Is ME a metabolic problem or a signalling problem?

[alex3619]

Theres a FB-group where ME-patients upload their lactic acid tests results, and given that these devices are somewhat reliable, many of them have readings in lactic acidosis territory.

Saw this on Wikipedia: "Lactic acidosis sometimes occurs without hypoxia, for example, in rare inborn errors of metabolism where mitochondria do not function at full capacity. In such cases, when the body needs more energy than usual, for example during exercise or disease, mitochondria cannot match the cells' demand for ATP, and lactic acidosis results"

Actual lactic acidosis is usually fatal without treatment. Elevated lactic acid is not the same thing, but can become lactic acidosis if it persists. However our lower than normal oxygen utilisation might confer some resistance to the problem. I do know we get elevated lactate, but it has to be continuous to lead to the main problems. In the process it results in the lactic acid version of hypoxia. Now for us the threshold is probably higher than for other people ... we can probably, not reliably, tolerate more lactic acid than regular people.

This leads me to speculate that if someone with ME kept pushing and pushing, through a crash, through PEM, and through all the symptoms, then after some days they might wind up with genuine lactic acidosis, which can be fatal. I do wonder though if we might compensate by severely worsening the ME ... its hard to overdo things if you cannot even move.

If resting restores the situation, if pacing restores the situation, its probably not lactic acidosis.

Endurance athletes can have elevated lactic acid, but marathons and ultra marathons are not several days of continuous running, and often rely on working up to the anaerobic threshold, rather than beyond it.

Someone with genuine lactic acidosis would have required urgent hospital treatment, or they would most likely have died.

That does not mean we are not at risk, only that its not the usual case.

Prolonged elevated lactic acid is a trigger condition for lactic acidosis, but its only the beginning of it.

 

[boolybooly]

FYI in case it is relevant, Dr Paul Cheney theorised that PWME had intracellular acidosis and extracellular alkalosis causing difficulties with desaturation which were measurable. This means there is plenty of oxygen in the blood but it is not leaving the corpuscles and entering the tissues.

http://cfs9.hypermart.net/cheney2.htm
NEW INSIGHTS INTO THE PATHOPHYSIOLOGY AND TREATMENT OF ME/CFS
SUMMARY OF A PRESENTATION BY PAUL CHENEY, M.D., Ph.D.
Sponsored by the CFIDS and FMS Support Group of Dallas-Fort Worth
Videotaped in Dallas, Texas, October, 2001

The first problem is that with intracellular acidosis, you get a compensatory extracellular alkalosis. The body does that: one part of the body gets more acidic, the blood gets more alkaline to balance it out. Alkaline blood inhibits oxygen transport; as the blood becomes alkaline, it inhibits oxygen transfer rates.

 

[alex3619]

Alkaline blood inhibits oxygen transport; as the blood becomes alkaline, it inhibits oxygen transfer rates.

In the short term yes, in the long term no. The body then compensates by increasing oxygen dumping, due to changes in enzyme synthesis. The short term changes in acid-base balance are compensated for by long term changes in enzyme synthesis. I am unsure what long term effects prolonged alkalinity would have, I have forgotten that part of the literature.

In any case, currently the best finding we have needs replication, and that is from Newton. At rest we are alkaline, in activity we are acidic. I am unsure what specific intracellular changes would occur across this range, my focus in the past has been on blood and general metabolism effects. It might be worth looking into.

On a side note, I have been wondering what secondary consequences might arise from elevated lactic acid. It turns out there is literature on liver failure, but I have not looked into it much as yet, in which elevated lactate is associated with liver failure. Its also unclear what happens if we keep flipping between acid and alkaline states.

 

[Marky]

@alex3619 Thanks for clarifying, I suspected there was something i misunderstood, as I thought u were in lactic acidosis if u were over 4 mmol/l even if it was transient. I guess our situation is closer to hyperlactatemia (2 mmol/l to 4 mmol/l) usually

 

[alex3619]

I guess our situation is closer to hyperlactatemia (2 mmol/l to 4 mmol/l) usually

Yes.

 

[beverlyhills]

It is a signalling problem - I am happy to bury this here.

If parts of the brain are over-exposed to the peripheral cytokines, you would have normal inflammatory molecules and no negative feedback loop for those molecules - they would just oxidize, be removed as detritus and essentially excreted as bare amino acids. The side effect of this is brain damage in its purest sense. This is the same mechanism by which a defective T-cell control would allow a higher baseline infestation of neurovirus and - properly but devastatingly - widen junctions to attack a higher load of EBV/CMV.They both would preferentially destroy salient motivational neurons (D2, D3) as well as decrease raw serotonin reservoirs (via it's anti-tryptophan activity).

This is probably a basal ganglia problem, but when these neurons are subject to metabolic interference and co-localized in the pons / medulla, it would rapidly increase cardiovascular output incommensurate with the true level of stress.

Literally nothing I mentioned in the prior paragraphs is remotely measurable in the blood. The detritus is measurable in terms of albumin ratios in the CSF, which no one has done, or extravasation in the blood brain barrier, which...

 

[alex3619]

The detritus is measurable in terms of albumin ratios in the CSF, which no one has done

There have been two large studies so far, which showed distinct issues in both ME/CFS and Lyme patients, with substantial overlap. I do not recall the details, maybe someone else can comment?

 

[beverlyhills]

There have been two large studies so far, which showed distinct issues in both ME/CFS and Lyme patients, with substantial overlap. I do not recall the details, maybe someone else can comment?

If you are referring to the comprehensive ones that Hornig did (plus Natelson) to my knowledge they did not include albumin. Plasma sphingosine-1-phosphate in some portion of people.

 

[boolybooly]

In the short term yes, in the long term no. The body then compensates by increasing oxygen dumping, due to changes in enzyme synthesis. The short term changes in acid-base balance are compensated for by long term changes in enzyme synthesis. I am unsure what long term effects prolonged alkalinity would have, I have forgotten that part of the literature.

In any case, currently the best finding we have needs replication, and that is from Newton. At rest we are alkaline, in activity we are acidic. I am unsure what specific intracellular changes would occur across this range, my focus in the past has been on blood and general metabolism effects. It might be worth looking into.

On a side note, I have been wondering what secondary consequences might arise from elevated lactic acid. It turns out there is literature on liver failure, but I have not looked into it much as yet, in which elevated lactate is associated with liver failure. Its also unclear what happens if we keep flipping between acid and alkaline states.

I am not sure how this theory matches/meshes with with Dr Cheney's clinical observations.

From personal experience I found about a decade ago that even 20 years after onset (33 now) I had problems with feeling like I could never breathe deeply enough to satisfy my sense of needing air. At a practical level this was improved by counterintuitively breathing less...! Which is advice given to hyperventilation patients who can induce blood alkalosis by overbreathing and eliminating too much CO2, probably because this lowers the pH of the blood via dissolved carbon dioxide forming carbonic acid.

Further to this I noticed for myself that eating anything with baking soda in tasted good and felt good regarding the discomfort I associated with acidosis causing muscle "burn" sensations e.g. bicarb added to mineral water "cooled" my muscles, but too much of it made the sense of air hunger even greater, whereas conversely acidifying my diet reduced it. So I conclude my body was hungry for bicarbonate to quench the fires of acidosis but too much of it was raising my blood pH and causing a reduction in desaturation rates.

I also noticed the muscular heat plus fatigue "burning" sensation I associated with acidosis was worse when I ate a lot of carb and embarked on a ketogenic diet using ketostix to monitor and found this also had a positive effect reducing the sensations of acidosis. Now I have a diet with much less carb but cannot eliminate it without feeling pretty unwell. I also found that adding apple cider vineger with mother to my mineral water seems to help and I am not sure why but perhaps part of it is acidifying my drinking water and thereby blood, balancing out the tendency to alkalosis. I also take sodium ascorbate in my water which is a buffering salt of ascorbic acid aka VitC which may also help reduce pH extremes.

My air hunger is much better now but any amount of physical activity throws the balance off and leads to "burning" fatigue states which take days to recover and affect my brain/emotions/cognitions as well as producing the acidosis related physical "burn" sensations.

 

[boolybooly]

There have been two large studies so far, which showed distinct issues in both ME/CFS and Lyme patients, with substantial overlap. I do not recall the details, maybe someone else can comment?

I dont know about these specific studies but it raises an increasingly important and politically relelvant issue regarding the nature of ME as a diagnosis, since these conditions share symptoms yet may also be distinguished at a fairly fundamental level regarding TH1 vs TH2 shift in Lymes / ME respectively.

The issue this raises is how ME should be considered for research etc, is it a singular disease or is it a common symptom of multiple diseases much as say POTS could be considered a symptom caused by different diseases affecting autonomic responses?

 

[sb4]

@boolybooly I too have lactic acid build up unrelated to deconditioning that is worse with carbs. I also had that breathless sensation when it was real bad, usually after meals. I found that shallow breathing also counter-intuitively helped. I read an article in a newspaper of someone who claimed buteyko breathing cured his CFS.
I have found MCT oil with carbs helped to alleviate some of the negative effects presumably by providing cells with extra energy source or skirting PDH problems. Perhaps you could try this?

So if cells are more acidic inside (due to lactic acid?) and alkaline outside, this could lead to blood being more alkaline (due to less CO2 produced from mito?) which then causes feelings of breathlessness. This means O2 struggles to be released as CO2 helps in this, which then causes more lactic acid and energy deficiency. Eating fats results in minimal lactic acid build up so somewhat halts the thing in its tracts.

So you say bicarbonate in high does caused worse breathlessness but less muscle burning which you think could be due to lower lactic acid in muscle cells?

 

[boolybooly]

@boolybooly

So you say bicarbonate in high does caused worse breathlessness but less muscle burning which you think could be due to lower lactic acid in muscle cells?

On that last question, yes bicarb definitely makes air hunger worse for me but helps carby burn. Dr Cheney thinks the body has a natural response which causes it to add bicarbonate ions to the blood so they can be used to neutralise cellular acidosis around the body. The liver naturally uses bicarbonate in the gut via the gall bladder so its probably stored there as well. Supplying more bicarb can help a bit IMHO but its a delicate balance not to go too far and make the blood too alkaline and air hunger worse. Dr Cheney's theory seems to fit or at least does not contradict my experience. I have seen no evidence either way about whether CO2 production levels are changed but I agree it seems like the products of ketogenic fat metabolism are not as unpleasant as the products of carb metabolism.

@boolybooly I too have lactic acid build up unrelated to deconditioning that is worse with carbs. I also had that breathless sensation when it was real bad, usually after meals. I found that shallow breathing also counter-intuitively helped. I read an article in a newspaper of someone who claimed buteyko breathing cured his CFS.
I have found MCT oil with carbs helped to alleviate some of the negative effects presumably by providing cells with extra energy source or skirting PDH problems. Perhaps you could try this?

I understand where you are going with this because MCT (medium chain triglyceride) is a ketogenic food and coconut/palm/dairy oil is tasty. On one level it makes sense but I have tried MCT and there was a problem for me because I am so TH2 shifted. For background info, I had sudden very severe allergy to grass pollen causing asthmatic hayfever June-July every year immediately after ME onset and also constant tendency to inflammatory responses including sudden severe swelling of skin in various places aka oedema which is always worse in August-September but I dont know why.

Eating lots of MCT made the oedema problem much worse, which I blogged in a couple of places. Which got better after I stopped eating MCT.
https://boolyblog.blogspot.com
https://forums.phoenixrising.me/threads/inner-ear-inflammation-made-worse-by-honey.52424/
There is a science paper which suggests why this might happen as linked in my blog.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563838/?report=classic
"Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice."

My guess is that if you are not too TH2 shifted then MCT would not cause you the problems it causes me and I would hope it doesn't. But if you do find yourself getting more inflammatory symptoms then MCT could be a contributor, which might be relevant to some people on this forum.

Eating heavier fats does not seem to cause this problem so I eat flax porridge regularly for example, have walnut oil in my salad dressings and lots of baked pecans and walnuts and have found a bulk supplier of unseasoned pork scratchings on ebay which are tasty and also ketogenic and carb free. So heavier oils are OK but the lighter MCTs are not in my case.

 

[Sing]

This is the most exciting discussion I have read lately.

 

[sb4]

@boolybooly I have read previously about the TH2 shift from MCT however I have noticed no such effects and am generally not alergic to things, it is unfortunate that you are the opposite. I have a problem with going too high fat due to gastroparesis.

Obviously this will be speculation but can you make sense of this. I have been using urine PH test strips and my results are consistently around 5.75. This is on varied diets and I even tried high dose K Citrate to get the PH up but it made very little difference. I understand most peoples urine PHs are somewhat acid due to diet but I am unsure why mine wont budge even with K citrate.

If the cells are more acidic and the blood more alkaline, shouldn't then my urine be more alkaline to keep the blood in balance. Something else must be going on.

 

[Jonathan Edwards]

Is there actually any evidence for cells being more acidic and blood more alkaline. I am not a metabolic doctor but it sounds a bit unlikely to me.

 

[sb4]

Is there actually any evidence for cells being more acidic and blood more alkaline. I am not a metabolic doctor but it sounds a bit unlikely to me.

Not sure what the evidence is but the lactic acid build up feeling the some get could be causing pH changes in the cell, right? pyruvic acid would not usualy build up, it would get used, but if your cell is struggling for energy you will import more which would then make sense if it makes the cell more acidic. Shouldn't this be temporary though as the lactate needs to enter the blood and go to the liver which would then lower blood pH.

 

[Jonathan Edwards]

I am really not familiar with cell pH control but I am not sure things work like that. Lactate and pyruvate ions are basic rather than acid in themselves. They mop up hydrogen ions like there's no tomorrow. If the blood is alkaline then presumably pyruvate would be more likely to be imported as base anion rather than as acid.

If pyruvate is converted to lactate I don't think a hydrogen ion is produced so no change in acidity or not much? I am not sure that the symptoms of lactate in muscle are pH related rather than lactate related. I just don't know but does anyone on the forum understand cellular pH control?

 

[lansbergen]

I just don't know but does anyone on the forum understand cellular pH control?

Anybody???

 

[sb4]

@Jonathan Edwards Not sure. I thought that excess NADH was used up by pyruvate to generate lactic acid. Pyruvate no excess hydrogens -> lactate 2 hydrogens.

Then the hydrogen disasociates meaning excess H in cell?

 

[Jonathan Edwards]

That looks to me like a redox change, not an acid-base change. Adding two uncharged hydrogens does not generate positive hydrogen ions. The added hydrogens are not part of the dissociating carboxyl group.