A recent article on the effect of thyroid function in chronic fatigue piqued my interest in the subject. The study showed that some people with chronic fatigue syndrome were suffering from what I would call a functional thyroid deficiency. Generally, low thyroid, or hypothyroidism, is clinically determined by the levels of thyroid stimulating hormone (TSH). Often, when the thyroid hormones T3 and T4 are low the pituitary gland will release thyroid-stimulating hormone(TSH). The thyroid-stimulating hormone should then stimulate the thyroid gland to release more T3 and T4. So, when thyroid-stimulating hormone is high that person is likely hypothyroid, but there are a number of other factors that affect the function of thyroid hormone and its relationship to thyroid stimulating hormone. (Extended article for Patreon subscribers is here Thyroid, Thiamine, And Chronic Fatigue.)
The thyroid gland produces two primary thyroid hormones. T4/thyroxine is produced in the largest quantity of the two hormones. T4 is a storage form of thyroid hormone, its purpose is to serve as a circulating reservoir ready for conversion to the active thyroid hormone. T3 is the active thyroid hormone. Some T3 is produced by the thyroid gland, most of the T3 used in the body is converted from T4 in various parts of the body, usually the liver is the greatest point of conversion.
T3 then acts on the cells. It kickstarts energetic metabolism. T3 is a more accurate measure of thyroid function than TSH. TSH is only useful if/when it tells us about T3 levels.
The liver produces another relevant hormone. The liver can convert T4 to T3, but it can also convert T4 to another hormone called reverse T3 (RT3). Reverse T3 blocks the action of T3. It is an anti-thyroid hormone.
There is always some amount of reverse T3 in circulation. Reverse T3 will increase in the case of hyperthyroidism – high levels of thyroid hormone. This is a protective mechanism that can prevent death from hyperthyroidism. There are any number of other environmental factors that can increase the production of reverse T3. The ratio of reverse T3 to T3 in circulation is another layer of thyroid function. As reverse T3 can block T3 it means that the absolute amount of T3 is irrelevant at a certain point. If T3 is low or if reverse T3 is high then the TSH level is irrelevant, or at least much less relevant. TSH is not always an accurate indicator of thyroid hormone function.
Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study
The above study describes chronic fatigue syndrome as “a heterogeneous disease with unknown cause(s)”. Another paper described fatigue syndrome as a protean metabolic disorder. Proteus was God of the Greek pantheon – the old man of the sea. In the mythology he is described as changing forms in order to avoid having to foretell the future, changing forms like the movement of the ocean. This ability to assume the many different forms is the basis of the adjective Protean. Chronic fatigue syndrome is not a disease per se, rather a combination of symptoms that may have different causes. It’s important to keep in mind when looking at chronic fatigue syndrome and related disorders. It is probably not one disease with one cause.
If you compare the myriad of symptoms listed in chronic fatigue syndrome to those associated with hypothyroidism you will see a strong overlap. “CFS symptoms resemble a hypothyroid state.” So it makes sense to do a thorough investigation of thyroid function in the case of chronic fatigue syndrome, and that’s what this study set out to do.
The study took some patients with chronic fatigue syndrome and a similar number of healthy controls, just less than one hundred in each group, male and female included. The study properly investigated thyroid function, it looked at metabolic inflammation, leaky gut, and performed a nutrient analysis. The patients with chronic fatigue syndrome had an average similar level of thyroid stimulating hormone to the healthy control group. In most cases this is normal TSH result would lead to somebody being categorised as “not hypothyroid”. If you speak to many medical professionals they will tell you that this result meant that these people are not hypothyroid, regardless of any other factor. “Clinical hypothyroidism” is usually defined exclusively by TSH.
The thyroid hormone (T3) tests showed a different picture. T3 levels were lower on average in the chronic fatigue syndrome group. T4, the storage form of thyroid hormone, was also lower in the chronic fatigue syndrome group. The enzymes involved in the release of thyroid hormones (deiodinases) from the thyroid gland were also lower in the chronic fatigue syndrome group. Participants with chronic fatigue syndrome also had higher reverse T3. CFS patients had lower functional thyroid capacity, regardless of TSH.
“Most remarkably, CFS patients exhibited similar thyrotropin, but lower free triiodothyronine (FT3) (difference of medians 0.1%), total thyroxine (TT4) (11.9%), total triiodothyronine (TT3) (12.5%), %TT3 (4.7%), sum activity of deiodinases (14.4%), secretory capacity of the thyroid gland (14.9%), 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3) (13.3%).”
Thyrotropin-releasing hormone is produced by the hypothalamus, it stimulates the release of thyrotropin (TSH). The active thyroid hormone T3 can become so low that it causes disease symptoms and this is described as “low T3 syndrome”. About one in eight CFS patients met the criteria for low T3 syndrome (functionally hypothyroid). This was more than double what was seen in the control group. The increased reverse T3 in the chronic fatigue syndrome group will move more of those people into the functionally hypothyroid category. This is because reverse T3 will block the activity of thyroid hormone T3. The authors note that chronic fatigue syndrome patients labs look similar to those of poor responders to T4 therapy. These are clinically hypothyroid people who are given only supplemental T4 and tend to convert a lot of it to reverse T3 instead of the active thyroid hormone. Thye become increasingly functionally hypothyroid when given the storage form of thyroid hormone.
“Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy.”
As the authors point out, if and when low T3 and/or high reverse T3 is the cause of chronic fatigue syndrome, then properly supplemented thyroid hormone (T3) could treat the symptoms. This study does not indicate that functional hypothyroidism is the only cause of chronic fatigue syndrome. Supplementing with too much active thyroid hormone (T3) can be extremely dangerous. It is something that should be supervised by somebody knows what they are doing and who is running frequent and complete blood tests.
Many associations have been made with chronic fatigue syndrome and the related condition fibromyalgia, both symptomatic and biochemical. In 2016 paper attempting a metabolic profile of sufferers from CFS/fibromyalgia showed excessive lactate production pointing toward a problem with an enzyme called pyruvate dehydrogenase.
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Initially, chronic fatigue syndrome was called myalgic encephalopathy. This translates to muscle pain (myalgia) and brain disorder (encephalopathy). Both myalgia and encephalopathy can be caused by an increase in lactate. A deficiency of the enzyme pyruvate dehydrogenase leads to an increase in lactate which may be a cause of chronic fatigue syndrome in some cases. Fibro-myalgia is a similar syndrome with potentially similar biochemical patterns.
“Pyruvate dehydrogenase complex deficiency is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.”
(It is these abnormalities in the citric acid cycle (TCA) that the previous study points towards.)
“Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients.”
They identify a deficiency in pyruvate dehydrogenase and an increase in pyruvate dehydrogenase kinase. Pyruvate dehydrogenase kinase is an enzyme that regulates/inhibits/ pyruvate dehydrogenase. An increase in pyruvate dehydrogenase kinase will generally lower pyruvate dehydrogenase. This is an attack on two fronts, crippling the ability to produce energy and increasing the buildup of lactate in the system.
“These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.”
There is interaction between pyruvate dehydrogenase and thyroid hormone. It seems that a deficiency of thyroid hormone can down regulate the action of pyruvate dehydrogenase.
“Pyruvate dehydrogenase complex activity was unchanged in the hyperthyroid state but was significantly reduced (by a third) in hypothyroid rats.”
Effect of thyroid hormone on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase.
Thyroid hormone can also increase the expression of pyruvate dehydrogenase kinase – probably a protective mechanism against hyperthyroidism – much like reverse T3 in some contexts.
The pyruvate dehydrogenase enzyme is critical for turning carbohydrates into fuel. Anything limiting these reactions can lead to lower production of energy and increased lactate – which reinforces the cycle.
“Instead, the cells of people with CFS stop making as much energy from sugar as usual, and start relying more on lower-yielding fuels, such as amino acids and fats. This kind of metabolic switch produces lactate, which can cause pain when it accumulates in muscles.”
In the second part of this article I’ll look into some of the other elements related to the involvement of pyruvate dehydrogenase in chronic fatigue syndromes. This is available for Patreon subscribers here