Metabolic conditions and the Liver

[mariovitali]

I wanted to start a thread that is looking to potential information after I came across a PDF which I will link below. I do not know if -looking at the associations below- it is warranted that patients are screened for such conditions. Recall that @Chris Ponting study identified "Liver disease" as a condition.

Link : https://www.iembase.org/gamuts/store/docs/Liver_disorders_in_inherited_metabolic_disorders.pdf

The PDF has several entries related to nitrogen metabolism, Porphyria, Hemochromatosis, Wilson disease, Carnitine Palmitoyltransferase deficiency and many others. I provide several examples below. @ME/CFS Science Blog what do you think ? This could be a tool for diagnosis or helping in differential diagnosis ?

1. From the PDF : Nitrogen metabolism is being looked by @MelbME and the OMF.


2. Hemochromatosis was mentioned on the HFE gene listed in the GWAS study. There are cases of patients who also found they have Wilson's disease (mentioned in forums).





3. We then have Porphyria, note the Hemin entry below :



and relevant post from MEAssociation (note that Porphyria is mentioned) :



4. Finally Carnitine Palmitoyltransferase deficiency :



and

 

[mariovitali]

Relevant thread on X : https://threadreaderapp.com/thread/2001627126118912376.html

 

[mariovitali]

Posts moved from: Genetic similarities between ME/CFS and other diseases

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I spoke with a patient just yesterday. He mentioned that he has elevated ALP (Liver-related enzyme). Another patient -a psychiatrist- , got COVID19 then LongCOVID and now he has symptoms similar to Fibromyalgia. He contacted me because he found to have elevated blood ammonia (=impacts the liver). He also has Gilbert's.

Question : Should elevated ammonia be dismissed as an offending factor, simply because not every patient has it? This is what we are discussing here.

Do I believe that the liver is the only responsible factor ? absolutely not. But it should not be dismissed out of the picture because "many people have liver problems and they do not have ME/CFS"

We could see insulin resistance and liver disease that @Chris Ponting' s study identified as factors that set the stage along with other factors. And I believe that synapses are one of them and this is where @paolo study excelled. So we have a kind of a perfect storm taking place : metabolic+immune+neural.

Also, we should not dismiss findings of the DecodeME study so easily and what could they suggest. They imply issues with vesicle trafficking, ER-golgi transport, organelle quality control and autophagy among others. Question : Do these concepts connect with synaptic function? If yes, what are the implications on the synapses if we have failure of these concepts upstream ?

Are we sure that we have checked everything ? Did we have an efferocytosis assay done for ME/CFS after all of these years?

Jack Hadflield, previously CEO of Amatica Health posts about a test that costs more than 1K dollars (yes I know what people think about their methodology). At the same time, he has elevated liver enzymes ever since he got COVID19 :

 

[Jonathan Edwards]

Question : Should elevated ammonia be dismissed as an offending factor, simply because not every patient has it? This is what we are discussing here.

In simple terms, yes it should.

In looking for "ME/CFS" we are looking for some common element to pathogenesis that justifies having this syndrome name, which is there because we suspect such a common element.

If elevated ammonia is not this common element, or part of a common sequence of elements, it is not 'the offending factor'. It might be one of several ways to feed in to such an offending factor but it is not the offending factor we are looking for.

Statistical shifts in values are never going to give us 'offending fctors' if many of the values are in the normal range. They may provide invaluable indirect or circumstantial eviedence of an offending factor nearby but no more than that.

 

[mariovitali]

In simple terms, yes it should.

In looking for "ME/CFS" we are looking for some common element to pathogenesis that justifies having this syndrome name, which is there because we suspect such a common element.

If elevated ammonia is not this common element, or part of a common sequence of elements, it is not 'the offending factor'. It might be one of several ways to feed in to such an offending factor but it is not the offending factor we are looking for.

Statistical shifts in values are never going to give us 'offending fctors' if many of the values are in the normal range. They may provide invaluable indirect or circumstantial eviedence of an offending factor nearby but no more than that.

Elevated ammonia should be dismissed as the universal offending factor in ME/CFS. But it should not be dismissed as biologically irrelevant in a subgroup. Are you suggesting this may not be the case?

if elevated ammonia is not present in most patients, then it is probably not the common causal element that defines ME/CFS but It may be one of several routes feeding into a more central pathology. In complex diseases, many important mechanisms are not present as abnormal lab values in every patient, correct?

In other words, ammonia is unlikely to be the universal cause of ME/CFS, but elevated ammonia or related urea-cycle/liver/nitrogen-handling abnormalities could be a subgroup signal or a clue to a common recovery-failure pathway that is responsible for PEM.

In relation to DecodeME, the same logic applies. RABGAP1L, KLHL20, ARFGEF2-like trafficking biology, autophagy, Golgi/endosome transport, immune signaling, and synaptic development are not “the biomarker” either. But they may point toward a network-level vulnerability. Are we able to dismiss this possibility and focus just to neurons?

 

[Jonathan Edwards]

Elevated ammonia should be dismissed as the universal offending factor in ME/CFS. But it should not be dismissed as biologically irrelevant in a subgroup.

I think those were the points I was making @mariovitali.
But we are looking for the universal offending factor. If there isn't one then the name ME/CFS was a mistake.

And to be honest I doubt that more than 1% of people with ME/CFS have a clinically relevant elevation in ammonia. 5% will have a statistically 'raised' level just because that is how it is defined. I have seen no evidence for even a trend on published studies.

 

[mariovitali]

I think those were the points I was making @mariovitali.
But we are looking for the universal offending factor. If there isn't one then the name ME/CFS was a mistake.

Is it reasonable to look for a universal offending factor in a polygenic disease (I believe Chris Ponting mentioned that many times)? Unless the results of this analysis suggest that ME/CFS is not a polygenic disease.

Talking about names, I really do not care whether we have been calling it in a wrong way and I believe that many patients feel the same. If the common offending factor is metabolic disruption that takes place via different routes be it a viral infection, chemical exposure to organophosphates or even intense stress then we could name it "Post-metabolic disruption syndrome".

Let's end the discussion here for the sake of this thread, I am sure that readers by now get the point.

 

[Jonathan Edwards]

Is it reasonable to look for a universal offending factor in a polygenic disease (I believe Chris Ponting mentioned that many times)?

Yes, if we think this is a distinct disease then by definition we think that there is some universal offending process stage. For rheumatoid arthritis that is widespread small immune complex based macrophage activation. There may be a variety of immunoglobulins comlexing and the outcome can be very varied but identifying a single central step justifies the idea that RA is a distinct syndrome.

The universal offending step need not be at the beginning nor at the end - it can be anywhere. Hypertension is another good example - the easiest because it is defined as the mediating step of high blood pressure. Diabetes is another good one - failure of glucose control.

If ME/CFS is a term worth having then there ought to be soeme step universal to all cases.

Being polygenic does not matter. RA is polygenic. Hypertension is polygenic.

If the common offending factor is metabolic disruption

But what is 'disruption' To me it is one of those vague, rather empotive terms that is not precise enough causally to be useful scientifically. The common step might be a generalised metabolic shift like in diabetes but to be honest I find it hard to see how you explain the ME/CFS clinical picture that way when we don't have any consistent findings out of range at present.

 

[mariovitali]

Posts moved from: Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration

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Pretty much all other findings can be downstream rather than upstream and so less informative.

I agree with everything apart from the text I quoted. I came across patients having hyperammonemia and this would definitely be an upstream cause as we know that elevated ammonia affects negatively the synapses.

https://pubmed.ncbi.nlm.nih.gov/1354386/
EDIT : I do not suggest that all ME/CFS patients have hyperammonemia.

Please, please do not dismiss these events that easily.

 

[Jonathan Edwards]

I agree with everything apart from the text I quoted. I came across patients having hyperammonemia and this would definitely be an upstream cause as we know that elevated ammonia affects negatively the synapses.

I don't think you can be sure. Let us say that ME/CFS induces shifts in neural or endocrine signals that alter metabolism in some way that can in some cases raise ammonia levels. The fact that very high ammonia levels impact on cognition in liver failure and can be shown to affect synapses in experimental systems does not ensure that any ME/CFS symptoms are downstream of ammonia levels.

Pathological mechanisms are often extremely complicated and confusing. Standard explanations for cliinical features taught to medical students are often wrong. For instance, every student is taught that oedema in nephrotic syndrome is due to low albumin levels. But it cannot be because oedema often occurs before there is any fall in albumin. Moreover, the same oedema occurs in nephritic syndrome where the albumin stays normal. Students are taught that you cannot get double vision when looking through one eye but this is not so. Astigmatism can lead to visual cortex interpreting a single image as two 'best fit' images. And so on and so on.

 

[mariovitali]

I don't think you can be sure. Let us say that ME/CFS induces shifts in neural or endocrine signals that alter metabolism in some way that can in some cases raise ammonia levels. The fact that very high ammonia levels impact on cognition in liver failure and can be shown to affect synapses in experimental systems does not ensure that any ME/CFS symptoms are downstream of ammonia levels.

Pathological mechanisms are often extremely complicated and confusing. Standard explanations for cliinical features taught to medical students are often wrong. For instance, every student is taught that oedema in nephrotic syndrome is due to low albumin levels. But it cannot be because oedema often occurs before there is any fall in albumin. Moreover, the same oedema occurs in nephritic syndrome where the albumin stays normal. Students are taught that you cannot get double vision when looking through one eye but this is not so. Astigmatism can lead to visual cortex interpreting a single image as two 'best fit' images. And so on and so on.

OK so let me change the " this would definitely be an upstream cause as we know that elevated ammonia affects negatively the synapses" to the following " this could be an upstream cause as we know that elevated ammonia can affect negatively the synapse function".

Nothing "experimental" about ammonia and brain function @Jonathan Edwards . We *know* that ammonia negatively affects the brain. I will not give any attention to other examples, I gave a very specific example with very specific (negative) effects to the brain. More so, since liver appears to be a factor.

A bit of elevated ammonia added to the signals about synapses we are getting may be a perfect storm. We are not in any position to dismiss anything at the moment.

 

[Jonathan Edwards]

Nothing "experimental" about ammonia and brain function @Jonathan Edwards . We *know* that ammonia negatively affects the brain.

You only know anything in science by using experimental systems. I was not meaning unvalidated systems. Yes, we have known for decades that ammonia affects brains. But is the ammonia level in ME/CFS cases a clinically relevant one? I rather doubt it, otherwise it would have been published I think.

It is not an issue of dismissing anything - just weighing up the likelihood of various things being relevant. I have no preference for any particular angle, but proposals need to be credible in dynamic contextual terms as well as just a consistent effect being seen in a different context.

 

[mariovitali]

But is the ammonia level in ME/CFS cases a clinically relevant one? I rather doubt it, otherwise it would have been published I think.

This is a very good question. Have we tested a good amount of ME/CFS patients for elevated ammonia with the right test conditions ? Is the number of patients with hyperammonemia significantly more than healthy controls?

Is it a fact that Urea cycle function is disrupted in ME/CFS patients or not?

Also why do we have these results here ?

The urea cycle in the liver is an important part of exercise metabolism because it is needed to remove high levels of ammonia that are produced during exercise [56,57]. Germain and colleagues also found that the urea cycle and the ammonia recycling SMPDB pathways were significantly altered in the plasma between ME/CFS female patients and controls in a pathway analysis when comparing the difference between metabolite levels at 24 h post-CPET (P3) and 15 min post-CPET (P2) [25]. Ammonia buildup has been previously linked to neurotoxicity and exercise-induced fatigue

Is all of the above just data fluke ? I am finding really hard to try to understand what is implied here.

 

[Jonathan Edwards]

Is all of the above just data fluke ?

These are shifts in levels across populations. I have not read in detail but the issue is whether or not these shifts are clinically relevant.