The Thyrotroph Thyroid Hormone Sensitivity Index (abbreviated TTSI, also referred to as Thyrotroph T4 Resistance Index or TT4RI) is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. ^{[1] [2]} Today it is also used to get an estimate for the set point of thyroid homeostasis, ^[3] especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses. ^[4]

How to determine TTSI

Universal form

The TTSI can be calculated with

${\displaystyle TTSI={100\cdot TSH\cdot FT4 \over l_{u}}}$

from equilibrium serum or plasma concentrations of thyrotropin (TSH), free T4 (FT4) and the assay-specific upper limit of the reference interval for FT4 concentration (l_u). ^[4]

Reference ranges

Short form

Some publications use a simpler form of this equation that doesn't correct for the reference range of free T4. It is calculated with

${\displaystyle TTSI={100\cdot TSH\cdot FT4}}$.

The disadvantage of this uncorrected version is that its numeric results are highly dependent on the used assays and their units of measurement.^{[ citation needed]}

Biochemical associations

In case of resistance to thyroid hormone, the magnitude of TTSI depends on which nucleotide in the THRB gene is mutated, but also on the genotype of coactivators. A systematic investigation in mice demonstrated a strong association of TT4RI to the genotypes of THRB and the steroid receptor coactivator ( SRC-1) gene. ^[5]

Clinical significance

The TTSI is used as a screening parameter for resistance to thyroid hormone due to mutations in the THRB gene, where it is elevated. ^[4] It is also beneficial for assessing the severity of already confirmed thyroid hormone resistance, ^[6] even on replacement therapy with L-T4, ^[7] and for monitoring the pituitary response to substitution therapy with thyromimetics (e.g. TRIAC) in RTH Beta. ^[8]

In autoimmune thyroiditis the TTSI is moderately elevated. ^[9]

A large cohort study demonstrated TTSI to be strongly influenced by genetic factors. ^[10] 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. ^[11]

Conversely, an elevated set point of thyroid homeostasis, as quantified by the TT4RI, is associated to higher prevalence of metabolic syndrome ^[3] and several harmonized criteria by the International Diabetes Federation, including triglyceride and HDL concentration and blood pressure. ^{[12] [13]}

In certain phenotypes of non-thyroidal illness syndrome, especially in cases with concomitant sepsis, the TTSI is reduced. ^[14] This reflects a reduced set point of thyroid homeostasis, as also experimentally predicted in rodent models of inflammation and sepsis. ^{[15] [16] [17]}

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. ^[18]

See also

• Thyroid function tests
• Thyroid's secretory capacity
• Sum activity of peripheral deiodinases
• Jostel's TSH index
• Thyroid Feedback Quantile-based Index

References