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 The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes a ...

. It was originally developed to deliver a method for fast

screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), a s ...

for

resistance to thyroid hormone Thyroid hormone resistance (also resistance to thyroid hormone (RTH), and sometimes Refetoff syndrome) describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, ...

. Today it is also used to get an estimate for the set point of thyroid homeostasis, especially to assess dynamic thyrotropic adaptation of the anterior

pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...

gland, including non-thyroidal illnesses.

How to determine TTSI

Universal form

The TTSI can be calculated with :

TTSI =

from equilibrium

serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...

or plasma concentrations of thyrotropin (TSH), free T4 (FT4) and the

assay An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity ...

-specific upper limit of the

reference interval In medicine and health-related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood, or ...

for FT4 concentration (''l_u'').

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 :

TTSI =

. The disadvantage of this uncorrected version is that its numeric results are highly dependent on the used

s and their

units of measurement A unit of measurement, or unit of measure, is a definite magnitude (mathematics), magnitude of a quantity, defined and adopted by convention or by law, that is used as a standard for measurement of the same kind of quantity. Any other qua ...

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 The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransfer ...

) gene.

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. 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 A TRIAC (triode for alternating current; also bidirectional triode thyristor or bilateral triode thyristor) is a three-terminal electronic component that conducts current in either direction when triggered. The term TRIAC is a genericized trad ...

) in RTH Beta. In

autoimmune thyroiditis In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

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 Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

and several harmonized criteria by the

International Diabetes Federation The International Diabetes Federation (IDF) is an umbrella organisation of over 240 national diabetes associations in more than 161 countries and territories. It is headquartered in Brussels, Belgium. Organization IDF is divided into seven reg ...

, including

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

and HDL concentration and

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

. In certain phenotypes of non-thyroidal illness syndrome, especially in cases with concomitant

sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...

, the TTSI is reduced. This reflects a reduced set point of thyroid homeostasis, as also experimentally predicted in rodent models of

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

and sepsis. Negative correlation of the TTSI with the urinary excretion of certain

phthalate Phthalates ( ), or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften ...

s suggests that

endocrine disruptor Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ...

s may affect the central set point of thyroid homeostasis.

References

{{Reflist, 2 Chemical pathology Blood tests Endocrine procedures Thyroidological methods Thyroid homeostasis Structure parameters of thyroid function Static endocrine function tests