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Thyroid function tests

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Thyroid function tests
MeSHD013960
MedlinePlus003444

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

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.

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 limit Upper limit Unit
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 type Lower limit Upper limit Unit
Normal adult 0.7,[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 d 2.0[14] 5.0[14] ng/dL
26[17] 65[17] pmol/L
Infant 3–30 d 0.9[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
Pregnant 0.5[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:

Test Lower limit Upper limit Unit
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 type Lower limit Upper limit Unit
Normal adult 3.0[11] 7.0[11] pg/mL
3.1[18] 7.7[18] pmol/L
Children 2–16 y 3.0[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 limit Upper limit Unit
12[12] 30[12] mg/L

Thyroglobulin

Reference ranges:

Lower limit Upper limit Unit
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 type Lower limit Upper limit Unit
Females 25[2] 35[2] %
In pregnancy 15[2] 25[2] %
Males 25[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 type Lower limit Upper limit Unit
Females 1.8[2] 5.0[2]
Males 1.3[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 limit Upper limit Unit
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 limit Upper limit Unit
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]

Parameter Lower limit Upper limit Unit
TSHI 1.3[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 limit Upper limit Unit
100 150

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 limit Upper limit Unit
-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]
Cause Drug Effect on hormone concentrations Effect 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.

References

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  2. ^ a b c d e f g h i j k l m n o p q r s t u v Military Obstetrics & Gynecology > Thyroid Function Tests In turn citing: Operational Medicine 2001, Health Care in Military Settings, NAVMED P-5139, May 1, 2001, Bureau of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C., 20372-5300 "Archived copy". Archived from the original on 25 December 2011. Retrieved 2011-12-25.{{cite web}}: CS1 maint: archived copy as title (link)
  3. ^ a b c d e f Spencer, Carole (1 January 2013). "Assay of Thyroid Hormones and Related Substances". Thyroid Disease Manager. Retrieved 5 November 2013.
  4. ^ a b c d e f g Toft, Anthony; Beckett, Geoffrey (2005). Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 329–344. ISBN 978-0-7817-5047-9.
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  8. ^ Hoermann, Rudolf; Midgley, John E. M.; Larisch, Rolf; Dietrich, Johannes W. (2015). "Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment". Frontiers in Endocrinology. 6: 177. doi:10.3389/fendo.2015.00177. PMC 4653296. PMID 26635726.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  11. ^ a b c d e f g h i j k l m n o Table 4: Typical reference ranges for serum assays Archived July 1, 2011, at the Wayback Machine - Thyroid Disease Manager
  12. ^ a b c d e f g h Normal Reference Range Table Archived 2011-12-25 at the Wayback Machine from The University of Texas Southwestern Medical Center at Dallas. Used in Interactive Case Study Companion to Pathologic basis of disease.
  13. ^ a b c d van der Watt G, Haarburger D, Berman P (July 2008). "Euthyroid patient with elevated serum free thyroxine". Clin. Chem. 54 (7): 1239–41. doi:10.1373/clinchem.2007.101428. PMID 18593963.
  14. ^ a b c d e f g h i j Free T4; Thyroxine, Free; T4, Free Archived 2010-12-22 at the Wayback Machine UNC Health Care System
  15. ^ Derived from molar values using molar mass of 776.87 g/mol
  16. ^ a b c d Reference range list from Uppsala University Hospital ("Laborationslista"). Artnr 40284 Sj74a. Issued on April 22, 2008
  17. ^ a b c d e f g h i j Derived from mass values using molar mass of 776.87 g/mol
  18. ^ a b c d Derived from mass values using molar mass of 650.98 g/mol
  19. ^ a b Cioffi M, Gazzerro P, Vietri MT, et al. (2001). "Serum concentration of free T3, free T4 and TSH in healthy children". J. Pediatr. Endocrinol. Metab. 14 (9): 1635–9. doi:10.1515/JPEM.2001.14.9.1635. PMID 11795654.
  20. ^ Dietrich JW, Stachon A, Antic B, Klein HH, Hering S (2008). "The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome". BMC Endocr Disord. 8: 13. doi:10.1186/1472-6823-8-13. PMC 2576461. PMID 18851740.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
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  22. ^ a b Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J (2012). "Nonthyroidal Illness Syndrome: Is it Far Away From Crohn's Disease?". J Clin Gastroenterol. 47 (2): 153–9. doi:10.1097/MCG.0b013e318254ea8a. PMID 22874844.
  23. ^ a b Dietrich, Johannes W.; Landgrafe-Mende, Gabi; Wiora, Evelin; Chatzitomaris, Apostolos; Klein, Harald H.; Midgley, John E. M.; Hoermann, Rudolf (9 June 2016). "Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research". Frontiers in Endocrinology. 7: 57. doi:10.3389/fendo.2016.00057. PMC 4899439. PMID 27375554.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  25. ^ Dietrich, J., M. Fischer, J. Jauch, E. Pantke, R. Gärtner und C. R. Pickardt (1999). "SPINA-THYR: A Novel Systems Theoretic Approach to Determine the Secretion Capacity of the Thyroid Gland." European Journal of Internal Medicine 10, Suppl. 1 (5/1999): S34.
  26. ^ a b Fan, S; Ni, X; Wang, J; Zhang, Y; Tao, S; Chen, M; Li, Y; Li, J (February 2016). "Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study". Medicine. 95 (6): e2640. doi:10.1097/MD.0000000000002640. PMC 4753882. PMID 26871787.
  27. ^ a b c d e f g Jostel A, Ryder WD, Shalet SM (October 2009). "The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index". Clin. Endocrinol. 71 (4): 529–34. doi:10.1111/j.1365-2265.2009.03534.x. PMID 19226261.
  28. ^ Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S (1997). "Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity". J. Clin. Endocrinol. Metab. 82 (5): 1608–14. doi:10.1210/jcem.82.5.3945. PMID 9141558.
  29. ^ Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S (1999). "Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene". J. Clin. Endocrinol. Metab. 84 (11): 3919–28. doi:10.1210/jcem.84.11.6080. PMID 10566629.
  30. ^ a b c Laclaustra, M; Moreno-Franco, B; Lou-Bonafonte, JM; Mateo-Gallego, R; Casasnovas, JA; Guallar-Castillon, P; Cenarro, A; Civeira, F (February 2019). "Impaired Sensitivity to Thyroid Hormones Is Associated With Diabetes and Metabolic Syndrome". Diabetes care. 42 (2): 303–310. doi:10.2337/dc18-1410. PMID 30552134.
  31. ^ "Schilddrüsenhormonresistenz und Risiko für Diabetes und metabolisches Syndrom". Diabetologie und Stoffwechsel. 14 (02): 78–78. 16 April 2019. doi:10.1055/a-0758-5718. {{cite journal}}: no-break space character in |title= at position 43 (help)
  32. ^ Paschou, Stavroula A.; Alexandrides, Theodoros (19 October 2019). "A year in type 2 diabetes mellitus: 2018 review based on the Endorama lecture". Hormones. 18 (4): 401–408. doi:10.1007/s42000-019-00139-z.
  33. ^ Guan, Haixia (April 2019). "Mild Acquired Thyroid Hormone Resistance Is Associated with Diabetes-Related Morbidity and Mortality in the General Population". Clinical Thyroidology. 31 (4): 138–140. doi:10.1089/ct.2019;31.138-140.
  34. ^ Lou-Bonafonte, José Manuel; Civeira, Fernando; Laclaustra, Martín (20 February 2020). "Quantifying Thyroid Hormone Resistance in Obesity". Obesity Surgery. doi:10.1007/s11695-020-04491-7.
  35. ^ "甲状腺素抵抗与糖尿病和代谢综合征有关？看TFQI怎么说". www.medinfo-sanofi.cn. Retrieved 14 April 2020.
  36. ^ Burtis CA, Ashwood ER, Bruns DE (2012). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th edition. Elsevier Saunders. p. 1920. ISBN 978-1-4160-6164-9.
  37. ^ Chatzitomaris, Apostolos; Hoermann, Rudolf; Midgley, John E.; Hering, Steffen; Urban, Aline; Dietrich, Barbara; Abood, Assjana; Klein, Harald H.; Dietrich, Johannes W. (20 July 2017). "Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming". Frontiers in Endocrinology. 8: 163. doi:10.3389/fendo.2017.00163. PMC 5517413. PMID 28775711.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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:

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