Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids (Germain, Levine, Hanson, 2020)

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Yes @SlamDancin careful examination of liver tissue should be done. I think liver biopsy would be the most useful way to go @junkcrap50 In the meantime I expect that simply improving the digestion of fats would be helpful. There are supplements that are used for this. How effective they are I dont know. Our resident 'Gutoligist' @ljimbo423 might have some ideas about improving fat digestion. When it comes to testing for liver dysfunction I wonder if young @Learner1 has any ideas. She is well up on testing and stuff like that. Thanks for the info on viruses that effect the liver @mariovitali The fact that Hepaititis causes symptoms that are in some ways similar to me/cfs was something that occured to me many years ago. But the match is not that close enough to be certain about it. The other visuses? Who knows but certainly a possibiility. More interested in Cholate at the moment. I need to get out more!!

I think most ME/CFS patients should get tested for mitochondrial antibodies (m2), which is implicated in the development of Primary Biliary Cholangitis - a disease that mirrors a lot of the same symptoms as ME/.CFS in the early stages. It has similar population statistics as ME/CFS (impacts women more than men), causes disruption in bile metabolites, causes disruption in amino acid profiles, causes PEM, and leads to gut dysbiosis. Blomberg speculated a couple years ago that the unknown particle in ME/CFS blood serum might be these IgA/IgG anti-mitochondrial antibodies, which have been shown to inhibit pyruvate dehydrogenase (PDH) activity in vivo. Untreated Primary Biliary Cholangitis has a very poor prognosis - usually requiring a liver transplant if not treated - so it is a good "rule out" rare disease for folks with ME/CFS.
 

andyguitar

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Untreated Primary Biliary Cholangitis has a very poor prognosis - usually requiring a liver transplant if not treated - so it is a good "rule out" rare disease for folks with ME/CFS.
I've been looking at some of these rare diseases @ShepherdK , in particular inborn metabolic disorders related to Cholate. Although it is very unlikley anyone here has them (usually profound symptoms show at an early age) And yes there are similarities to ME/CFS symptoms and Primary Biliary Cholangitis. So we may well be on the right track by looking at the liver. Bit of a suprise all this.
 

Rufous McKinney

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Our resident 'Gutoligist' @ljimbo423 might have some ideas about improving fat digestion.

Curious what are the observable symptoms of problems with bile acid digestion, poor liver function etc.?

Is there a way to know one is not digesting fats well....?

(last 36 hours my whole digestive system blew up....full of air....GastroP still happening...blaming all food again)

The fact that Hepaititis causes symptoms that are in some ways similar to me/cfs was something that occured to me many years ago.

And Eppstein Barr, known to go hide out in the liver....well its had access to mine for decades now. So you just figure the liver met an excess of toxins, or the function is altered by...the EB critter...or both.
 
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I've been looking at some of these rare diseases @ShepherdK , in particular inborn metabolic disorders related to Cholate. Although it is very unlikley anyone here has them (usually profound symptoms show at an early age) And yes there are similarities to ME/CFS symptoms and Primary Biliary Cholangitis. So we may well be on the right track by looking at the liver. Bit of a suprise all this.

I'm going to get tested for PBC this week - I've always had a liver/spleen component to my symptoms, so better safe than sorry.

I tested the Russian performance enhancing drug Meldonium (Mildronate) for five days last week and had to stop due to liver and spleen pain + increasing fatigue. The drug works by inhibiting CPT1 and forcing the body to dump L-Carnitine, which causes systemic metabolic changes - namely upregulation of several enzymes in the glycolysis + TCA cycle. It generally has very few side effects and has been used in the world of sports doping for several decades to enhance cardio recovery. These side effects make a ton of sense if something (non-ROS related) is inhibiting the breakdown of pyruvate.
 

ljimbo423

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Our resident 'Gutoligist' @ljimbo423 might have some ideas about improving fat digestion.

Thanks for the new title!:D:thumbsup: The things I think of right off the top of my head are ox bile, which helps to digest fat, L-carnitine/Acetyl-Lcarnitne helps to burn fat in the mito. and choline also helps with a fatty liver etc.

There are countless other supplements that help to improve liver function in different ways though.
 
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@ShepherdK I have been tempted to try Meldonium. Did you notice any improvements on it? Did your tolerance to carbs increase?

Perhaps I am way off here but could the low cholines be linked somehow to methylation and why some improve on it? Choline spares methyl groups.

I ran Meldonium for five days total, 500mg twice a day. The second and third days were pretty great - tons of energy - however it made me eat quite a bit of carby/sugary foods. This makes sense, since it forces your body to favor glycolysis, which requires sugars to break down. Days 4 and 5 is where things went south - super fatigued, physically very cold, started developing liver pains. My guess is that an increase in glycolysis (and thus, an increase in pyruvate production, which wound up as lactic acid due to PDH issues) led to increased liver stress since the liver metabolizes lactic acid. I would put Meldonium into the "moderately dangerous" category of drugs for ME/CFS patients based on my own experiences + what we know about ME/CFS metabolic disturbances.

Dichloroacetate sodium (DCA) or a fibrate drug (Bezafibrate) might be alternative metabolic enhancers to explore next.
 

sb4

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@ShepherdK I didn't have much luck with DCA but others have. Just had a quick wikipedia of Bezafibrate but unsure how it helps metabolism, what does it do?

Its very interesting how on days 2 and 3 you had increased energy before going south. Why do you think this is? Did you induce a relative deficiency in minerals / vitamins (thiamine?)? I understand that if PDH is broke then Meldonium would be counter productive but on days 2 and 3 it must have been stimulating PDH somehow. Maybe it would be worth trying again with high dose thiamine?
 
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@ShepherdK I didn't have much luck with DCA but others have. Just had a quick wikipedia of Bezafibrate but unsure how it helps metabolism, what does it do?

Its very interesting how on days 2 and 3 you had increased energy before going south. Why do you think this is? Did you induce a relative deficiency in minerals / vitamins (thiamine?)? I understand that if PDH is broke then Meldonium would be counter productive but on days 2 and 3 it must have been stimulating PDH somehow. Maybe it would be worth trying again with high dose thiamine?

Bezafibrate upregulates PPARa activity, but it is also a CPT2 enzyme agonist. Technically it does the opposite of Meldonium by increasing the rate by which fatty acids can be broken down by cells to generate ATP. Bezafibrate is being investigated as an adjunct therapy for fatigue in primary biliary cholangitis - which is interesting since it can be speculated that the two diseases share a common pathology (PDH inhibition). The early results are extremely promising - nearly 40% of primary biliary cholangitis patients reported a major improvement in fatigue without any side effects.

I have two theories regarding Meldonium: 1) the initial energy boost from the extra glycolytic activity was great, but I experienced the beginnings of lactic acidosis leading to hepatic injury, or 2) the benefits of Meldonium are seen when taken over 2+ weeks, but the transition period where the metabolic adaptations occur is not pleasant when you start from a metabolically broken place. Theory #2 does have some merit, as it does take 4-6 weeks to see the full metabolic adaptations that Meldonium induces according to the literature. Maybe a smaller dose (500mg) over a longer period of time would work?
 

sb4

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@ShepherdK The bezafibrate does sound interesting, thanks for the info.

So you think that in days 2/3 you experienced extra glucose (and lactate) activitiy in combo with fat oxidation, yet after day 3 the fat oxidation was reduced such that you only experienced increased lactate?
 
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@ShepherdK The bezafibrate does sound interesting, thanks for the info.

So you think that in days 2/3 you experienced extra glucose (and lactate) activitiy in combo with fat oxidation, yet after day 3 the fat oxidation was reduced such that you only experienced increased lactate?

Yep! There is also one other potential unintended consequence of increasing glycolysis - increased glycolysis is often associated with increased immune cell activity. Allergy-like symptoms can be seen in healthy patients taking Meldonium due to an increased immune response. If ME/CFS is due to an autoimmune-induced metabolic disorder, then Meldonium can also exacerbate the release of auto-antibodies, which would lead to disease progression. This would eventually balance out due to PPARa activation, but short term would induce inflammatory pathways in susceptible individuals.
 

andyguitar

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If ME/CFS is due to an autoimmune-induced metabolic disorder, then Meldonium can also exacerbate the release of auto-antibodies, which would lead to disease progression.
Sounds pretty risky, particularly for those who are very unwell @ShepherdK
Curious what are the observable symptoms of problems with bile acid digestion, poor liver function etc.?

Is there a way to know one is not digesting fats well....?
The symptoms of lack of bile acid and a faliure to digest fats properly would include deficiency of fat soluble vitamins, A;D;E; and K. I expect you know what that can mean. If fats are not being digested then it should show up in an chemical analysis of poo! Any abnormalities in the composition of bile acids should also show up if the right lab tests are done. Cant say what those tests are as I am not that familiar with this subject. Any potential liver issues need to be investigated by a Doc. The results might be very revealing or it might lead nowhere. I think the most encouraging thing about the research is that it points the finger at abnormalities that can cause the symptoms of ME/CFS and those abnormalities can be revealed by tests. They can also be corrected.
 
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Sounds pretty risky, particularly for those who are very unwell @ShepherdK

Yep, I would emphasize: if you have ME/CFS, then playing with metabolism altering drugs is VERY RISKY - even when the known side effect profile is small in healthy populations. I tried Meldonium and experienced a partial crash. The anecdote might be useful in the future for some, but I recommend staying away from this particular substance.
 

Rufous McKinney

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I think the most encouraging thing about the research is that it points the finger at abnormalities that can cause the symptoms of ME/CFS and those abnormalities can be revealed by tests.

In my experience, few tests exist, Few tests are undertaken. My insurance, the fabulous kind, has little interest in tests.

Then if your too sick to visit doctors, and doctor appointments make you get PEM, how does one obtain the results of more tests?

And if the doctor prescribes some thing to try, its denied because its offlabel, compounded, or any other excuse they can find.

I'm too tired to deal with it any longer. To cognitively impaired to resolve my illness.
 

andyguitar

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In my experience, few tests exist, Few tests are undertaken. My insurance, the fabulous kind, has little interest in tests.
If you cant get tests done then you can make a guess as to what might be wrong by looking at the results of this research. Low steroids. Low cholate.
And if the doctor prescribes some thing to try, its denied because its offlabel, compounded, or any other excuse they can find
You dont need a presciption for the supplements that might help. Fat soluable vitamins and digestive enzymes.
 

Marylib

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I missed that interesting point.

Here also the Sphingolipids may fit in, as Acetylcholine is associated with learning in non-typical situations (I think it´s even this paper mentioning a metaplasticiy), and here Sphingolipids are important for new synapses. So this could be pretty concrete (though difficult in all details, I would think).

(I might even mail them and ask if they may gather informations about the seasons in which all the blood samples (Naviax, Naviaux, Nagy-Szakal) have been taken, though also other circumstances may account for the differences.)
So acetylcholine - isn't this compound affected by mestinon - pyridostigmine? Or am I more mixed up than usual? Asking because I am one of those people with a good response to pyridostigmine. Obviously not good enough, or I might be able to understand this better. :)
 

Marylib

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I am currently menopausal, and started to suffer hot flashes and nocturnal sweating a few months ago.
It's a long time since my progesterone decreased, but I still had some estrogen until recently. When it went low, the hot flashes appeared...
So after one year without any mense I started Tibolone three weeks ago, a drug that has some progesterone + estrogen + androgen activity, depending of tissu metabolism. His effect on muscle and brain sounded interesting to me.
This drug quickly made the difference for me, pain has mostly resolved, brain fog and headache are gone, mood is much better, energy is back. It's hard to believe that such a miracle is going to last, but I wish it will!
@pattismith Glad to hear that! Hope this improvement lasts for you. Naturally, now I am wondering how I can get my hands on some. But I am years past the point you are. Doing regular HRT now, and I think it does help some. Like you, just taking progesterone alone was awful. And I always had bad responses to birth control pills, which I was placed on as a teen, to try to deal with really bad cramps. Made me feel terrible but in those days, they gave you birth control pills for everything under the sun.
 

Annikki

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This reminded me of choline supplements. I checked if there were any cases of people feeling improvement from ME/CFS through use of choline supplements. I found these articles:
Choline Supplements
https://cfsremission.com/2016/03/14/choline-supplements/

In my last post, I reviewed one of the four ingredients in Parasym Plus, Acetylcholine-Esterase Inhibitors, the patented supplement sold by the Driscoll Protocol. In this post, I will move on to a second ingredient (with the other two reviewed over the next two days).

Low choline levels appear to come into play with some CFS patients. This can be exposed from headaches using piracetam etc. The question of supplementation arose — and it does not look like it is a simple question to answer.

“The MR spectroscopy (MRS) study revealed remarkable elevation of the choline/creatine ratio in the patients with CFS.” [2000]
“Patients with hepatitis C virus (HCV) infection frequently complain of symptoms akin to the chronic fatigue syndrome… we have shown elevations in basal ganglia and white matter choline/creatine ratios in patients with histologically-mild hepatitis C, compared with healthy volunteers and patients with hepatitis B. This elevation … suggests that a biological process underlies the extrahepatic symptoms in chronic HCV infection.” [2001]
Relative increase in choline in the occipital cortex in chronic fatigue syndrome[2002] “The mean ratio of choline (Cho) to creatine (Cr) in the occipital cortex in CFS (0.97) was significantly higher than in the controls (0.76; P=0.008).”
Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. ” A highly significant increase in the spectra from choline-containing compounds was seen in the CFS patient group”
” the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids.” [2004]
“The choline/creatine ratio of the GWS group was not different from that for either control group.” [2004] Suggesting that Gulf War Syndrome and CFS are different….
“Radiological imaging studies (SPECT, Xe-CT, and MRS) revealed decreased blood flow in the frontal and thalamic areas, and accumulation of choline in the frontal lobe.” [2004]
” The findings produced by neuroimaging techniques are quite similar in both illnesses[CFS and MS] and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.”

There are some web pages worth reviewing on

PhoenixRising [2005] – no clinical trials of possible treatment
“it sounds as though you have an unusual response to choline supplementation. Elevated acetylcholine in the central nervous system can cause depression. My guess is that your body may overproduce acetylcholine, or it may not be able to break acetylcholine down as rapidly as normal, and one or the other of these may account for the depression on supplementing choline. This sounds like a genetic issue…” Rick van K
Dr. Myhill advocates supplementation if your temperament indicates it.

Bottom Line

It appears individual genetics may be the key factor in supplementation (or not to supplement). If you supplement and things improve — good, if things get worst, stop.

The root cause appears to be believed to due to phages / immune response /etc. In my model, likely the microbiome shift.
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Next article:
POTS, Chronic Fatigue, and Autoimmune Disorders
August 10, 2015 | Dr. Linda J. Dobberstein, DC, Board Certified in Clinical Nutrition
https://www.wellnessresources.com/news/choline-helps-pots-chronic-fatigue-autoimmune-disorders

There are an estimated one to three million Americans and millions more around the world, who struggle with POTS (Postural Orthostatic Tachycardia Syndrome). POTS affects the autonomic nervous system, heart and blood pressure, with rapid heart rate, dizziness, and several other symptoms upon standing. It can lead to mild problems or can be severely disabling. Several autoimmune disorders, including Chronic Fatigue Syndrome and MS are known to cause or be associated with POTS. The recent information may help many of these individuals better manage this often disabling disorder.

What is POTS?
The main feature of POTS is a form of orthostatic intolerance, wherein symptoms occur upon standing and are often relieved by lying down. There may be symptoms of tachycardia or elevated heart rate upon standing with other symptoms of palpitations, fatigue, exercise intolerance, light headedness, nausea, trouble concentrating, near fainting, and feelings of trembling. Depending on the subset of POTS, blood pressure may drop, remain normal, or elevate in response to standing. There may be difficulties or disturbances in sweating, temperature regulation and even bowel and bladder function (motility, irritation, etc). It may make individuals unable to exercise because the activity brings on fainting spells or dizziness.

Anyone at any age can develop POTS, but the majority of individuals affected (between 75 and 80 percent) are women between the ages of 15 to 50 years of age. Some women report an increase in episodes of POTS right before their menstrual periods. POTS often begins after a pregnancy, major surgery, trauma, or a viral illness. Daily life activities are often a struggle for many of these individuals. The amount of functional impairment can be similar to that of persons struggling with congestive heart failure or COPD. Often these individuals are dismissed or misdiagnosed with anxiety or panic disorder as the diagnosis is easily missed. The gold standard in diagnosis is a tilt table test to observe heart rate, skin changes, blood pressure, and blood levels of various neurotransmitter levels.

POTS and Autoimmune Inflammation
A recent study in Journal of the American Heart Association found that patients with POTS had elevated antibodies to adrenergic receptors. This isn’t completely new information as previous findings identified problems with receptors sites and imbalanced norepinephrine. The new discoveries, however, show that it is an autoimmune attack on the receptor sites. Adrenergic receptors are receptors sites for catecholamines (norepinephrine and epinephrine) that are involved with the tone and regulation of the sympathetic autonomic nervous system. This antibody activity is thought to change the receptor site function that mediates the actions of adrenaline type compounds. This change leads to a build-up of norepinephrine in the blood stream and results in tachycardia and other symptoms of POTS. They did not identify the specific trigger, but as we know with autoimmune concerns, often there are numerous possibilities. These findings provide strong evidence that POTS is by itself an autoimmune disorder.

A study published in Neurology April 2015 by Mayo Clinic also identified changes in antibody levels in patients with POTS. The researchers found that at least one-third of the patients with POTS had evidence of antibodies attacking other specific organs. Most of the patients with POTS had IgG antibodies specific to the thyroid or to gastric parietal cells. Gastric parietal cells are needed for stomach acid production and to help with the absorption of vitamin B12. Most of the patients in the study were female.

Further information released June 2015 showed other autoimmune markers and disorders in patients with POTS. Just like the Mayo Clinic study, they found that Hashimoto’s autoimmune thyroid disorder was the most prevalent. This was followed by rheumatoid arthritis, and SLE (systemic lupus erythematosus). Ninety percent of the patients with POTS in this study were female. In this patient population, 25 percent had positive ANA antibodies, 7 percent had positive anti-phospholipid antibody (aPL antibody) and 20 percent had some other current autoimmune disorder.

There are several other autoimmune disorders that are known to be associated with POTS. Some of these other disorders include amyloidosis, chiari malformation, Chronic Fatigue Syndrome, deconditioning, diabetes and prediabetes, Ehlers-Danlos Syndrome, infections with mononucleosis, Epstein Barr virus, Lyme’s disease, mycoplasma pneumonia and hepatitis C, multiple sclerosis, mitochondrial disorders, mast cell activation disorders, paraneoplastic syndrome, toxicity from alcohol, chemotherapy, or heavy metal poisoning, and vaccinations.

Chronic Fatigue Syndrome and Choline Receptor Antibodies

As we saw earlier, there are many autoimmune disorders that are associated with POTS, including patients with Chronic Fatigue Syndrome/Mylagic Encephalomyelitis (CFS/ME). Interestingly, back in 2003, researchers identified that certain groups of patients with CFS/ME had autoimmune antibodies to a specific type of cholinergic receptors, CHRM1. The study identified only this aspect and did not look further into treatment options. In this particular study, the patients who had the auto-antibodies to the CHRM1 choline receptors had symptoms of muscle weakness, forgetfulness, and difficulty thinking. If you take this finding and think about these CFS/ME symptoms in context of choline, it is striking that these symptoms are often seen with choline deficiency within the brain and seen much later in life with various dementias including Alzheimer’s. This makes me wonder, is there a correlation with poor choline function earlier in life with CFS/ME affecting methylation, mitochondria, oxygenation, and brain inflammation that causes perhaps similar symptoms to later life issues of Alzheimer’s?

Summary

The expanded findings of autoimmune antibodies present with POTS and that POTS is often found in other neuro-immune disorders opens the door for exploration, understanding, and new options of support. The additional discovery that choline defects and deficits lead to loss of cell membrane integrity, mitochondrial dysfunction, and impaired oxygen use are an exciting find that may help patients with POTS and CFS/ME, MS and many other autoimmune sufferers with POTS. It should also raise questions for those with other concerns related to choline insufficiency with family history of Alzheimer’s disease. Others may have problems with non-alcoholic fatty liver disease, (NAFLD) methylation defects, elevated homocysteine levels, or problems with PEMT enzyme and gene as seen with your commercial genetic profile, may need much higher intake of choline in your diet or as a supplement. This may especially be the case if you have been of the mindset that eggs, especially egg yolks are bad for heart health.

Given the decades long fear of egg yolks as being bad for you or the Standard American Diet, it is not surprising to see choline deficiency present in the population. Beef liver and egg yolks have some of the highest amounts of choline in foods. Other foods that contain choline in lesser amounts include cod, chicken breast, wheat germ, cauliflower, broccoli, amaranth, spinach, quinoa and others. Incorporating these foods into your diet on a regular basis can help support fundamental needs, but if you have one of these concerns, then consider supplementation for additional fortification. This powerful essential nutrient just might help turn your life around and improve your tolerance for gravity and being upright!
 

Mary

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This is from Table S4 in the supplemental materials - it shows the high level systems that are dysfunctional, with the p-value and Impact Score.
@ShepherdK - is it possible to explain briefly what p-value and impact score mean? e.g., glutathione metabolism has an impact score of 0.01, which doesn't sound like much at all, but I don't know how to read that number, whereas taurine has an impact score of 0.51. And if it's not possible to dumb it down for a non-scientist, no worries!
 
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