Another paper acknowledging deficiencies in using reference ranges as fixed for all patients

Here is another paper with interesting conclusions for those who don't get on ell using diagnosis by rigidly sticking to the FT4/TSH reference range:

1.Theor Biol Med Model. 2014 Aug 8;11(1):35. [Epub ahead of print]

The homeostatic set point of the hypothalamus-pituitary-thyroid axis - maximum curvature theory for personalized euthyroid targets.

Leow MK, Goede SL.



Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual.


We have previously shown that the dose-response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the 'knee' region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic.


The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals.


In this treatise, we provide evidence supporting a set point-based approach in tailoring

euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.

PMID: 25102854 [PubMed - as supplied by publisher]

Its a bit technical but the message is clear.

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15 Replies

  • Very technical Diogenes, but a bit more grist to the mill. Thank you.

  • Diogenes, thanks once again. So they will have to set up their computers for testing the patients within the above recommendation.

    I think we will have to put flyers through each surgery and send to each Endocrinology Dept.

  • This is another wonderful advancement in the right direction, thank you Diogenes. We can only hope that the powers that be take note and act positively.

    I don't know if there are any diagrams of the "calculated HP curve parameters using the parsimonious mathematical model" as it might explain things for me more clearly.

    Thanks :-)

  • You can download the whole 43 pages of the paper free of charge. Heavy going, but the diagrams are there as well as a lot of maths.

  • Diogenes, have they ever figured out how to model those of us with a touch of thyroid hormone resistance? PR

    PS for those that want a PDF copy of the study.

    For the PDF.

  • Johannes Dietrich is busy revising his computer model of the pituitary-thyroid-peripheral feedback system in the light of the new knowledge we've come up with - namely that it looks likely that the thyroid produces a significantly bigger fraction of T3 directly than presently assumed, and secondly that TSH influences not only the thyroid output of T4/3 but also controls the T4-T3 conversion in the tissues other than thyroid in a "feed forward" mode. When this model comes out, simple adjustments to the various T4-T3 conversion feeds will model resistance. People who have lost their thyroid entirely simply cannot restore the original T4-3 relationships that they had when euthyroid and healthy. Some can get to normal FT3 by TSH-suppressing doses of T4, but others can't get there with any T4 dose, because their peripheral enzymes can't convert enough T4 to T3. This finding is all in a paper we've submitted and hope will be accepted soon.

  • Diogenes, that would be truly amazing. If you need a guinea pig I'd volunteer to test the model. PR

  • Me too!

  • Diogenes, my only concern is that we don't end up in the same place we are with the TFTs where the doctor treats the blood test instead of the patient. The patient's signs and symptoms and how they feel have to be a part of the process in determining the final outcome. Because doctors have such little time (the 5 to 15 minute appointment) I fear we might end up with the doctor saying 'the model says you are fine, end of story'. We have to get doctors actually paying attention to the patient again. PR

  • The process of thyroid function testing has through the TSH-only screen, become akin to soap powder selling. Feel the advert, hear the salesman, buy the product! In short, because there are large numbers of patients, the concept of appropriate treatment has become telescoped into a perceived optimum time/price/treatment paradigm, and any attempt to make the process thoughtful and individual regarding patient treatment is perceived as expensive and thus not to be countenanced in limited budgets. The great lacuna is the extra social costs encurring in failed diagnoses, inappropriate expense in false treatment procedures without resolution of problems, which in my opinion far outweigh getting it right in the first place using the appropriate tests. That's the lesson the medical profession has to understand in my opinion - as have the funding politicians.

  • Diogenes, a bit off subject but I've never been able to find Dr. Hoermann's CV, is his PhD in Biochemistry? PR

  • I think he did endocrinology, and certainly was a post doc for a while at Harvard. I believe therefore that his Ph.D will be in endocrinology.

  • Diogenes, what you said in the 3rd paragraph up has been rolling around in my head ever since. As we have talked about science has never been able to understand why NDT works so well for so many of us other than the DIO2 polymorphism and perhaps people that have had a full or partial thyroidectomy. The common criticism is that the T3 ratio is too high compared to the thyroid's output. If "TSH influences not only the thyroid output of T4/3 but also controls the T4-T3 conversion in the tissues other than thyroid in a "feed forward" mode" then isn't it possible that when we are on supplementation, which decreases TSH, some of us do not get enough T3 out of the total system and that the higher amount of T3 in NDT is not actually too much for our system to handle.

    The other aspect that science is clueless about is the fact that many of us on NDT drive the TSH to full suppression, or close to it, before we feel 'normal' and yet we do not have any symptoms of being hyper. I admit that I'm an odd duck but this is fairly common so it can't just be genetics or epigenetics, you would think.

    As Dr. Bianco said, "the biological imperative is to defend T3". That is all many of us are trying to do, is to get enough T3 in our system.

    The other area that is completely unknown is why some people need T3 monotherapy in order to get back to 'normal'. There is always a persistent minority, maybe 5-10%, that seem to need T3 only. As we have talked about this could be because of some 'damage' to the system, receptors, deiodinases, or something. PR

    This is from Dr. Lindner. "When we decide to take over the function of the thyroid gland by supplying thyroid hormone orally, it makes sense to replace everything that our thyroid glands make. It is true that NDT is much higher in T3 than is our normal

    thyroidal production. However this is beneficial for oral thyroid therapy as the TSH is low or suppressed on such therapy, and TSH is necessary for normal T4-to-T3 conversion throughout the body. When we lower the TSH, we must provide more T3."

  • Now all we have to do is convince the BTA and RCP to accept these results! Oh, wait! They won't while the big pharmaceutical companies are paying for their conferences etc!

  • Thank you so much for posting this paper and for whoever posted the link to the actual paper. I worked in Public Health in an English PCT for several years and part of my role was to select papers for group review. As a result we had some letters published in BMJ etc. However, whenever I suggested a paper from a study which was conducted outside of the 'west', it was rejected for discussion because "We don't pay much attention to these studies as they are usually faked". I hope the final version of this study report will be accepted for publication by a Western journal. I can just about follow the equations but don't have enough focus to stick with all the variables. I'll print it for my GP and see if he or she (depends) responds! I've already dragged T3 out of them but now need to try NDT.

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