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Health Rising by Cort Johnson
Health Rising by Cort Johnson
Hypothyroidism of the Muscle? A New Thyroid Subset Emerges in ME/CFS
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Something new! Thanks so much to Geoff for doing a voice narration of the blog :). If you have any problems please let us know. 

This is the first of two blogs on atypical thyroid issues in diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long COVID. If you’re taking thyroid and aren’t getting the boost you expect, these blogs might be for you. They’re also for people who’ve never had their thyroid thoroughly checked out. In a recent YouTube talk, Jarred Younger stated that he regularly finds people with undiagnosed thyroid disease, diabetes, etc. in his ME/CFS studies.

thyroid gland

Thyroid hormones regulate the metabolic rate of virtually every cell in the body. The thyroid gland, though, is just the beginning of the story.

All you need to understand why the thyroid is of interest to people with these diseases is to read the following sentence from a 2023 German study, “Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone“. It reads:

“Thyroid hormone (TH) is a central regulator of temperature, energy metabolism and psychic well-being.”

When you look at the symptoms associated with low thyroid (hypothyroid) (fatigue, increased sensitivity to cold, muscle and joint pain, muscle weakness, irregular menstrual periods, anxiety), you can see why many doctors often turn to the thyroid when fatigued, sleep-deprived patients show up at their door.

When the authors said “central”, they meant really “central” – as in fundamental for most of the cells in our body. It turns out that the production of thyroid hormone (thyroxine – T4) by the thyroid gland is just the beginning of the process. T4 then has to be broken down into its usable form – T3 (triiodothyronine) – and that’s where things get interesting.

Health Rising by Cort Johnson
Health Rising by Cort Johnson
Hypothyroidism of the Muscle? A New Thyroid Subset Emerges in ME/CFS
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THE GIST 

  • This is the first of at least two blogs on atypical thyroid issues found in ME/CFS, fibromyalgia, and possibly long COVID
  • Thyroid hormones are one of the master regulators of the body. The authors of this study stated, “thyroid hormone (TH) is a central regulator of temperature, energy metabolism, and psychic well-being.” When they say central, they mean central: thyroid hormones regulate the metabolic rate of nearly every cell in the body.
  • When you look at the symptoms associated with low thyroid (hypothyroid) (fatigue, exercise intolerance, increased sensitivity to cold, muscle and joint pain, muscle weakness, irregular menstrual periods, and anxiety), you can see why many doctors quickly turned to the thyroid when fatigued, sleep-deprived patients showed up at their door.
  • The thyroid hormone produced by the thyroid called T4 is just the beginning of the process. T4 is then converted into its usable form – T3 – not in the thyroid, mostly, but in cells in the brain, liver, kidneys, muscles, etc. Selenium-based enzymes play a critical role in transporting T4 into the cells to be converted into T3.
  • Since the thyroid gland mainly produces T4, thyroid supplementation seems straightforward: simply provide T4 and the system should work. In a significant subset of people getting T4, though, it doesn’t and they remain fatigued, have difficulty exercising, experience muscle and joint pain, etc. Since they’re getting enough T4, it stands to reason that a problem may exist in getting the active form of the thyroid (T3) into their cells.
  • A German team of researchers examined whether the selenium-based T4 transporters were getting attacked by autoantibodies in a large number of ME/CFS patients and healthy controls. They found increased levels of  selenium autoantibodies in about 10-20% of ME/CFS patients.
  • The high autoantibody levels were associated with several findings suggestive of thyroid hormone failure: “particularly low” enzyme activity, low free T3 levels, low total T3 to total T4 (TT3/TT4), and low free T3 to free T4 (FT3/FT4) ratios.
  • If you’re not getting the boost you should be getting from thyroid supplementation, these increased autoantibody levels could be why. The senior study author proposed this scenario would cause, “hypothyroidism in muscle, with poor activation of the mitochondria and consequently low ATP levels (explaining fatigue and PEM).”
  • Further study is needed, but the authors suggested that selenium supplements plus pure T3 could be helpful. The senior study author stated, “Se supplementation is safe within the limits known from many intervention studies, i.e., up to 300 micrograms extra per day.”
  • Because T3 – the pure, active form of thyroid – is so potent, using it is trickier. The author stated, “With respect to T3, as with all thyroid hormone treatments, it is a very personal and individualized issue. One does need to increase the dosage slowly, titrating it, under monitoring TSH levels, and most importantly, monitoring the patient’s well-being… We assume that in particular, those hypothyroid patients with impaired expression of Se-dependent deiodinases would respond favorably to the T3/T4 combinations, as their activation of T4 to T3 in the peripheral tissues is compromised.”
  • A test for selenium autoantibodies is available in Germany but not yet in other countries.
  • Next up – exploring another atypical thyroid condition in ME/CFS, FM and long COVID – low T3 syndrome.
Most of that breakdown process does not occur in the thyroid – it occurs in our cells – particularly cells in the liver, brain, muscles, thyroid gland, and pituitary gland. Virtually every cell in our body contains thyroid enzymes (isozymes) that convert T4 into T3. This is because of how fundamental T3 is to cellular functioning.

Once in the cell, T3 regulates the metabolic rate of nearly every cell in the body. It does this by increasing the gene expression of Na+/K+ ATPase enzyme, resulting in increased oxygen consumption, energy production, and body temperature. T3 affects muscle control and brain, heart, and digestive functioning. In short, it’s one of the master regulators of the body. (To think that it all starts in a little butterfly-shaped gland in the front of our neck.)

Given the exercise intolerance in ME/CFS, it’s intriguing that thyroid problems (either hypo or hyperthyroidism) can also cause exercise intolerance. Reduced workloads and heart rates at the anaerobic threshold have been found.

It’s no wonder that thyroid problems are one of the first options doctors turn to when fatigued, exercise-intolerant ME/CFS/FM and long-COVID patients show up.

The Crucial Conversion

The inactive form of the thyroid hormone (T4) is converted to the active form (T3) by 3 selenium-based enzymes (isozymes: DIO1, DIO2, DIO3).

  • DIO1 and DIO convert T4 to active T3
  • DIO3 converts T4 to inactive reverse-T3 (rT3), and T3 to T2

Because these isozymes or enzymes rely on selenium to function properly, a selenium deficiency can result in thyroid problems and affect iodine excretion.

The Hashimoto Disease Connection

The paper’s authors first worked on a problem found in some Hashimoto’s syndrome patients. Because Hashimoto’s disease involves the destruction of the thyroid gland, it would seem to be amenable to a simple fix – simply supplement with the main end product of the thyroid gland – T4.

The T4 supplementation doesn’t always work, however – some Hashimoto’s patients remain fatigued and impaired. Hashimoto’s Disease, it should be noted, is not the only disease in which thyroid supplementation can be a bust. We’ll see in the next blog it’s not uncommon for people on thyroid medication to feel not up to par.

Since thyroid supplementation brought the T4 levels up to normal, it appeared that something was interfering with the conversion of T4 to T3.

Selenium-Based Enzymes Take a Beating

Looking for an answer, Schomburg’s German group dug into the selenium-based isoenzymes that break T4 down. Because the thyroid isozymes are only found within the cells, and can’t be readily studied, they looked for signs of selenium issues elsewhere, and landed on testing another selenium-based enzyme called glutathione peroxidase (GPx3).

Low levels of glutathione peroxidase (GPx3) in the poor T4 responders with Hashimoto’s suggested selenium was not getting into their GPx3 enzymes either.

The Autoantibody Connection

The next step was to see if autoantibodies that might be inhibiting selenium entry to the cells were present – and they were: increased levels of autoantibodies (SELENOP-aAb) to the selenium transporter (selenoprotein P) were found.

Se-TableImage

Autoantibodies attacking selenium-based enzymes provided the crucial link. (Image from Wikimedia Commons)

With that, they had indirect validation of their hypothesis: the Hashimoto’s patients who weren’t responding to the standard thyroid hormone (T4 – levothyroxine) because their cells weren’t converting T4 to T3 as they should.

The T4/T3 conversion was blocked by selenium autoantibodies that were preventing selenium from entering the cells. That left the selenium-based isozymes needed to convert T4-T3 in the cell high and dry.

The ME/CFS Study

With that, they turned to chronic fatigue syndrome (ME/CFS) and tested selenium levels, selenium autoantibodies (SELENOP-aAb), and glutathione peroxidase (GPx3) in a lot of patients (n=167) and healthy controls  (n = 545).

They found greatly increased levels of SELENOP-aAb in a subset of ME/CFS patients and hardly any healthy controls (9.6–15.6% in ME/CFS patients versus 0.9–2.0% of healthy controls, depending on what the cutoff for a positive result was). They reported that the “prevalence of SELENOP-aAb in CFS was about 10 times elevated in comparison to controls” and exceeded that reported in thyroid or cancer patients.

They dug deeper. Because selenium plays a crucial role in the glutathione peroxidase enzyme, selenium levels should be correlated with glutathione peroxidase levels; i.e. higher selenium levels should be correlated with higher glutathione peroxidase levels. The fact that they were not in ME/CFS suggested that the autoantibodies were preventing the selenium from being used properly elsewhere in the body.

That’s an interesting finding given that glutathione is the major antioxidant in the body and high levels of oxidative stress have repeatedly been found. Because glutathione peroxidase is the main antioxidant in the body, it was not surprising to see elevated levels of nasty free radicals/reactive oxidative stress species called isoprostanes in the urine. That finding jived with several studies in the mid to late 2000s from UK researchers which found increased levels of isoprostanes in ME/CFS.

Effects of thyroid hormone

Thyroid hormones affect the functioning of many systems in the body.

Plus, the high Se autoantibody group stood out in a group of ME/CFS patients and healthy controls who had undergone extensive thyroid testing. The high Se autoantibody group exhibited “particularly low” DIOD isoenzyme activity, low free T3 levels, low total T3 to total T4 (TT3/TT4)  and low free T3 to free T4 (FT3/FT4) ratios.

Those findings suggested T4 was not being properly converted to the usable form of the thyroid hormone (T3) in this group.

Going further, they also found low urinary iodine levels in this group. Because iodine is released from T4 when it is converted to T3, the low urinary iodine levels suggested (again) that T4 was not being broken down properly.

The authors proposed that ME/CFS clinical trials involving selenium and T3 take place.

The Schomburg Interview

I asked the senior study author, Lutz Schomburg, how he got involved in this study, what safe levels of selenium might be, and what’s next for him and his crew. Schomburg is Dept. Director of the Institute of Experimental Endocrinology at Charité Universitätsmedizin Berlin. Schomburg wrote:

“Once I had the honor to get into personal contact with some CFS patients and learn about the devastating nature of the disease, myself and my full research team became highly motivated to dedicate a lot of our efforts towards this topic, as it also nicely falls into our primary research issue of nutrition, autoimmunity and thyroid hormone research.”

He said he was convinced that this selenium autoantibody – thyroid interaction is present in 10-20% of ME/CFS patients.

“I am convinced that the link between impaired Se transport and ME/CFS is real and operative in a subset of patients (10-20%). We are currently testing the hypothesis that it may even be a general mechanism, also of relevance for tumor (post-cancer) fatigue or long-COVID.”

Concerning selenium supplementation, Schomburg said this:

“Se supplementation is safe within the limits known from many intervention studies, i.e., up to 300 micrograms extra per day. There is a slight risk of side-effects (type 2 diabetes) for overweight males residing in Se-rich areas like the USA, but there is no indications for any side effects for women or subjects residing in Se-poor areas like Europe.”

Several studies suggest that supplementing selenium with myo-inositol can improve thyroid function. (Reduced selenium levels have been associated with an increased risk of Hashimotos Disease.)

T3 is a more complicated subject:

“With respect to T3, as with all thyroid hormone treatments, it is a very personal and individualized issue. One does need to increase the dosage slowly, titrating it, under monitoring TSH levels and most importantly, monitoring the patient’s well-being.”

 

“Thyroid hormones in excess carry the risk of tachycardia and arrhythmia – that is why usually the prohormone T4 and not the active hormone T3 is prescribed and supplemented. But recent research has indicated that many (especially female Hashimoto’s) patients do profit from a T3/T4 combination, like the normal secretion pattern from the thyroid gland and like found in dried thyroid extracts (at a ration of around 1/10th of T3 compared to T4).”

 

“We assume that, in particular, those hypothyroid patients with impaired expression of Se-dependent deiodinases would respond favorably to the T3/T4 combinations, as their activation of T4 to T3 in the peripheral tissues is compromised.”

Schomburg then spelled out how low T3 problems could impair muscle activity and produce exercise intolerance.

“If you imagine muscle as target tissue, impaired T4 to T3 conversion would mean hypothyroidism in muscle, with poor activation of the mitochondria and consequently low ATP levels (explaining fatigue and PEM). The diagnostic problem is that we cannot determine T3 status in muscle, only in the circulation, which of course is not always a reliable mirror of what is going on in the target tissues.”

 

“Yet, while I am convinced that the patients with impaired Se transport will profit from such Se and T3 treatment, other patients with intact Se status and transport may not, and may even experience cardiovascular side effects from hyperthyroidism.”

 

“This is why I strongly recommend to test these experimental treatment strategies only in collaboration with the treating physician, and ideally after an analysis of Selenium and Selenoprotein P (SELENOP) concentrations, and an assessment of potential autoimmunity to SELENOP.”

 

“Unfortunately, these analyses are not (yet) available in the USA, but I am very happy that we have succeeded in convincing a diagnostic provider to offer these analyses in Germany, and hopefully soon also elsewhere. (https://www.biovis.eu/de/).”

Thanks to Sue for the link to this intriguing finding!

  • Next up – The Atypical Thyroid Issues in ME/CFS, FM, and long COVID Pt. 2 – Low T3 Syndrome

 

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