes are increased, doctors (that I met) don't care. They only care if those enzymes are sky high.

Interestingly, I share @Milo's experience regarding EBV and the gallbladder, nearly 1:1, only that my gallbladder wasn't removed (lucky me).

That’s right, only if the liver enzymes are 5 times the upper limit of normal they will start to worry or consider further testing.

Amd in my case, @Inara i am very glad not to have my gallbladder anymore as it was necrotic. I was very sick and in a lot of pain and was hospitalized for 10 days. After a couple gallbladder attacks in my opinion it is best to consider to have it removed via laparoscopy. Mine was through a big ‘zipper’, and complicated.

 

[mariovitali]

@mariovitali, would the vagus nerve hypothesis by van Elzekker fit into your findings? Or, if there were vagus nerve issues, how would that influence the liver?
I think there are so many possible reasons for liver dysfunction though...

The Vagus nerve is identified by Machine Learning as important but i do not know why unfortunately. Given the signals i am getting from using it, the Liver / Gut / Gallbladder are the most likely targets to focus on.

 

[mariovitali]

cc: @JaimeS @Andy H @Inara @Simon M @ScottTriGuy

One more potential connection of Liver disease with Jarred Younger's findings in neuroinflammation ? Recall that Maureen Hanson and others have found disrupted Bile acids Metabolism. Dr Fluge also said that we have something happening resembling Primary Biliary Cirrhosis (PBC) - something also mentioned to me by Carmen Scheibenbogen.

Neuroinflammation is a process that has gained increased attention in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, and has also been described in hepatic encephalopathy [3]. According to the data published in this issue of the Journal of Hepatology, neuroinflammation may also participate in more subtle neurological manifestations of liver disease. The article by Nguyen et al. investigates the underlying mechanisms of sickness behaviour in a murine model of cholestasic liver injury (bile duct ligation, BDL). In agreement with other studies [4], sickness behaviour is related to an increase in serum interleukin-6 (IL-6). In the current model, the generation of IL-6 was clearly shown to originate in the cholestasic liver and induced IL-6 signalling in the brain via endothelial activation, as suggested by an increase in the expression of p-STAT3 in endothelial cells of the hippocampus. These observations support the notion that systemic symptoms such as fatigue, frequently present in chronic cholestasic diseases, may originate from the effects of liver-induced inflammation on the brain. This is an interesting concept that may initiate a new approach for treating the symptoms associated with chronic liver disorders

Source : https://www.journal-of-hepatology.eu/article/S0168-8278(11)00802-6/fulltext

 

[Inara]

The Vagus nerve is identified by Machine Learning as important but i do not know why unfortunately. Given the signals i am getting from using it, the Liver / Gut / Gallbladder are the most likely targets to focus on.

Branches of the vagus nerve are connected with every organ. I was wondering if issues with the vagus nerve (like low-grade inflammation, e.g. of the ganglia - what else?) could lead to symptoms like POTS, gastoparesis, heart problems, stomach problems (like too much or too low stomach acid), asthma etc., and maybe - due to its connection - to liver problems as well.

Of course, it would be interesting to know if organ problems - e.g. in the liver, or gut dysbiosis - could lead to vagus nerve issues - e.g. "inflammation" - which could lead to POTS and all the other stuff.

If the vagus nerve is a topic in my case I can't say, but I'm sure it's a problem in a family member (due to herpes viruses, amongst others, because who knows), and my grandfather had a vagotomy, so the doctors then had the opinion the vagus nerve was an issue for him.

There seems to be a connection to mast cells and microglial cells, but I'm still reading papers. I'm looking for a connection to calcium metabolism. Unfortunately, these are theoretical connections (from my side), I think research would be needed to say if it makes sense.

The thing is, everything seems to be intertwined...It's complex.

@mariovitali, thanks for the info!