This constitutes a summary of Q and A between us and the Endocrine Society, for those interested
Sorry it's rather long but there were many questions. TUK might feel some of the Q and A useful to record.
Solving the hypothyroidism puzzle
Q & A
Let’s start with the Frontiers paper: What made you want to look at endocrine regulating in the HPT axis? This preservation/adaptation dynamic is interesting.
1) We wanted to find out why the set (balance) point is so heavily guarded for optimum thermodynamic efficiency, and yet under certain circumstances, the system can change quite distant from its previous sate with its own system of regulation. Let me explain a bit more, the endocrine system is designed to protect a state of integrity and inner workings of the system when faced with adverse conditions and challenges arising outside of the system. This means, in the hypothalamic-pituitary-thyroid (HPT) axis regulation, the thyroid hormone FT4, and even more so its biologically more active sister hormone FT3, are maintained in a tight concentration range, termed homeostasis, to allow the proper functioning of the many dependent metabolic processes. However, if the previous homeostatic level becomes indefensible it may be advantageous to adapt it to a new level. This flexibility to choose between the preservation of homeostasis and its adaptation (allostasis) supports optimum resilience in stressful situations. Since the classical HPT model of TSH-FT4 regulation does not account for such properties we came to the conclusion that HPT axis regulation needs to include T3.
You write about previous studies not being well suited to identify underlying mechanisms of HPT axis regulation, and their results could be compromised by their inability to take into account the different physiological mechanisms. Can you speak more to that?
2) In the diagnosis and treatment of hypothyroidism, TSH has been assigned an predominant role, mainly under the wrong assumption that a person’s own pituitary may be best suited to accurately reflect the peripheral thyroid state of that person. Thereby, "subclinical hypothyroidism" is diagnosed when the TSH value exceeds its reference range, but FT4 concentration is still within range. While the sensitive pituitary response to a minor decline in thyroid function leads to an early TSH increase, this laboratory constellation is not hypothyroidism-specific, rather ambiguous. TSH can equally rise in adaptation to prevalent stressors, such as such as seasonal change, cold exposure, fasting, weight gain, infectious diseases, and psychological stress. Many clinical studies have obscured a clear distinction between these different entities, reporting conflated statistical outcomes. Given the thyroidal T3 shunt and its influence on HPT regulation - namely that TSH feedforward controls T3 secretion and T4-T3 conversion efficiency - TSH cannot be regarded as passively responsive and reflective, rather acting pro-actively and correctively. Therefore, "subclinical hypothyroidism" does not define an entity or disease in need of treatment. The distinction lies not so much in the moderate TSH increase, but in its etiology and whether or not its corrective action is successful in preserving FT3 homeostasis. The therapeutic target can no longer be defined by TSH and its "normalisation" but shifts to restoration of FT3 homeostasis. The latter is more closely associated with symptom relief according to recent clinical studies. That way, a better understanding of the regulatory mechanisms translates to improved patient care. Further, you write about how top-down control works in the technical world, but not necessarily the natural world, and that a reconsideration has begun in psychology and the neurosciences.
What does that reconsideration look like, even among other sciences and specialties?
3) In the technical world, the regulatory goal is mostly about the setting of a fixed target by the higher center, as does the thermostat to control the heating. This is typical of top-down control. In contrast, most natural systems opt for more flexible adaptation, requiring an interaction of top-down and bottom-up regulation to achieve the desired outcome. As an example, adaptation of FT3 is important and subject to both central control and local control in various tissues, as it is closely related to the energetic and metabolic needs of the body. FT3 generation is secured by three different mechanisms, 1) T4-dependent and TSH-independent extra-thyroidal conversion, 2) T4- and TSH-dependent mainly intra-thyroidal T4 to T3 conversion, and 3) T4- and TSH-independent T3 secretion. The combination of mechanisms provides a considerable amount of variation and redundancy to the HPT regulation. On the other hand, in feeding back to the pituitary and hypothalamus, the summation effect of the extrathyroidal FT3 production provides bottom-up information on the hormone-dependent energetic state of the organs to the upper centers, which is required to adopt a new target. All of this makes the attainment of a certain TSH value conditional rather than a fixed target. Similarly, neuropsychological perceptions can be presented from bottom-up or as top-down expectations, to alter both the expression of top-down control, thereby blurring hierarchical distinctions and giving rise to greater plasticity.
Can you talk a little bit about the ODEs and the various scenarios you investigated?
4) Our extended system incorporates FT3 homeostasis as a system goal, including feedforward of TSH on FT3 at the lower level and feedback of FT3 on TSH and TRH at the upper levels. The examination of various mechanisms, mathematically expressed by a system of ODEs, agrees with Billlman’s assertion that "disruption of homeostatic mechanisms is what leads to disease, and effective therapy must be directed toward re-establishing these homeostatic conditions." As above, this means that thyroidectomy and the loss of the intra-thyroidal T3 shunt shift the balance between TSH, FT4 and FT3 levels, compared to that prior to surgery. Together with other clinical studies, it explains why their former TSH level is no longer indicative of the euthyroid state, and these patients may continue to suffer from residual symptoms.
You write that in the absence of any T3 sources other than the thyroid, HPT axis regulation remains self-sufficient to support FT3 homeostasis. That seems like an important finding. Can you speak more to that and what its implications might mean for human health?
5)Despite the complexity of the controlling HPT system, when normalising the relative strengths of the various feedback and feedforward components, we can readily demonstrate the attainment of a solution of perfect FT3 homeostasis. These mechanisms protect the level of FT3, independently of any variations of FT4 and TSH. A supporting extreme example is the life-sustaining controlled dominant T3 production in animals with intact HPT but deficiency of all deiodinases. Strong T3-protective rescue and redundancy mechanisms are likely to be operative in humans as well. We note that extra-thyroidal T3 production is largely exempt from direct centralized control. This does not imply autonomous function, because it provides feedback for adaptive HPT regulation.
Can you talk about what the traditional view has been in diagnosing and treating thyroid patients, and a little more to how your studies and other more recent ones are challenging that traditional view?
6) The presently held view is that in athyreotic patients on LT4 monotherapy the system is restorable to its former level of homeostasis. This is because the TSH-dependent and direct T3 production by the thyroid gland is ignored as a minor unimportant entity. By this assumption there is only HPT feedback to consider from the T4 point of view. As explained, both the mechanisms of HPT regulation and recent clinical studies contradict this long-held belief. Treatment with LT4 and its TSH based dose adjustment has been shown to frequently result in FT3 levels that are insufficient to achieve metabolic normality and symptom relief. Apart from untreated overt hypothyroidism, symptomatic change correlates best with serum thyroid hormone levels, not TSH.
What’s next in this area of work? What do you hope Endocrine Society members take away from your study?
7) To improve the situation for patients we should account for the conditionally of the FT4/FT3 levels when aiming for them in treatment. The FT4/FT3 ratio in thyroid disease will alter from the healthy state in lowering the ratio in hypothyroidism, and in nonthyroidal disease by raising it (low FT3 syndrome). We should therefore reconsider the importance of measuring FT3. It is the chief biologically active thyroid hormone and more integral to HPT axis regulation than previously thought.
Now to the BMC paper: Talk a little about this over-reliance on TSH, and how it’s given rise to patient complaints.
8) Given the existence of the thyroidal T3 shunt, the diagnostic reliance based solely on TSH leads to misclassification and consecutive dissatisfaction of patients. On the total loss of the gland, LT4-monotherapy will probably compensate for the T4 and T3 lost in the below mid-range group, at the expense of a raised FT4/FT3 ratio. Patients in the upper FT3 range will need more T4 in their attempt to regain a healthy condition. In the absence of a working thyroid and a larger requirement of T3, this may not be possible to achieve, and these patients may benefit from combination therapy when the corporeal deiodinases cannot produce enough from LT4. We have to appreciate that TSH is a sensitive marker of primary hypothyroidism, but not an equally reliable indicator of the euthyroid state. TSH "normalisation" is by no means equivalent to the patient being "euthyroid". Therefore, residual symptoms may be expected to persist despite this achievement.
You write that focus on biochemistry rather than patient symptom relief should be re-assessed. Can you speak a little more to that?
Patient complaints should not be dismissed because of a seemingly normal TSH value. TSH is too respected as a diagnostic for both hypothyroidism per se and T4 treatment. As above, the healthy situation is not repeated in therapy. If the thyroid is failing, then FT4/FT3 ratio changes in favour of T3’s bigger contribution stimulated by more TSH. In therapy, a satisfactory outcome may require more T4 to optimize FT3. The interpretation of a given TSH value should be conditional, as appropriate to the condition and the resulting FT4 and FT3 levels.
What would you say to a clinician who may be apprehensive about shifting how they do things, or may be experiencing clinical inertia?
9) I’d say the good news is that clinicians will get valued more for their skills in recognising the typicality of symptoms over a laboratory test. It comes at a cost that more effort and training will be required, as a single TSH measurement won’t do the job.
You write about that dramatic rise in patient complaints in recent years and go over some reasons for that. Can you go over those reasons again for us here?
10) Not recognising the limitations and conditionality of isolated sensitive TSH measurements has resulted in a large number of patients complaining about residual hypothyroid symptoms. In order to get the FT3 to the same level it has been prior to thyroidectomy, many patients on LT4 would need a suppressed TSH after surgery to achieve this goal, which does not mean hyperthyroidism to them, because their balance point has shifted in the absence of TSH feedforward onto FT3. Denying these patients T3 normalisation does not help their symptoms. We should not place a TSH value, which we may yet have to fully understand, over patient complaints we understand well as a doctor. This is not to say all is easy - there are non-specific and overlapping symptoms with other diseases. However, it is equally clear there are residual symptoms in the presence of a "normal" TSH.
This shift again speaks to individualized care, as you point out in the paper. Can you speak more to the kinds of studies you’d like to see going forward?
11) In realising each patient achieves a unique balance between their FT3, FT4 and TSH levels, we have to avoid inappropriate generalisation and a one-size-fits-all approach. This is important since the amalgamation of dissimilar subgroups (whose members do not share the same average) in clinical studies results in a statistical error (collider stratification bias). We also suggest to blindly study patient satisfaction against FT4/FT3 and TSH values in different subgroups of patients on differing treatment modalities.
This part stuck out to me: “Treatment choices no longer rest primarily on the personal interaction between patient and doctor but have become a mass commodity, based on the increasing use of guidelines not as advisory but obligatory for result interpretation and subsequent treatment. Contrary to all proclaimed efforts towards a more personalised medicine, this has become a regulated consumer mass market as with many other situations.” Can you elaborate on that? I know some physicians point to big pharma as the culprit. Is that fair to say?
I don’t think that big pharma are the main culprits. The primary error was, when sensitive TSH assays became widely available, the simplified thinking I’ve written above about how the HPT control is the same in health, disease and on therapy misled the field to diagnose according to that wrong belief. Clinical presentation should have predominated over biochemistry to resolve the conflict. The guidelines have a role in standardising patient care, but in doing so they tend to marginalise patients that do not fit in. They were meant to provide general guidance only but not to be instrumentalized as a legal imperative to treat everybody the same.
What do you hope Endocrine Society members take away from this paper?
12) The endocrine mechanisms of the HPT control should be extended to address important aspects of T3 physiology, together with the predominance of presentation and uniqueness of each patient’s biochemistry. This offers a chance of a rebirth of endocrinology as a unique regulatory discipline beyond the predominant statistical area of research.
Thyroid hormone homeostasis in levothyroxine-treated patients: Findings from ELSA-Brasil
