After virtually two years of work on this topic, we have had our paper on how the HPT + body axis works (Hypothalamus[H], Pituitary[P], Thyroid[T], Body Conversion [B]). The essential problem to overcome was to answer the question "how can the body simultaneously be robust to thyroid axis changes in health and yet, when the need arises, in illness to move smoothly to a radically different situation appropriate for the condition. The mathematics looks more formidable than it really is. There are five things going on at once, each described by its own rather simple equation. Studying one factor would be easy, but to study 5 at once needs a computer to solve the overall question. This is done by iterative computing - the computer searches for and finds the optimum answer by repeated trials of numbers until the system can realistically describe the different situations . However, there is more. Taken as a whole with some exceptions, the field will not or cannot subscribe to the importance of the direct production of T3 by the thyroid as a fine control of what the body is doing in T4-T3 conversion. For example, Banco wants to describe things as changes in hormone output by mutation in deiodinases etc. The field simply cannot explain this simultaneous robustness and adaption when needed. The whole paper is we think a complete description of the HPT axis and body reactions and discusses its impact on diagnosis and treatment.
Nearly 3 years from first consideration, but it was always our "Holy Grail" for ultimate understanding of literally knowing how the HPT axis works, and the implications for the patient with thyroid disease or nonthyroidal illness.
I've been holding on for at least two years since you first started saying things about a comprehensive explanation.
Totally delighted to see it published. Yes, for us here, but also so very much for you and your associates. I'm sure you'd do so anyway, but please pass on my, indeed our, thanks and appreciation and congratulations.
Now the hard bit - reading and understanding (as far as I can).
Thank you diogenes for all your outstanding work! I hope this makes a real impact in the application of thyroid treatment. I don't fully understand it, I must say, not as clever as some here, but I sort of grasp the outline of it's importance. I need to sit down with it later and go over it slowly. Honestly it's great what you're doing.
The skill is knowing when you don’t understand. You can then work towards getting it. The real menaces are the ones that think they understand, but they don’t get it at all!
Congratulations to all...I cannot pretend to understand the depth of this study but do recognise that it is an important piece of work that must reach the highest echelons of the thyroid world.
I'm with DD . I don't understand myself the the study well enough. But Congratulations is in order and a big shout out to Diogenes for the hard work well done. And advocating for us the silent voices .Thank You ! Thank You! Thank You!.
I can't really answer you yes or no. What is now clear is that patients, whoever they are and what their symptoms are, should be treated as individuals and not as participants in statistics. The picture is not black and white, with hard edges. There are so many potential effects on top of thyroid problems, which insist on an individual approach. This is done not by applying ranges, but looking and listening.
We live in the fuzzy areas of probability, likelihood and inference on most/all levels: time for them to finally accept that the thyroid cannot be excluded from this.
This is my best shot at “simplifying” First, what do we have to rationalise in the working of the HPT axis and its response to pressures on it. By simply looking we know that in health, the thyroid hormone levels, especially FT3 and FT4 are kept within bounds typical of the particular subject. We also know that if one becomes significantly nonthyroidally ill, FT4 is usually maintained at health levels but FT3 drops considerably out of its usual range. How can we reconcile these two apparently contradictory situations, so that we can explain how the healthy state changes into the disease state and is recovered on regaining health. The obvious reason is that the body responds suitably to the two situations, whenever they occur. BTW I strongly believe that my FT3 went down like a rocket on my heart attack a number of years ago. So, the body’s essential need is to produce FT3 appropriate to all conditions, and above everything else.
Now we come on to successful modelling of the HPT axis workings. The paradigm held by present thyroidology not only fails to involve FT3 in approaching hypothyroidism (explaining why it doesn’t fall as much as FT4 does) but also believes there is a strong relationship between FT4 and TSH (FT4 falls, TSH goes up). This is true in hypothyroidism itself, but isn’t true in health. The next fact to bring in now, is that the thyroid produces about 20% +/- we don’t know of T3 direct and the rest is made up by T4-T3 conversion in the body. So, without considering the T3 so produced, with little working thyroid, the field assumes that the body deiodinases are stimulated to convert whatever T4 here is to maintain normal FT3 levels. On the contrary, it’s been demonstrated directly, and indirectly discovered by us, that as the thyroid dies, the T4 producing part is diminished, but the higher TSH stimulates the T3 producing part to continue right up to the final death throes of the gland. Everything then collapses and T4 treatment then has to compensate not just for the loss of the gland, but the T3 it used to make. This now has to be made good by extra T4 in dosage. Therefore with patients with no thyroid, the FT4/FT3 ratio is higher than for normals. This mechanism is a “feedforward” device – TSH stimulating gland T3 production. So, only if we include this action of the thyroid can we explain 1) the steadiness of FT3 in health, 2) its partial maintenance in a failing thyroid. And 3) how nonthyroidal illness by inhibiting deiodinase body action can inhibit T4 conversion in the body, thus again raising the FT4/FT3 ratio.
So, putting these findings and requirements all together, we show that only our model can explain the changes that occur, and the outcome for people on T4 therapy. Also of course, we emphasise the need to stop considering statistically defined diagnosis of those on therapy, but the individualty which requires a much more patient-oriented diagnosis and treatment.
It is a fascinating read - the maths went over my head but I got what it was driving at. It’s a brilliant piece of work that should change everything for the better.
Shocked to hear you had a heart attack and trust you are well now. How I zipped up and down from TSH 0 to 110 and got through it I don’t know but my heart did a lot of complaining but thankfully that was all. I was nearing the end in terms of thyroid destruction - ultrasound shortly on revealed it was just a crisp of a thing with any function highly unlikely. I think I was pretty darn lucky to pull through, only NDT allowed me to properly regain my health.
Brilliant! Congratulations to you and your team on this significant achievement. I'm sure it's beyond my ken, but I hope it gets the recognition it surely deserves. Thank you for your work and dedication.
A big congratulations diogenes and colleagues! 🙌 👏👏👏 Thank you to the entire team for all your hard work and perseverence!!
Biological feedback loops are fascinating and I can imagine it was a bear to simulate. Great abstract and I look forward to reading the rest when more clear headed.
Thank you so much for your summary diogenes That makes things much clearer. I am still however, trying to figure out how this paradigm fits with my situation.
On diagnosis, my TSH was 2.9, but my T4 was below the range at 10 (12 -22). My T3 was 4.2 (0.3- 6.8). I felt terrible. I have faulty DIO2, heterozygous.
On my understanding of the newly outlined paradigm, my T3 was being prioritised as best it could, to help overcome my lack of T4, but why was my TSH not raised? That level of T3 might feel ok for some, but for me, because of my poor conversion, I need T3 at the top of the range and a suppressed TSH.
Why didn't my TSH rise? I was tested for pituitary problems, but nothing was found.
Thank-you and your team for this study. It’s easy to do a simple experiment and get headline results, these difficult tasks are often underestimated.
If I understand the paper, it makes sense, feedback is the dominant mechanism in health maintaining steady fT3 levels whereas feedforward takes the lead role in adaptation to illness or external factors. An exquisite system which like all systems is prone to failure. Sadly, the endocrine community invariably consider failure of the components (thyroid, pituitary, hypothalamus but never the system.
The system is even more complex than your HPT study! TSH (and fT3, fT4) not only regulate the HPT axis but also peripheral deiodinases, the rate and location of T4 to T3 conversion and local T3 levels in crucial tissues such as the brain, skeletal muscles, and heart. We sometimes see reports of patients with quite high TSH levels of e.g., 20.0 or 30.0 with a low fT4 who feel quite well. The system can be very robust.
On the other hand, over the past two or three years I’ve seen around 100 posts on this forum from people with profound signs and symptoms with TSH, fT3, fT4 all within or just outside their reference intervals. These results are similar to the example in Figure 6F for critically ill patients in intensive care, except the thyroid patients usually have a lower fT4.
TSH, fT3 and fT4 are usually interpreted as independent variables, which is nonsense. Your models, for the first time, facilitate a mathematical interpretation of the relationship between these three hormones. It should be possible to define an envelope of normal HPT axis values as seen in healthy individuals – with a fair bit of allowance for individual variations. Such a mechanism would be invaluable in diagnosing a failing axis (and enable the ‘treat the numbers’ brigade to occasionally get it right).
I hope I’m not losing everyone at this point. The model allows us to picture the range of TSH, fT3, fT4 values that occur in healthy individuals. For example, low normal TSH, fT3 and fT4 (all three) in someone without severe illness indicates hypothyroidism but this is dismissed because the numbers are just within their reference intervals.
The above example is a case of adaptation mechanism failure which has dire consequences. This model helps us identify such failures, even if we don’t know the cause. The effects go beyond the HPT axis because an abnormally low TSH (for given fT3, fT4) reduces peripheral deiodinase (especially D2) depriving organs such as the brain of adequate T3. Thus, this failure of the adaptation mechanism induces additional local hypothyroidism which isn’t fully reflected in the TFTs.
An added complication which the model doesn’t cover is the effect adaptation has on TSH isoforms. Low TRH stimulation results in TSH isoforms of reduced bioactivity. Less TSH with less activity.
Lastly, there may be a couple of typos in the paper. I may be wrong because my ability to concentrate is poor.
1. At the top of p. 14 on the third line it references ‘Figure 5D’. Should this be ‘Figure 6D’?
2. Near the top of p. 14 on the RHS the comments beginning ‘Our modelling shows …’ states that top-down control is responsible for homeostasis and bottom-up for adaptation. Should this be the other way around? Feedforward controlling adaptation and feedback regulating homeostasis?
Thanks for your interest. We can only describe the system with the broadest of brushes and define the essential roots of the working system almost as a tableau. In our eyes,body deiodinases do the horse work, but the thyroidal T3 production is like the driver keeping up a steady trot. But when the system has to change on a different gradient, the driver changes his guiding into a pace suitable for that. And when you lose the driver the poor horse is at a loss as to what to do.
Yes. One point I missed is that with no thyroidal T3 more T4 is needed to achieve the same serum T3 resulting in a lower TSH. A lower TSH reduces peripheral deiodinase with a reduction in local T3 levels. We can't really observe this effect in TFTs other than the presence of lower fT3/fT4 ratios, these ratios vary greatly between individuals and within individuals over time.
Thus, the loss of thyroidal T3 has effects beyond the availability of serum T3. I believe it has some effect on local T3 levels. I also believe that any fault in the adaptation mechanism which results in reduced feedforward (lower TRH, TSH) will have profound effects even if TSH, fT3 and fT4 are within their reference intervals.
Congratulations on your research paper, I'm going to try and understand the summary and hope that it will help me understand my current situation and explain it to my endo!
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At long last my test results are here despite the Covid delays
