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CFS/ME and intracellular hypothyroidism

pattismith

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Thyroid Hormone Transport into Cellular Tissue

Source: Journal of Restorative Medicine, Volume 3, Number 1, 1 April 2014, pp. 53-68(16)

New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and is proving to have considerable clinical significance.

Reduced T4 and T3 transport into the cells in peripheral tissues is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic dieting and aging, while the intracellular T3 level in the pituitary often remains unaffected.

The pituitary has different transporters than every other tissue in the body.

The thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected.

Because the pituitary remains largely unaffected and is able to maintain intracellular T3 levels while the rest of the body suffers from significantly reduced intracellular T3 levels, there is no elevation in thyroid-stimulating hormone (TSH) despite the presence of wide-spread tissue hypothyroidism, making the TSH and other standard blood tests a poor marker to determine the presence or absence of hypothyroidism.

Because the T4 transporter is more energy dependent than the transporter for T3, it is also not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial.

Thus, if a patient with a normal TSH presents with signs or symptoms consistent with hypothyroidism, which may include low basal body temperature, fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention, slow reflex relaxation phase or PMS, a combination of both clinical and laboratory assessment, which may include a T3/reverse T3 ratio and the level of sex hormone binding globulin (SHBG), should be used to determine the likely overall thyroid status and if a therapeutic trail of straight T3 or a T4/T3 combination is indicated and not based solely on standard thyroid function tests.
 

pattismith

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This article may look like a not yet proved theory, but I have several reasons to think that impaired energy metabolism in CFS/ME is related to an impaired thryroid hormons metabolism, that doesn't show in the usual thyroid tests. (fT3 fT4 TSH), and this article fits pretty well with my perception of it.

If we could find the link between the Cell Danger Response and the protective Euthyroid Sick Syndrome, I believe we will have the key....

It seems that another scientist shares the point of view of the previous article, his subject is Pipolar disorder and intracellular thyroid metabolism dysfunction:


An examination of myth: A favorable cardiovascular risk-benefit analysis of high-dose thyroid for affective disorders
TammasKelly
2015
Abstract

Introduction
High dose thyroid (HDT) is included in major treatment guidelines for the treatment of bipolar disorders. Yet it is seldom used partly based on perceived cardiovascular risks. The cardiovascular risks of HDT are examined.

Methods
A literature search was conducted for the cardiovascular risks of HDT and for comparisons sake psychiatric medications. Case reports of atrial fibrillation (afib) associated with HDT are reported.

Results
While hyperthyroidism is a significant cardiovascular risk factor causing a 20% premature death rate, HDT treatment does not appear to be of significant cardiovascular risk. HDT differs from hyperthyroidism in significant ways. The sequela of hyperthyroidism are increasingly tied to autoimmune complications which are absent with HDT. Equating hyperthyroidism with HDT is incorrect. The five case reports of HDT treatment associated with afib were potentially caused by other factors. If HDT increases the risks of afib, monitoring for afib would minimizes the risk. Even in overt hyperthyroidism the risk of other arrhythmias are minimal. When compared to many psychiatric medications HDT is as safe or safer.

Limitations
There are no direct studies of cardiovascular risks of HDT for affective patients. High tolerance of a medication does not necessarily imply lack of risk. The five case reports were spontaneous, other cases may not have been reported.

Conclusion
The cardiovascular risks of HDT appear to be low. HDT is at least as safe as or safer than many psychiatric medications. It is effective and well tolerated.


A hypothesis on the mechanism of action of high-dose thyroid in refractory mood disorders
TammasKelly(MD)
2016
Abstract

Multiple lines of evidence suggest the hypothesis that high dose thyroid therapy corrects for cellular hypothyroidism found in bipolar disorders. Evidence indicates that bipolar disorders are associated with mitochondrial dysfunction which results in low cellular adenosine 5′-triphosphate (ATP) levels.

Transport of thyroid hormones into cells is energy intensive and dependent on ATP except in the pituitary gland. Inadequate ATP levels makes it difficult to get thyroid hormone into cells leading to cellular hypothyroidism.

This creates a condition where the blood and pituitary levels of thyroid hormone are normal but low in other tissues.

High dose thyroid therapy produces a gradient that is sufficient for thyroid hormone to diffuse into cells correcting cellular hypothyroidism.
If this hypothesis is correct there are number of implications.
The two most important are: On average patients suffering from a bipolar disorder die 10–20 years earlier than the general population.
The medical sequelae associated with bipolar disorders cause far more deaths than suicide.
If high dose thyroid corrects for cellular hypothyroidism it could well decrease the medical morbidity and mortality associated with bipolar disorders that are the result of cellular hypothyroidism.
Thus high dose thyroid would be a first treatment that decreases the considerable medical morbidity and mortality associated with the bipolar disorders. This would stand in stark contrast to most psychiatric medications that can that increase morbidity and mortality. It would also reinforce the safety of HDT.

The second implication is thyroid hormone blood levels in patients suffering from a bipolar disorder do not accurately reflect the true thyroid status.

and last but not the least, this clinical study is also quoting Hortolf's article:


Pesticide Exposure and the Level of Reverse Triiodothyronine on School Children in Brebes District—Indonesia

Authors: Budiyono, .1; Suhartono, .1; Kartini, Apoina1; Hadisaputro, Soeharyo2; Pambayun, Tjokorda G. D2

Source: Advanced Science Letters, Volume 23, Number 4, April 2017

Publisher: American Scientific Publishers


Background:

School children in agriculture area in Brebes District are involved agriculture activities. Pesticide metabolites were detected in 31.25% out of 48 school children.

Pesticide activated de-iodinase type 3 enzymes (DIO3) and produce reverse Triiodothyronine (rT3).

Reverse T3 influences uptake of cellular thyroid hormone.

The study aimed to describe the pesticide exposure and level of rT3 in school children.

Method
:

Subjects were 84 school children who lived in agriculture area in Brebes District, Indonesia.

The study used cross-sectional design.

Pesticide metabolites in urine were measured by HPLC with Triple Quadrupole Tandem Mass Spectrometry detector. Serum samples were examined by ELISA method for rT3 detection.

Data were analyzed using Mann-Whitney tests (α = 0.05). Results: In 51.2% out of 84 subjects, three of six types of dialkyl phosphate metabolite were detected in urine.

The type of pesticide metabolites were diethylthiophospate (35.7%), dimethylthiophospate (28.6%), and dimethyldithiophosphate (8.3%).

The mean levels of diethylthiophospate were 0.01±0.019 ppm (0.001–0.1 ppm), of dimethylthiophospate 0.015±0.034 ppm (0.001–0.14 ppm), and of dimethyldithiophosphate 0.042±0.013 ppm (0.026–0.064 ppm).

The mean level of rT3 was 323.21±193.78 pg/ml (97.22–864.56 pg/ml).

All subjects had rT3 above the normal level (25–75 pg/ml).

There was a significance different between the mean level of rT3 among school children who were exposed and non exposed to pesticide (p < 0.001).


Conclusion
:

Pesticides exposures are thought to increase the activity of DIO3 and have an impact on increasing the levels of rT3 level in school children in the agriculture area. All subjects may indicate cellular hypothyroidism and needs to be confirmed by assessed free T3/reverse T3 ratio.
 
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andyguitar

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Pesticide info is interesting. The thyroid theory needs further investigation and I hope someone takes up the challenge and does a large scale study to see if it is a cause of some symptoms OR a result of something else.
 

ljimbo423

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The thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected.
I can't help but wonder how many of the symptoms seen in CFS are caused by mito. dysfunction. Without enough energy from the mito, cells and therefore any organ effected, cannot work right.

Weather it's the brain, thyroid, immune system etc. Without enough energy from the mito, no organ can function at a normal level.

The mito. dysfunction probably varies from organ to organ in CFS. One reason being the energy needs of that specific organ. The more energy that is needed by the organ, the more dysfunction in that organ, mito. dysfunction could cause.

The cells lining the gut are very energy demanding. Completely renewing themselves every 3-6 days. I wonder how big a role mito. dysfunction plays in maintaining a leaky gut?

Jim
 

andyguitar

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Well for what it's worth it seems most likley to me that mito dysfunction is the primary factor in ME and some cases of CFS. But that said there is a problem in thinking that it is something wrong with mito in general. People are not sick enough. Now that may sound daft but consider the fact that many of the bodies systems work ok, even in those who are very ill. What @ljimbo423 says about mito dysfunction in the gut is a good point. But I am more inclined to see leaky gut as a separate issue that is not influenced by mito dysfunction. More of a physical problem in the gut lining caused by abnormal gut flora, allergic reaction and infection. I would put my money on mito dysfunction in the brain. The cause being inflammation (of the mito). As to what causes the inflammation, well its a long list. Abnormal gut flora could play a part but I am not convinced yet. But my mind is, if not open, is still ajar! One thing that does spring to mind is the neurotransmitters that are produced by gut flora- including those contained in some supplements. I do wonder if they could produce inflammation if the patient took the wrong ones.
 

Learner1

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Abnormal gut flora could play a part but I am not convinced yet. But my mind is, if not open, is still ajar! One thing that does spring to mind is the neurotransmitters that are produced by gut flora- including those contained in some supplements. I do wonder if they could produce inflammation if the patient took the wrong ones.
This is the conclusion to Maureen Hanson's paper:

Taken together, our results suggest an ongoing damage to the gut mucosa, leading to increased microbial translocation in ME/CFS, which in turn could alter antimicrobial regulators and disregulate the innate immune system.

Differences between the gut microbiomes of healthy individuals and patients with ME/CFS were identified in terms of relative abundance of specific genera.

There is no single precise alteration of the gut microbiota in all ME/CFS patients we examined, but our data converges to support the concept of a less diverse and unstable community of bacteria in the disorder. It highlights the association of specific bacterial taxa with ME/CFS, and the identification of the underlying role of this altered commensal gut microbiota could lead to novel diagnostic and therapeutic strategies that would improve clinical outcome.

Future studies may also reveal additional molecular markers that could be combined with gut microbiome information to enhance the sensitivity and specificity of ME/CFS diagnostic assays.

The cause of ME/CFS is unknown, but gut dysbiosis could be contributing to some of the symptoms and their severity. Developing therapeutic interventions aimed at reducing local inflammation, restoring gastrointestinal tract immunity and integrity and modifying the intestinal microbiome may ameliorate ME/CFS symptoms in a number of affected patients.
 

andyguitar

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Thanks for posting that @Learner1. Oh and I like your new avatar :thumbsup:. I dont doubt that some with ME have problems with gut flora. Twice I have met sufferers with the severe version of ME who tested positive and had drug treatment for Helico infection. Both had gastritis, nausea and appetite disturbance. When the Helico was eradicated those symptoms went. They never came back. The other thing I noticed was that although they still got a bit stressed up the nature of the anxiety changed. They stopped having the horrible experience of the same fearful thoughts going round and round for weeks on end. But they still had ME.
 

pattismith

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I can't help but wonder how many of the symptoms seen in CFS are caused by mito. dysfunction. Without enough energy from the mito, cells and therefore any organ effected, cannot work right.

Weather it's the brain, thyroid, immune system etc. Without enough energy from the mito, no organ can function at a normal level.

The mito. dysfunction probably varies from organ to organ in CFS. One reason being the energy needs of that specific organ. The more energy that is needed by the organ, the more dysfunction in that organ, mito. dysfunction could cause.

The cells lining the gut are very energy demanding. Completely renewing themselves every 3-6 days. I wonder how big a role mito. dysfunction plays in maintaining a leaky gut?

Jim
I agree! The question I am currently wondering is about the primary and the secondary.

Is the mitochondrial dysfunction primary to the impaired intracellular TH transport....Or is the impaired intracellular TH transport coming first and the mitochondrial dysfunction a secondary consequence (knowing that a lack of T2 lead to impaired OXPHOS)...

My feeling is that both could exist in ME/CFS and that we may have some subgroups with one or the other possibilities.
 

Rlman

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Transport of thyroid hormones into cells is energy intensive and dependent on ATP except in the pituitary gland. Inadequate ATP levels makes it difficult to get thyroid hormone into cells leading to cellular hypothyroidism.

This creates a condition where the blood and pituitary levels of thyroid hormone are normal but low in other tissues.
if thyroid hormones are only getting into the pituitary in such conditions, wouldn't that mean the thyroid gland itself would not be getting thyroid hormones into its cells, and thus not be making enough thyroid hormones in the first place? i am assuming is they thyroid gland needs thyroid hormones in order to function normally and produce thyroid hormones- is that a mistaken assumption?
 

pibee

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When I switched to T4+T3 (natural pig thyroid) from Synthroid, it saved my life because I had big psychiatric problems on t4-only... but it actually in a way made my ME worse, i started getting symptoms out of nowhere, etc. Messing with hormone gives me mixed results in ME, which I'd just link to autoimmunity.

Meaning, I definitely wouldnt link CFS too much to T3.
 

pattismith

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Nope, none.
(Of course I'm not recommending anyone else do this!)
If You had not any effect after taking T3, either bad or good ones, I would make the hypothesis that you may have some blockage of T3 transporters into cells or T3 nuclear receptors or mitochondria receptors
pollution can block TH transporters, and could be a main or an accessory cause of cellular hypothyroidism .

I Found this enlighting study after I changed my avatar (but I couldn't find a better one !)

In vitro assay shows that PCB metabolites completely saturate thyroid hormone transport capacity in blood of wild polar bears (Ursus maritimus).

Abstract
Persistent chemicals accumulate in the arctic environment due to their chemical reactivity and physicochemical properties and polychlorinated biphenyls (PCBs) are the most concentrated pollutant class in polar bears (Ursus maritimus). Metabolism of PCB and polybrominated biphenyl ether (PBDE) flame-retardants alter their toxicological properties and these metabolites are known to interfere with the binding of thyroid hormone (TH) to transthyretin (TTR) in rodents and humans. In polar bear plasma samples no binding of [125I]-T(4) to TTR was observed after incubation and PAGE separation. Incubation of the plasma samples with [14C]-4-OH-CB107, a compound with a higher binding affinity to TTR than the endogenous ligand T(4) resulted in competitive binding as proven by the appearance of a radio labeled TTR peak in the gel. Plasma incubation with T(4) up to 1 mM, a concentration that is not physiologically relevant anymore did not result in any visible competition. These results give evidence that the binding sites on TTR for T(4) in wild living polar bears are completely saturated. Such saturation of binding sites can explain observed lowered levels of THs and could lead to contaminant transport into the developing fetus.
 
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pattismith

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When I switched to T4+T3 (natural pig thyroid) from Synthroid, it saved my life because I had big psychiatric problems on t4-only... but it actually in a way made my ME worse, i started getting symptoms out of nowhere, etc. Messing with hormone gives me mixed results in ME, which I'd just link to autoimmunity.

Meaning, I definitely wouldnt link CFS too much to T3.
I am euthyroid with low T3 and very high reverse T3, and I am bad with T4 med, but all my symptoms disappear with a small dose of T3 for 9 hours. By the way, if I take more than one dose per day, the good effect lower and lower over time. More over, when I tryed supplementing with T 3 some years ago, it didn't work, so thyroid resistance is not a simple issue to solve.
Did you tested your reverse T3 when you were on T4 med?
 

pibee

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I tested rT3 when i switched to NDT and before learning about ME (and Lyme). The range was weird but it was highish. And considering how awfully sick I was with Lyme etc, it's normal for rt3 to be high in many chronic conditions? I think i read it's high in cancer, depression, ... and a bunch of others chr condtiions.

for a while i took next to NDT also synthetic t3. I ended up doing only NDT, ... feel like what I got from NDT in start is most I can get out of it in terms of improvement. Somehow on NDT i started to develop faster neuropathies, burning stabs in my abdomen.. which later resolved with antibiotics...

. I am sooooo confused. Whatever I do - antivirals, antibiotics, immunomodulators, MCAS treatment, has strong or at least significant effect on my symptoms but it's like perfect chaos...
 
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This is the conclusion to Maureen Hanson's paper:
It should be noted that people live perfectly healthy lives even after having their large intestines removed (called a colectomy). The large Intestine is the home to the microbiome, at least the most important part. If the microbiome was an absolutely essential part of our health, a colectomy should result in very bad health ... and that generally does not happen. I have a distant relative who had a colectomy decades ago, and she is absolutely fine. It's a non issue for her.
I'm not suggesting that the microbiome isn't important to our health, but the fact that we can live quite well without it, suggests to me that it is not an absolutely essential. Many other organs in our body, we can't even stay alive without, but we can live just fine, without a colon (large Intestine).
However, it's probably better to have no colon, than a very sick one.
The Maureen Hansen paper states things very well as far as I'm concerned. She takes a larger, more comprehensive view of one's overall digestive health as a major factor in CFS, and doesn't solely focus on just the altered microbiome. I'm in agreement with that, at least in my case.