Wednesday, May 11, 2016

Thyroid-immune interactions; rT3 and TGF-beta1

Let's cut right to the core study:

Stephen A. Huang, Michelle A. Mulcahey, Alessandra Crescenzi, Mirra Chung, Brian W. Kim, Carmen Barnes, Wichert Kuijt, Helen Turano, John Harney, and P. Reed Larsen
Molecular Endocrinology 2005 19:12, 3126-3136

That title should link to the full study. Here's the abstract on PubMed:

Why is this important from a general biomedical standpoint? It shows that in the periphery (i.e. outside the thyroid itself) molecules of the immune system can affect the signal cascade of thyroid hormones. More specifically, a cytokine involved in inflammation can drive symptoms of hypothyroidism (e.g. low energy, depressed mood, cold extremities). This makes intuitive sense, the body is shunting energy away from quotidian activities in order to combat the source of inflammation. Under normal circumstances this works just fine: you get a severe tissue injury or a case of the flu, rest for a few days, then get on with your life. Unfortunately the modern world abounds with things that can drive chronic inflammation, and thus chronic hypothyroidism-esque symptoms. Though thyroid hormones may be involved, abnormalities won't necessarily be detected by standard thyroid work-ups.

As mentioned in the abstract of the above study, Type 3 Deiodinase (Dio3), is an enzyme that converts T4 into the inactive Reverse T3 (rT3). In normal healthy functioning the other deiodinases convert T4 into T3. T4 is produced by the thyroid, circulates in the blood and is converted into T3 by the liver, or by other cells of the body when they need T3. Compared to T4, T3 is the mover-and-shaker; it triggers metabolic changes, acts as a transcription factor for genes, and is a real go-getter. For day-to-day functioning you need your thyroid to produce adequate T4, and you need the other cells of your body to efficiently convert it into active T3, not rT3.

Transforming Growth Factor Beta1 (TGF-β1) is a pleiotropic cytokine. "Pleiotropic cytokine" is a complicated phrase, and yet it doesn't even come close to capturing how complicated TGF-β1 is. Cytokines are signaling molecules of the immune system, but TGF-β1 can be produced by other cell types as well (such as those involved in laying down the extracellular matrix that connects cells). "Pleiotropic" means it has many functions, often functions that would seem to be unrelated. TGF-β1 shows up in studies of wound healing, in studies of autoimmune disease, in studies of cancer, in studies of kidney disease, in studies of schizophrenia... the list goes on.

I first became interested in TGF-β1 because my rheumatologist tested my levels as part of extensive bloodwork. After 8 years of feeling incredibly sick it was the first test that came back unequivocally out of range. My rheumatologist says he sees highly elevated TGF-β1 in almost all of his fibromyalgia and MECFS patients. 

In recent months I have been sifting through papers on TGF-β1, with a particular interest in how it pertains to fibromyalgia and MECFS. A thorough blog post is forthcoming (hopefully within a week of this post, health allowing).

Prior to finding this wonderful rheumatologist I had spent years oscillating between visiting MDs (who usually treated me like a hypochondriac) and alternative practitioners (who didn't help much either). Constant fatigue made me suspect I had thyroid issues. A series of doctors refused to dig much deeper than measuring TSH, which was always in normal lab ranges. I became a bit pushy with a Physician's Assistant and managed to procure a Free T3, but it was also within normal range, albeit at the low end. Fortunately I stumbled upon WellnessFX and their thyroid panel:

Some things were out of range, but when I presented my doctors with my privately-ordered results they were dismissive. Oh. Kay. Then.

Further propitious interweb ambling led me to Stop The Thyroid Madness and its handy Reverse T3 calculator:

My ratios were completely out of whack. No wonder I had extreme fatigue. I felt validated by finally pinning down the fabled Objective Quantifiable Biomarker.

Ah, but the Unicorn had not been trapped by a qualified medical professional! That second step of validation didn't come until over a year later. I was fortunate enough to find the aforementioned rheumatologist. He takes a holistic approach to biomarkers, and does not treat patients with iatrical condescension. It was he who corralled a real Chimera, a beast I had not even heard of before:

Transforming Growth Factor Beta1

Additionally, he was not fazed when he saw my WellnessFX thyroid panel. Right away he looked at my rT3/T3 ratio. In his clinical experience, this is another element that is commonly misaligned in fibromyalgia patients. After a few months under his care my energy and cognitive function began to improve and I redoubled, 'requadrupled', 'reoctupled', and eventually 'rehexadecimalled' my meanderings through PubMed. I became curious about a possible link between my primary biomarkers. Sure enough, a simple Google search for "transforming growth factor beta deiodinase" returned the above study as the top result. You can try this yourself, and I strongly advocate this approach in general; if you juxtapose two arcane terms in a Google query you'll always get interesting results.


Post Script:

In the process of preparing this blog post I found several other relevant studies. Due to time and energy constraints, I'll have to defer them to a later post. As a teaser, I'll say that they show further interactions between (other) cytokines and (other) deiodinases. If you're curious/impatient, I encourage you to try the Googling method mentioned in the previous paragraph. You might find things I've missed! :)

Also, it appears that neurons have receptors for T3, but not the necessary deiodinases to convert T4 to T3. This vital task is handled by neighboring glia. I find this particularly interesting because microglia (the immune cells of the brain) have been implicated in fibromyalgia and MECFS. Perhaps if microglia are busy fighting off invaders (be they active pathogens, or inert inflammatory molecules) they are impaired when it comes to producing T3 for neurons. This could be a cause of brain fog.

...Okay, I should at least track down and post that last study:

Thyroid Hormone and the Neuroglia: Both Source and Target
Petra Mohácsik, Anikó Zeöld, Antonio C. Bianco, and Balázs Gereben, “Thyroid Hormone and the Neuroglia: Both Source and Target,” Journal of Thyroid Research, vol. 2011, Article ID 215718, 16 pages, 2011. doi:10.4061/2011/215718

Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.

Thanks for reading, and best of luck on your road to recovery!

Sean of LavenderDojo


  1. This post is interesting to me as I have a thyroid condition which was diagnosed many years ago. I take t2 and t3 but continued on from this to get autoimmune conditions and fibromyalgia. i do find your info quite technical though and therefore difficult for my foggy brain!

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  3. Sorry to hear about your difficulties. As I'm sure you know, thyroid, autoimmune, and fibro conditions are often comorbid. Fortunately there are nutritional interventions and GI-healing protocols that can help relieve all 3.

    Apologies for the dense technical discussion; I like to geek out about the nuts and bolts at the molecular level, and sometimes my own brain fog interferes with my ability to express things fluently. Since writing this post I have found that Amy Myers, a Functional Medicine MD, has some great material on thyroid function.