Why are some people extremely hypothyroid while their TSH is above reference range, while others have no symptoms and are completely healthy?
How important is the Free T3 test when diagnosing true “euthyroid” status within the TSH reference range? Is it true that a normal TSH alone, or a normal TSH and normal FT4 test together, can assure us that the FT3 will also be at a healthy level within thyroid therapy?
Could I take my TSH, FT4 and FT3 test results from when I had a healthy thyroid gland, and use them as treatment targets after thyroid disease or thyroidectomy, or would some adjustment be necessary?
These and other fundamental questions are answered in this third and final section of my paraphrase of Hoermann et al’s 2016 article on “relational stability” among thyroid hormones and TSH.
Relational Stability between Thyroid Parameters[Paraphrase begins]
Recent studies have demonstrated that risk of cardiovascular disease and mortality increases even as TSH rises within the “normal” thyroid function range. This suggests that the transition into thyroid disease occurs gradually, and risks may not be accurately assessed using “normal” TSH range boundaries. Viewing thyroid health as a combination of all thyroid parameters and their interrelationships may provide a more comprehensive picture of thyroid hormone health.
A moderately raised TSH could either indicated the failure to restore thyroid balance or a successful adaptation. In the case of less severe or temporary disruptions in thyroid hormone balance, the system’s early defense strategy may be to adapt the equilibrium between TSH and thyroid hormones. Clinical studies support this view that an elevated TSH can sometimes be a healthy adaptation, showing that mildly elevated TSH levels (5-10 mIU/l) – that is, when they occur naturally, outside of thyroid therapy – are not associated with adverse outcomes such as mortality, cardiovascular events, fracture risk, or cognitive impairment. Conversely, in elderly patients with “subclinical hypothyroidism” (again, outside the context of thyroid therapy), risk of lower life expectancy was found with lower, not higher, TSH values.
Therefore, we hypothesized that early-phase TSH adaptation to a system under stress should be testable by studying the expression of homeostatic equilibria across a wide spectrum of patients with normal thyroid function.
We called the concept “relational stability,” which was intended to describe the adaptive interrelationships between thyroid parameters rather than an univariate expression of normality of a single component (such as TSH alone) maintaining system stability.
In our research, we found an inverse correlation between TSH-standardized T4 production and conversion into T3 across the entire “euthyroid” reference range for TSH. In other words, both T4 and T3 synthesis and T4-T3 conversion shifted in favor of T3 as TSH rose throughout its normal reference range. [See figure from Hoermann et al, 2016a]
This finding of a continuous inverse relationship contradicts the widespread assumption that the relationship between TSH and thyroid hormones is randomly defined by genetic variations among individual set points.
Instead, it indicates physiological control of homeostasis long before thyroid gland failure progresses to the stage of both FT3 and FT4 hormone reduction.
Even as the TSH rises in reference, for example from 1.5 to 3.5, important adjustments are being made in thyroidal hormone secretion and conversion. To maintain a symptom-free euthyroid state, the intact HPT axis maintains a stable FT3 around the mid-reference mean to compensate for a mildly lower-than-mean FT4.
The euthyroid reference range for Free T3 is therefore dependent on a progressive alteration in the controlling interplay among TSH, Free T4 and Free T3 across this euthyroid spectrum.
This concept extends even into the state of untreated overt thyroid disease, such as primary thyroid failure in autoimmune thyroiditis, where the pattern of homeostatic control is found to be similar in its TSH-T4 inverse relationship, but shifted to a far lower level of T4 and T3 production.
Hence, maintaining stable FT3 positions always takes biological priority over the concept of maintaining a fixed set point of TSH and T4 whenever the thyroid homeostasis system compensates for early-onset thyroid stress, such as early thyroid failure from autoimmune thyroid disease.
The thyroid hormone economy progressively increases the body’s global deiodinase activity, upregulating deiodinase type 1 and type 2 in order to increase peripheral conversion of T4 to T3 as it experiences a decline in production of T4 and T3 hormone from the thyroid gland.
We therefore hypothesize that TSH has a feed-forward control over deiodinase activity that acts to stabilize Free T3 levels in bloodstream.
Even as we examine studies of daily circadian rhythmicity of FT3 and TSH levels in blood in healthy individuals, we see that their phase shifts are closely coupled together, further demonstrating their mutually adaptive behavior.
(As TSH rises after midnight, the Free T3 level rises shortly afterward, at a slightly delayed circadian rhythm, while FT3 is tightly controlled around the mid-reference mean. [See Russell et al, 2008.])
Studies of thyroid hormones in patients without thyroid glands on levothyroxine (LT4) therapy has further suggested the direct role of TSH in integrating the cooperative elements of “central control” (TSH controlling thyroidal hormone production) and “peripheral control” (the balance between deiodinase type 1, type 2 and type 3 activity). TSH seems to be involved in influencing both systems of thyroid hormone homeostasis—central and peripheral.
Studies on rats and genetically modified animals bred with genetic handicaps in their deiodinase enzymes also suggest that the organism places a high priority on defending appropriate FT3 concentrations in blood.
Animal studies make possible invasive procedures not ethically possible in human studies, thereby extending our findings to hormonal equilibria within human bodily tissues. When we take blood samples and measure FT3 and FT4, we can now extend our reasoning to what is likely occurring within tissues and cells.
Our proposed concept of relational stability gives equal priority to maintaining T3 stability and controlling the normal TSH-T4-T3 homeostatic set point.
When there are conflicts between these two priorities, maintaining T3 stability takes priority over maintaining the statistically normal TSH-T4-T3 set point.
Importantly, this indicates that the traditional set point is dramatically altered in well-studied extreme conditions such as “nonthyroidal illness” NTIS, also known as “low T3 syndrome” or “consumptive hypothyroidism,” when T3 levels drop very low while TSH remains normal.
Understanding the progressive variation in relational stability of thyroid homeostasis has important implications for clinical decision-making.
First of all, it brings a new perspective to the controversial debate on the validity of TSH reference range boundaries and “subclinical” disease classifications.
Some authors have proposed lowering the conventional reference range for TSH to 2 mIU/l, based on imposing a statistical normal distribution to the range in order to more sensitively define “subclinical hypothyroidism.” But others see no need to redefine the upper reference limit, since the 2 mIU/l limit may not indicate the system’s response to the beginning of disease, but rather an early response to stress on the system. When the system is under stress to produce more thyroid hormone, it will raise TSH, either temporarily or permanently. But in the presence of a healthy thyroid gland and a good T4-T3 conversion rate, the elevated TSH will result in a healthy amount of thyroid hormone secretion, and equilibrium will be restored.
The more conservative view is that the upper limit of TSH should not be lowered. This view would favor a more cautious, conservative approach, hesitating to begin thyroid hormone therapy in patients whose TSH is classified in the “subclinical hypothyroidism” range. This is currently the gray area between the upper limit of normal TSH to 10 mU/L.
Nevertheless, if clinical presentation of chronic and severe hypothyroid symptoms warrants it, even modest elevations of TSH should not rule out appropriate medical treatment with thyroid hormones. This is because wide individual variations exist even within the TSH reference range. (Because of individual variation, someone with a high-normal TSH could indeed be hypothyroid if their homeostatic setpoint requires a higher T4 and therefore also a TSH in the lower part of reference range.)
Secondly, unexpected outcomes may result from balancing the effects of feedback and feedforward regulation among thyroid hormones. (The “feedforward” mechanism is TSH’s regulatory influence–its ability to raise and lower the level of thyroid hormone secretion.)
For example, LT4 medication may impair the system’s feedforward regulation by reducing TSH’s stimulatory levels far lower than was anticipated given the dose, thereby resulting in decreased FT3 concentrations in autoimmune thyroiditis patients who still have some living thyroid tissue.
This phenomenon encourages further study of the parameters and measures of relational stability among hormones.