The TTSI is used as a screening parameter for resistance to thyroid hormone due to mutations in the THRB gene, where it is elevated. It is also beneficial for assessing the severity of already confirmed thyroid hormone resistance, even on replacement therapy with L-T4, and for monitoring the pituitary response to substitution therapy with thyromimetics (e.g. TRIAC) in RTH Beta.
In autoimmune thyroiditis the TTSI is moderately elevated.
A large cohort study demonstrated TTSI to be strongly influenced by genetic factors. A variant of the TTSI that is not corrected for the upper limit of the FT4 reference range was shown to be significantly increased in offspring from long-lived siblings compared to their partners.
Conversely, an elevated set point of thyroid homeostasis, as quantified by the TT4RI, is associated to higher prevalence of metabolic syndrome and several harmonized criteria by the International Diabetes Federation, including triglyceride and HDL concentration and blood pressure.
In certain phenotypes of non-thyroidal illness syndrome, especially in cases with concomitant sepsis, the TTSI is reduced. This reflects a reduced set point of thyroid homeostasis, as also experimentally predicted in rodent models of inflammation and sepsis.
Negative correlation of the TTSI with the urinary excretion of certain phthalates suggests that endocrine disruptors may affect the central set point of thyroid homeostasis.