Thyroid function tests

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Thyroid function tests
MeSH D013960
MedlinePlus 003444

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. [1]

Contents

TFTs may be requested if a patient is thought to suffer from hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid), or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

A TFT panel typically includes thyroid hormones such as thyroid-stimulating hormone (TSH, thyrotropin) and thyroxine (T4), and triiodothyronine (T3) depending on local laboratory policy.

Thyroid-stimulating hormone

Thyroid-stimulating hormone (TSH, thyrotropin) is generally increased in hypothyroidism and decreased in hyperthyroidism, [2] making it the most important test for early detection of both of these conditions. [3] [4] The result of this assay is suggestive of the presence and cause of thyroid disease, since a measurement of elevated TSH generally indicates hypothyroidism, while a measurement of low TSH generally indicates hyperthyroidism. [2] However, when TSH is measured by itself, it can yield misleading results, so additional thyroid function tests must be compared with the result of this test for accurate diagnosis. [4] [5] [6]

TSH is produced in the pituitary gland. The production of TSH is controlled by thyrotropin-releasing hormone (TRH), which is produced in the hypothalamus. TSH levels may be suppressed by excess free T3 (fT3) or free T4 (fT4) in the blood.[ citation needed ]

History

First-generation TSH assays were done by radioimmunoassay and were introduced in 1965. [3] There were variations and improvements upon TSH radioimmunoassay, but their use declined as a new immunometric assay technique became available in the middle of the 1980s. [3] [4] The new techniques were more accurate, leading to the second, third, and even fourth generations of TSH assay, with each generation possessing ten times greater functional sensitivity than the last. [7] Third generation immunometric assay methods are typically automated. [3] Fourth generation TSH immunometric assay has been developed for use in research. [4]

Current status

Third generation TSH assay is the current requirement for modern standards of care. At present, TSH testing in the United States is typically carried out with automated platforms using advanced forms of immunometric assay. [3] Nonetheless, there is currently no international standard for measurement of thyroid-stimulating hormone. [4]

Interpretation

Accurate interpretation takes a variety of factors into account, such as the thyroid hormones i.e. thyroxine (T4) and triiodothyronine (T3), current medical status (such as pregnancy [3] ), [4] certain medications like propylthiouracil, [4] temporal effects including circadian rhythm [8] and hysteresis, [9] and other past medical history. [10]

Thyroid hormones

Total thyroxine

Total thyroxine is rarely measured, having been largely superseded by free thyroxine tests. Total thyroxine (Total T4) is generally elevated in hyperthyroidism and decreased in hypothyroidism. [2] It is usually slightly elevated in pregnancy secondary to increased levels of thyroid binding globulin (TBG). [2]

Total T4 is measured to see the bound and unbound levels of T4. The total T4 is less useful in cases where there could be protein abnormalities. The total T4 is less accurate due to the large amount of T4 that is bound. The total T3 is measured in clinical practice since the T3 has decreased amount that is bound as compared to T4.

Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:

Lower limitUpper limitUnit
4, [11] 5.5 [12] 11, [11] 12.3 [12] μg/dL
60 [11] [13] 140, [11] 160 [13] nmol/L

Free thyroxine

Free thyroxine (fT4) is generally elevated in hyperthyroidism and decreased in hypothyroidism. [2]

Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:

Patient typeLower limitUpper limitUnit
Normal adult0.7, [14] 0.8 [12] 1.4, [14] 1.5, [12] 1.8 [15] ng/dL
9, [16] [17] 10, [11] 12 [13] 18, [16] [17] 23 [13] pmol/L
Infant 0–3 d2.0 [14] 5.0 [14] ng/dL
26 [17] 65 [17] pmol/L
Infant 3–30 d0.9 [14] 2.2 [14] ng/dL
12 [17] 30 [17] pmol/L
Child/Adolescent
31 d – 18 y
0.8 [14] 2.0 [14] ng/dL
10 [17] 26 [17] pmol/L
Pregnant0.5 [14] 1.0 [14] ng/dL
6.5 [17] 13 [17] pmol/L

Total triiodothyronine

Total triiodothyronine (Total T3) is rarely measured, having been largely superseded by free T3 tests. Total T3 is generally elevated in hyperthyroidism and decreased in hypothyroidism. [2]

Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:

TestLower limitUpper limitUnit
Total triiodothyronine 60, [12] 75 [11] 175, [11] 181 [12] ng/dL
0.9, [16] 1.1 [11] 2.5, [16] 2.7 [11] nmol/L

Free triiodothyronine

Free triiodothyronine (fT3) is generally elevated in hyperthyroidism and decreased in hypothyroidism. [2]

Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:

Patient typeLower limitUpper limitUnit
Normal adult3.0 [11] 7.0 [11] pg/mL
3.1 [18] 7.7 [18] pmol/L
Children 2–16 y3.0 [19] 7.0 [19] pg/mL
1.5 [18] 15.2 [18] pmol/L

Carrier proteins

Thyroxine-binding globulin

An increased thyroxine-binding globulin results in an increased total thyroxine and total triiodothyronine without an actual increase in hormonal activity of thyroid hormones.

Reference ranges:

Lower limitUpper limitUnit
12 [12] 30 [12] mg/L

Thyroglobulin

Reference ranges:

Lower limitUpper limitUnit
1.5 [11] 30 [11] pmol/L
1 [11] 20 [11] μg/L

Other binding hormones

Protein binding function

Thyroid hormone uptake

Thyroid hormone uptake (Tuptake or T3 uptake) is a measure of the unbound thyroxine binding globulins in the blood, that is, the TBG that is unsaturated with thyroid hormone. [2] Unsaturated TBG increases with decreased levels of thyroid hormones. It is not directly related to triiodothyronine, despite the name T3 uptake. [2]

Reference ranges:

Patient typeLower limitUpper limitUnit
Females25 [2] 35 [2] %
In pregnancy15 [2] 25 [2] %
Males25 [2] 35 [2] %

Other protein binding tests

Mixed parameters

Free thyroxine index

The Free Thyroxine Index (FTI or T7) is obtained by multiplying the total T4 with T3 uptake. [2] FTI is considered to be a more reliable indicator of thyroid status in the presence of abnormalities in plasma protein binding. [2] This test is rarely used now that reliable free thyroxine and free triiodothyronine assays are routinely available.

FTI is elevated in hyperthyroidism and decreased in hypothyroidism. [2]

Patient typeLower limitUpper limitUnit
Females1.8 [2] 5.0 [2]
Males1.3 [2] 4.2 [2]

Structure parameters

Derived structure parameters that describe constant properties of the overall feedback control system may add useful information for special purposes, e.g. in diagnosis of nonthyroidal illness syndrome or central hypothyroidism. [20] [21] [22] [23]

Secretory capacity (GT)

Thyroid's secretory capacity (GT, also referred to as SPINA-GT) is the maximum stimulated amount of thyroxine the thyroid can produce in one second. [24] GT is elevated in hyperthyroidism and reduced in hypothyroidism. [25]

GT is calculated with

or

: Dilution factor for T4 (reciprocal of apparent volume of distribution, 0.1 l−1)
: Clearance exponent for T4 (1.1e-6 sec−1)
K41: Dissociation constant T4-TBG (2e10 l/mol)
K42: Dissociation constant T4-TBPA (2e8 l/mol)
DT: EC50 for TSH (2.75 mU/l) [24]

Lower limitUpper limitUnit
1.41 [24] 8.67 [24] pmol/s

Sum activity of peripheral deiodinases (GD)

The sum activity of peripheral deiodinases (GD, also referred to as SPINA-GD) is reduced in nonthyroidal illness with hypodeiodination. [21] [22] [26]

GD is obtained with

or

: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 l−1)
: Clearance exponent for T3 (8e-6 sec−1)
KM1: Dissociation constant of type-1-deiodinase (5e-7 mol/l)
K30: Dissociation constant T3-TBG (2e9 l/mol) [24]

Lower limitUpper limitUnit
20 [24] 40 [24] nmol/s

TSH index

Jostel's TSH index (JTI or TSHI) helps to determine thyrotropic function of anterior pituitary on a quantitative level. [27] It is reduced in thyrotropic insufficiency [27] and in certain cases of non-thyroidal illness syndrome. [26]

It is calculated with

.

Additionally, a standardized form of TSH index may be calculated with

. [27]

ParameterLower limitUpper limitUnit
TSHI1.3 [27] 4.1 [27]
sTSHI-2 [27] 2 [27]

TTSI

The Thyrotroph Thyroid Hormone Sensitivity Index (TTSI, also referred to as Thyrotroph T4 Resistance Index or TT4RI) was developed to enable fast screening for resistance to thyroid hormone. [28] [29] Somewhat similar to the TSH Index it is calculated from equilibrium values for TSH and FT4, however with a different equation.

Lower limitUpper limitUnit
100150

TFQI

The Thyroid Feedback Quantile-based Index (TFQI) is another parameter for thyrotopic pituitary function. It was defined to be more robust to distorted data than JTI and TTSI. It is calculated with

from quantiles of FT4 and TSH concentration (as determined based on cumulative distribution functions) [30] . Per definition the TFQI has a mean of 0 and a standard deviation of 0.37 in a reference population [30] . Higher values of TFQI are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality [30] [31] [32] [33] [34] [35] .

Lower limitUpper limitUnit
–0,74+0.74

Effects of drugs

Drugs can profoundly affect thyroid function tests. Listed below is a selection of important effects.

Effects of some drugs on Tests of Thyroid function [36] [23] [37]
CauseDrugEffect on hormone concentrationsEffect on structure parameters
Inhibited TSH secretion Dopamine, L-DOPA, glucocorticoids, somatostatin ↓T4; ↓T3; ↓TSH↔SPINA-GT; ↓JTI
Inhibited synthesis or release of thyroid hormone Iodine, lithium ↓T4; ↓T3; ↑TSH↓SPINA-GT; ↔JTI
Inhibited conversion of T4 to T3 (Step-up hypodeiodination) Amiodarone, glucocorticoids, propranolol, propylthiouracil, radiographic contrast agents ↓T3; ↑rT3; ↓, ↔, ↑T4 and fT4; ↔, ↑TSH↓SPINA-GD
Inhibited binding of T4/T3 to serum proteins Salicylates, phenytoin, carbamazepine, furosemide, nonsteroidal anti-inflammatory agents, heparin (in vitro effect)↓T4; ↓T3; ↓fT4E, ↔, ↑fT4; ↔TSH↓T4/fT4 ratio
Stimulated metabolism of iodothyronines Phenobarbital, phenytoin, carbamazepine, rifampicin ↓T4; ↓fT4; ↔TSH
Inhibited absorption of ingested T4 Aluminium hydroxide, ferrous sulfate, cholestyramine, colestipol, iron sucralfate, soybean preparations, kayexalate ↓T4; ↓fT4; ↑TSH
Increase in concentration of T4-binding proteins Estrogen, clofibrate, opiates (heroin, methadone), 5-fluorouracil, perphenazine ↑T4; ↑T3; ↔fT4; ↔TSH↔SPINA-GT; ↔SPINA-GD; ↔JTI; ↑T4/fT4 ratio
Decrease in concentration of T4-binding proteins Androgens, glucocorticoids ↓T4; ↓T3; ↔fT4; ↔TSH↔SPINA-GT; ↔SPINA-GD; ↔JTI; ↓T4/fT4 ratio

↓: reduced serum concentration or structure parameter; ↑: increased serum concentration or structure parameter; ↔: no change; TSH: Thyroid-stimulating hormone; T3: Total triiodothyronine; T4: Total thyroxine; fT4: Free thyroxine; fT3: Free triiodothyronine; rT3: Reverse triiodothyronine

See also

Reference ranges for blood tests, sorted by mass and molar concentration, with thyroid function tests marked in purple boxes in left half of diagram. Blood values sorted by mass and molar concentration.png
Reference ranges for blood tests, sorted by mass and molar concentration, with thyroid function tests marked in purple boxes in left half of diagram.

Related Research Articles

Thyroid Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in the neck consisting of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thyroid is located at the front of the neck, below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis, and in children, growth and development. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

Hypothyroidism Endocrine disease

Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Iodothyronine deiodinase class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

Thyroxine-binding globulin mammalian protein found in Homo sapiens

Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the SERPINA7 gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration relative to transthyretin and albumin, which also bind T3 and T4 in circulation. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.

Triiodothyronine chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

Myxedema Human disease

Myxedema is a term used synonymously with severe hypothyroidism. However, the term is also used to describe a dermatological change that can occur in hyperthyroidism and (rare) paradoxical cases of hypothyroidism. In this latter sense, myxedema refers to deposition of mucopolysaccharides in the dermis, which results in swelling of the affected area. One manifestation of myxedema occurring in the lower limb is pretibial myxedema, a hallmark of Graves disease, an autoimmune form of hyperthyroidism. Myxedema can also occur in Hashimoto thyroiditis and other long-standing forms of hypothyroidism.

Levothyroxine chemical compound

Levothyroxine, also known as L-thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency, including the severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken by mouth or given by injection into a vein. Maximum effect from a specific dose can take up to six weeks to occur.

Thyroid disease type of endocrine disease

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Desiccated thyroid, also known as thyroid extract, is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism. It is less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to 3 weeks to occur.

Hypothalamic–pituitary–thyroid axis part of the neuroendocrine system responsible for the regulation of metabolism.

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

Reverse triiodothyronine pair of enantiomers

Reverse triiodothyronine (3,3’,5’-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3’ triiodothyronine, T3).

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences and impaired assay characteristics in critical illness.

Thyroid hormones hormones produced by the thyroid gland

Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards.This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

Roger Ekins FRS was a British biophysicist and professor at University College London. He was awarded the 1998 Edwin F. Ullman Award.

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of deiodinases outside the central nervous system and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase.

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI) is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial.

SimThyr Medical research simulation software

SimThyr is a free continuous dynamic simulation program for the pituitary-thyroid feedback control system. The open-source program is based on a nonlinear model of thyroid homeostasis. In addition to simulations in the time domain the software supports various methods of sensitivity analysis. It provides a GUI, which allows for visualising time series, modifying constant structure parameters of the feedback loop, storing parameter sets as XML files and exporting results of simulations in various formats that are suitable for statistical software. SimThyr is primarily intended for educational purposes and in-silico research.

References

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  18. 1 2 3 4 Derived from mass values using molar mass of 650.98 g/mol
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Further reading

CDC laboratory procedure manuals

The Centers for Disease Control and Prevention has published the following laboratory procedure manuals for measuring thyroid-stimulating hormone:

Beckman Coulter procedure manuals

Beckman Coulter provides the equipment and reagents used in the 2009-2011 CDC manuals, and has published the following manuals for performing the procedure: