Thyroid Allostasis – The Neglected Second Control Mode of Thyroid Function

What is it about?

Thyroid hormones, e.g. thyroxine (T4) or triiodothyronine (T3) are so-called pleiotropic mediators - i.e. their profound action impacts most, if not all, tissues of the vertebrate organism. Given the manifold effects of thyroid hormones, it is not surprising that the function of the thyroid gland is controlled by multiple intertwined feedback loop mechanisms (in summary also referred to as thyrotropic feedback control, hypothalamus-pituitary-thyroid axis or HPT axis). It is, however, a common misconception that this control system follows a fixed and always unchanging set point. This would imply that concentrations of TSH and peripheral thyroid hormones were always constant and that every deviation from reference ranges would signify disease. Research of the previous decades revealed, however, thyroid homeostasis to be a dynamic system that is able to change its mode of operation in certain situations. Reduced concentrations of T3, and occasionally also T4 and TSH, are a common observation in situations, where the organism lacks energy. Examples of this situation are starvation, exhausting exercise, and critical illness. Similar patterns are also seen in depression and in fetal life. It is important to note that these changes in thyroid homeostasis occur in the absence of any thyroid or pituitary disease. Rather, they represent a turned-down set point of the control system. Many researchers assume that this adaptive response is beneficial since it helps to save energy in situations, where energy expenditure exceeds supply. This kind of "stability through change" is known in biology as type 1 allostasis. Although routine assay systems are not readily available numerous investigations also described increased concentrations of reverse T3 (rT3) and 3,5-diiodothyronine (3,5-T2) in type 1 thyroid allostasis. In other situations somewhat opposite patterns of thyroid adaptation may be observed: Here, concentrations of T3, and sometimes also T4 and TSH, are increased, while rT3 levels are reduced. Typical examples of this kind of situation are obesity, endurance training, pregnancy, adaptation to cold and some psychiatric conditions including acute schizophrenia and post-traumatic stress disorder (PTSD). All of these situations represent a form of predictive adaptation, where the organism prepares for expectedly increased demand or reduced availability of energy (although the current supply is usually sufficient for the current needing). This kind of predictive adaptation is referred to as type 2 allostasis. As in type 1 thyroid allostasis, ​the thyroid and the pituitary gland typically work well. The exquisite matching of thyroid response to particular biological, behavioural and neural states implies that "fluctuations arise not from poor control but from precise control", to cite Peter Sterling. This review article gives a comprehensive overview of physiological situations that are accompanied by type 1 and type 2 thyroid allostasis. It also provides a synopsis of the physiological mechanisms underlying the mechanisms leading to allostatic responses of HPT axis.

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Why is it important?

Changed concentrations of TSH and peripheral thyroid hormones are a common observation in certain diseases and in common straining life situations. A typical example is non-thyroidal illness syndrome (NTIS), also referred to as euthyroid sick syndrome (ESS) or thyroid allostasis in critical illness, tumours, uraemia and starvation (TACITUS). Other instances include but are not limited to starvation, pregnancy, exercise, thermal stress and certain psychiatric conditions. If not properly recognised, allostatic responses may result in differential diagnostic problems, right up to overt misdiagnosis of thyroid dysfunction, although the thyroid works well.

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