Chicken vs Egg vs House-on-Fire vs Other Analogies

A short post on the tangled knot of Fibromyalgia/MECFS etiology and sustained allostasis.

I'd like to start with a situation many of us will have encountered. A friend, family member, or doctor will say something like:

"You're complaining about a lot of symptoms. You can't possibly have so many things going wrong!" 

This is akin to a firefighter showing up to a burning building and saying:

"More than one or two rooms are on fire? How could the whole house be on fire?!"

A house on fire serves as a decent analogy. The fire may have started in one room, but if it was not put out promptly, it will have spread to the whole house. Now it doesn't matter much where it started, every room must be doused. The same is true with these nebulous neuroimmune conditions.

Unusual infections, unusually high numbers of infections, and unusual presentation/persistence of 'common' infections are frequent findings (or at least theories) in MECFS and fibromyalgia. Do they clear up but leave the immune system exhausted, or does a preexisting immune issue allow them entry? This is a Chicken-and-Egg question that doesn't really provide much solace to the suffering.

Many things can subtly weaken the immune system: genetic predisposition, nutritional deficiencies, toxin exposure, dysbiosis, and ANS dysregulation. This last one can be due to PTSD, chronic stress, or an extremely 'Type-A" personality. All these things can alter the functioning of the HPA-axis, subsequently knocking the nervous system and endocrine system out of line. This domino effect then hits the immune system. Unfortunately, these dominos are arranged on something like MC Escher's infinite stairs (Penrose Stairs). Problems with the immune system can interfere with the nervous system, endocrine system, detoxification, etc. As soon as one domino, one body system, tries to get on its feet it gets knocked back down by the the collapse of another.

A final analogy: imagine your body systems as a collection of friends marching forward together as you journey through life. If one or two of these friends get sick or injured they can lean on the others for support. But if most of them are sick, or hopping around on one leg, then when they turn to each other for support they're more likely to just knock each other over. In systems engineering, this is termed Cascading Failure:
https://en.wikipedia.org/wiki/Cascading_failure

The good news is that if you work on several body systems at once, some of them can become robust enough to start to pull the others back up too.


Thanks for reading. For science-based discussions of how different body systems interact, check out some of my older posts. Deeper discussion is forthcoming (there's a lot of medical literature to dig through!)

How nutritional deficiencies can make viruses worse:
http://lavenderdojo.blogspot.com/2016/04/mutant-viruses.html

How molecules of the immune system can make pain worse:
http://lavenderdojo.blogspot.com/2016/03/pain-and-inflammation-nociception-and.html

How molecules of the immune system can cause low energy and brain fog:
http://lavenderdojo.blogspot.com/2016/05/thyroid-immune-interactions-rt3-and-tgf.html



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Addenda
Some studies that look promising:

This can't be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response.

http://www.ncbi.nlm.nih.gov/pubmed/26409212

Caudle M. This can’t be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response. Physiol Behav. 2015

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181830/?report=reader
Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience. 2006;8(4):383-395.

(for this last study, if you use the search function in the upper right-hand corner, you can find little nuggets by searching "immune")

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

May 12th Awareness Day

Today is May 12th, Invisible Illness Awareness Day / M.E. Awareness Day / Fibromyalgia Awareness Day. I would like to share Hanlon's Razor:

Never attribute to malice that which can be adequately explained by stupidity

I'm not saying there has never been foul play in the history of how these conditions are viewed/treated, but I do think ignorance and misinformation (and biomedical limitations for testing biomarkers) are the primary drivers. That's why awareness days are important. 

For fibromyalgia, I made a short video that attempts to shed a little light on the nature of invisible pain. It didn't quite go as I'd liked, but I guess I can always burn myself on camera again, in a more grisly fashion, hah, heh, ergh. 

Oh, any ideas for things traditionally considered painful that don't do lasting damage? Leave suggestions in the comments please!

https://www.youtube.com/watch?v=iX1Vgl0GCKQ

Pairs well with my post on nociceptors and cytokines:

http://lavenderdojo.blogspot.com/2016/03/pain-and-inflammation-nociception-and.html

I've heard it put forth that Flea of the Red Hot Chili Peppers had MECFS for a few years. So, via some kind of logic (or lack thereof) here's a RHCP cover:

https://www.youtube.com/watch?v=AtpCO3S18Dc

Over the years of feeling ill, songwriting was an outlet that helped keep me sane. I particularly like finding slant-rhymes for tricky words like 'orange' and 'chrysanthemums'. Digital art is also fun:

Combine all that with digging through hundreds of medical studies, and the existential crisis that occurs after years of being sick and maligned, and yarr: a song about science and religion teaming up to fight disease

https://www.youtube.com/watch?v=euXi86vrGHM

Best of luck on your road to recovery. Or, if you're not ill, please be understanding towards those who are.

Sean @ LavenderDojo

Thyroid-immune interactions; rT3 and TGF-beta1

Let's cut right to the core study:

Transforming Growth Factor-β Promotes Inactivation of Extracellular Thyroid Hormones via Transcriptional Stimulation of Type 3 Iodothyronine Deiodinase

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:
http://www.ncbi.nlm.nih.gov/pubmed/16037131

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:

http://www.wellnessfx.com/thyroid

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:

http://www.stopthethyroidmadness.com/rt3-ratio/

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.

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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

http://www.hindawi.com/journals/jtr/2011/215718/

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

Abstract:

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

Consolidating Online Presence

(not particularly important post)

A little bit of housekeeping:
I'm preparing to post more content, higher quality content, in more mediums and through more channels. Hopefully my peregrinations on PubMed (and other knowledge I've garnered over the last decade of illness) will add value to the spoonie community. I'd like to put myself out there more, and make at least a modest positive impact.

Lavender Dojo
/
LavenderDojo

I'll endeavor to stick to this name. The intent is that it is unique enough to be a top hit on Google if you search for those words, but mundane enough to not need spelling out. For this blog, I was originally using the name Lavendogh. Lavendogh was a word I made up so that this blog was the only result for the query "lavendogh". Unfortunately, the spelling was not intuitive if I mentioned the blog name in conversation. The hope is that "lavender" and "dojo" are both common enough to not require explanation, but a weird enough juxtaposition to be memorable.

Over the years, I've also had very sporadic activity on Twitter and SoundCloud under the pseudonym Feeble Asclepius / @FeebleAsclepius. I intend to change those accounts to LavenderDojo also, but in case there are any hitches this blog post can act as a signpost.

Youtube account has gone from "phrygianechinoderm" to "lavendogh" and will presently be "LavenderDojo".

Uf! Online identity and digital footprints are interesting topics, but I digress. A series of important Fibromyalgia and MECFS posts are in the pipeline.