Sum activity of peripheral deiodinases

Sum activity of peripheral deiodinases
SynonymsSPINA-GD, GD, deiodination capacity, total deiodinase activity
Reference range20–40 nmol/s
Test ofMaximum amount of T3 produced from T4 by peripheral deiodinases
MeSHD013960
LOINC82367-4

The sum activity of peripheral deiodinases (GD, also referred to as deiodination capacity, total deiodinase activity or, if calculated from levels of thyroid hormones, as SPINA-GD) is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation.[1] 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.

How to determine GD

GD can be determined experimentally by exposing a cell culture system to saturating concentrations of T4 and measuring the T3 production. Whole body deiodination activity can be assessed by measuring production of radioactive iodine after loading the organism with marked thyroxine.[2]

However, both approaches are faced with draw-backs. Measuring deiodination in cell culture delivers little, if any, information on total deiodination activity. Using marked thyroxine exposes the body to thyrotoxicosis and radioactivity. Additionally, it is not possible to differentiate step-up reactions resulting in T3 production from the step-down reaction catalyzed by type 3 deiodination, which mediates production of reverse T3. Distinguishing the contribution of distinct deiodinases is possible, however, by sequential approaches using deiodinase-specific blocking agents, but this approach is cumbersome and time-consuming.[2]

In vivo, it may therefore be beneficial to estimate GD from equilibrium levels of T4 and T3. It 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: Binding constant of type-1-deiodinase (5e-7 mol/L)
K30: Binding constant T3-TBG (2e9 L/mol)[3]

The method is based on mathematical models of thyroid homeostasis.[1][3] Calculating deiodinase activity with one of these equations is an inverse problem. Therefore, certain conditions (e.g. stationarity) have to be fulfilled to deliver a reliable result.

Reference range

Lower limitUpper limitUnit
20[3]40[3]nmol/s

The equations and their parameters are calibrated for adult humans with a body mass of 70 kg and a plasma volume of ca. 2.5 L.[3]

Clinical significance

Validity

SPINA-GD correlates to the T4-T3 conversion rate in slow tissue pools, as determined with isotope-based measurements in healthy volunteers.[1] It was also shown that GD correlates with resting energy expenditure,[4] body mass index[3][5][6] and thyrotropin levels in humans,[7][8] and that it is reduced in nonthyroidal illness with hypodeiodination.[5][9][10][11][12] Multiple studies demonstrated SPINA-GD to rise after initiation of substitution therapy with selenium, a trace element that is essential for the synthesis of deiodinases.[13][14][15][16]

Clinical utility

Compared to both healthy volunteers and subjects with hypothyroidism and hyperthyroidism, SPINA-GD is reduced in subacute thyroiditis. In this condition, it has a higher specificity, positive and negative likelihood ratio than serum concentrations of thyrotropin, free T4 or free T3.[3] These measures of diagnostic utility are also high in nodular goitre, where SPINA-GD is elevated.[3] Among subjects with subclinical thyrotoxicosis, calculated deiodinase activity is significantly lower in exogenous thyrotoxicosis (resulting from therapy with levothyroxine) than in true hyperthyroidism (ensuing from toxic adenoma, toxic multinodular goitre or Graves' disease).[17] SPINA-GD may therefore be an effective biomarker for the differential diagnosis of thyrotoxicosis.[18]

Compared to healthy subjects, SPINA-GD is significantly reduced in euthyroid sick syndrome.[19]

Pathophysiological and therapeutic implications

Recent research revealed total deiodinase activity to be higher in untreated hypothyroid patients as long as thyroid tissue is still present.[8] This effect may ensue from the existence of an effective TSH-deiodinase axis or TSH-T3 shunt. After total thyroidectomy or high-dose radioiodine therapy (e.g. in treated thyroid cancer) as well as after initiation of substitution therapy with levothyroxine the activity of step-up deiodinases decreases and the correlation of SPINA-GD to thyrotropin concentration is lost.[20]

In two large population-based cohorts within the Study of Health in Pomerania SPINA-GD was positively correlated to some markers of body composition including body mass index (BMI), waist circumference, fat-free mass and body cell mass,[21] confirming earlier observations in the NHANES dataset.[22] This positive association was age-dependent and with respect to BMI significant in young subjects only, but with respect to body cell mass stronger in elderly persons.[21]

SPINA-GD is reduced in low-T3 syndrome[23] and certain chronic diseases, e.g. chronic fatigue syndrome,[24] chronic kidney disease,[25][26] short bowel syndrome[27] or geriatric asthma.[28] In Graves' disease, SPINA-GD is initially elevated but decreases with antithyroid treatment in parallel to declining TSH receptor autoantibody titres.[4] Although takotsubo syndrome (TTS) results in most cases from psychosocial stressors, thereby reflecting type 2 allostatic load, SPINA-GD has been described to be reduced in TTS.[29] This may result from concomitant non-thyroidal illness syndrome, so that the clinical phenotype represents overlapping type 1 and type 2 allostatic response.

In hyperthyroid[30] men both SPINA-GT and SPINA-GD negatively correlate to erectile function, intercourse satisfaction, orgasmic function and sexual desire. Substitution with selenomethionine results in increased SPINA-GD in subjects with autoimmune thyroiditis.[13][14][15][16]

Deiodination capacity proved to be an independent predictor of substitution dose in a trial with over 300 patients on replacement therapy with levothyroxine.[31]

Probably as a consequence of non-thyroidal illness syndrome, SPINA-GD predicts mortality in trauma[19] and postoperative atrial fibrillation in patients undergoing cardiac surgery.[11] Correlations were also shown to age, total atrial conduction time, and concentrations of 3,5-diiodothyronine and B-type natriuretic peptide.[11] In a population suffering from pyogenic liver abscess SPINA-GD correlated to markers of malnutrition, inflammation and liver failure.[23] A study on subjects with Parkinson's disease found SPINA-GD to be significantly decreased in tremor-dominant and mixed subtypes compared to the akinetic-rigid type.[32]

Endocrine disruptors may have pronounced effects on step-up deiodinases, as suggested by positive correlation of SPINA-GD to urine concentrations of cadmium and phthalate metabolites[33][34][35] and negative correlation to mercury and bisphenol A concentration.[33][34]

See also

References

  1. 1 2 3 Dietrich JW, Landgrafe-Mende G, Wiora E, Chatzitomaris A, Klein HH, Midgley JE, Hoermann R (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. S2CID 14210899.
  2. 1 2 Bianco, AC; Anderson, G; Forrest, D; Galton, VA; Gereben, B; Kim, BW; Kopp, PA; Liao, XH; Obregon, MJ; Peeters, RP; Refetoff, S; Sharlin, DS; Simonides, WS; Weiss, RE; Williams, GR (January 2014). "American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models". Thyroid. 24 (1): 88–168. doi:10.1089/thy.2013.0109. PMC 3887458. PMID 24001133.
  3. 1 2 3 4 5 6 7 8 Dietrich JW (2002). Der Hypophysen-Schilddrüsen-Regelkreis. Berlin, Germany: Logos-Verlag Berlin. ISBN 978-3-89722-850-4. OCLC 50451543. OL 24586469M.
  4. 1 2 Kim, Min Joo; Cho, Sun Wook; Choi, Sumin; Ju, Dal Lae; Park, Do Joon; Park, Young Joo (2018). "Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves' Disease". International Journal of Endocrinology. 2018: 9863050. doi:10.1155/2018/9863050. PMC 5960571. PMID 29853888. S2CID 44088904.
  5. 1 2 Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J (February 2013). "Nonthyroidal illness syndrome: is it far away from Crohn's disease?". Journal of Clinical Gastroenterology. 47 (2): 153–9. doi:10.1097/MCG.0b013e318254ea8a. PMID 22874844. S2CID 35344744.
  6. ↑ Dietrich JW, Landgrafe G, Fotiadou EH (2012). "TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis". Journal of Thyroid Research. 2012: 1–29. doi:10.1155/2012/351864. PMC 3544290. PMID 23365787. S2CID 15996441.
  7. ↑ Hoermann R, Midgley JE, Larisch R, Dietrich JW (February 2013). "Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?". European Journal of Endocrinology. 168 (2): 271–80. doi:10.1530/EJE-12-0819. PMID 23184912.
  8. 1 2 Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R (December 2014). "Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment". Clinical Endocrinology. 81 (6): 907–15. doi:10.1111/cen.12527. PMID 24953754. S2CID 19341039.
  9. ↑ Rosolowska-Huszcz D, Kozlowska L, Rydzewski A (August 2005). "Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure". Endocrine. 27 (3): 283–8. doi:10.1385/ENDO:27:3:283. PMID 16230785. S2CID 25630198.
  10. ↑ Han G, Ren J, Liu S, Gu G, Ren H, Yan D, Chen J, Wang G, Zhou B, Wu X, Yuan Y, Li J (September 2013). "Nonthyroidal illness syndrome in enterocutaneous fistulas". American Journal of Surgery. 206 (3): 386–92. doi:10.1016/j.amjsurg.2012.12.011. PMID 23809674.
  11. 1 2 3 Dietrich JW, Müller P, Schiedat F, Schlömicher M, Strauch J, Chatzitomaris A, Klein HH, Mügge A, Köhrle J, Rijntjes E, Lehmphul I (June 2015). "Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling". European Thyroid Journal. 4 (2): 129–37. doi:10.1159/000381543. PMC 4521060. PMID 26279999. S2CID 207639541.
  12. ↑ 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. S2CID 14016461.
  13. 1 2 Krysiak, Robert; Szkróbka, Witold; Okopień, Bogusław (October 2018). "The effect of vitamin D and selenomethionine on thyroid antibody titers, hypothalamic-pituitary-thyroid axis activity and thyroid function tests in men with Hashimoto's thyroiditis: a pilot study". Pharmacological Reports. 71 (2): 243–7. doi:10.1016/j.pharep.2018.10.012. PMID 30818086. S2CID 73481267.
  14. 1 2 Krysiak, Robert; Kowalcze, Karolina; Okopień, Bogusław (December 2018). "Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis and low vitamin D status". Pharmacological Reports. 71 (2): 367–73. doi:10.1016/j.pharep.2018.12.006. PMID 30844687. S2CID 73486105.
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  17. ↑ Hoermann, R; Midgley, JEM; Larisch, R; Dietrich, JW (March 2020). "Heterogenous biochemical expression of hormone activity in subclinical/overt hyperthyroidism and exogenous thyrotoxicosis". Journal of Clinical & Translational Endocrinology. 19: 100219. doi:10.1016/j.jcte.2020.100219. PMC 7031309. PMID 32099819.
  18. ↑ Dietrich, Johannes W. "SPINA in Science and Research: Year in Review: 2020". sourceforge.net. Retrieved 2 January 2021.
  19. 1 2 Dietrich, J. W.; Ackermann, A.; Kasippillai, A.; Kanthasamy, Y.; Tharmalingam, T.; Urban, A.; Vasileva, S.; Schildhauer, T. A.; Klein, H. H.; Stachon, A.; Hering, S. (19 September 2019). "Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata". Trauma und Berufskrankheit. 21 (4): 260–267. doi:10.1007/s10039-019-00438-z. S2CID 202673793.
  20. ↑ Hoermann R, Midgley JE, Larisch R, Dietrich JW (2017). "Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine". PLOS ONE. 12 (11): e0187232. Bibcode:2017PLoSO..1287232H. doi:10.1371/journal.pone.0187232. PMC 5695809. PMID 29155897. S2CID 6407766.
  21. 1 2 Ittermann, T; Markus, MRP; Bahls, M; Felix, SB; Steveling, A; Nauck, M; Völzke, H; Dörr, M (18 May 2021). "Low serum TSH levels are associated with low values of fat-free mass and body cell mass in the elderly". Scientific Reports. 11 (1): 10547. Bibcode:2021NatSR..1110547I. doi:10.1038/s41598-021-90178-7. PMC 8131378. PMID 34006958.
  22. ↑ Chatzitomaris, A; Hoermann, R; Midgley, JE; Hering, S; Urban, A; Dietrich, B; Abood, A; Klein, HH; Dietrich, JW (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.
  23. 1 2 Xu, J; Wang, L (2019). "Low T3 Syndrome as a Predictor of Poor Prognosis in Patients With Pyogenic Liver Abscess". Frontiers in Endocrinology. 10: 541. doi:10.3389/fendo.2019.00541. PMC 6691090. PMID 31447784. S2CID 199435315.
  24. ↑ Ruiz-Núñez, Begoña; Tarasse, Rabab; Vogelaar, Emar F.; Janneke Dijck-Brouwer, D. A.; Muskiet, Frits A. J. (20 March 2018). "Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case–Control Study". Frontiers in Endocrinology. 9: 97. doi:10.3389/fendo.2018.00097. PMC 5869352. PMID 29615976. S2CID 4550317.
  25. ↑ Chen, Y; Zhang, W; Wang, N; Wang, Y; Wang, C; Wan, H; Lu, Y (2020). "Thyroid Parameters and Kidney Disorder in Type 2 Diabetes: Results from the METAL Study". Journal of Diabetes Research. 2020: 4798947. doi:10.1155/2020/4798947. PMC 7149438. PMID 32337292.
  26. ↑ Yang, S; Lai, S; Wang, Z; Liu, A; Wang, W; Guan, H (December 2021). "Thyroid Feedback Quantile-based Index correlates strongly to renal function in euthyroid individuals". Annals of Medicine. 53 (1): 1945–1955. doi:10.1080/07853890.2021.1993324. PMC 8567884. PMID 34726096.
  27. ↑ Wan, S; Yang, J; Gao, X; Zhang, L; Wang, X (22 July 2020). "Nonthyroidal Illness Syndrome in Patients With Short-Bowel Syndrome". Journal of Parenteral and Enteral Nutrition. 45 (5): 973–981. doi:10.1002/jpen.1967. PMID 32697347. S2CID 220698496.
  28. ↑ Bingyan, Zhan; Dong, Wei (7 July 2019). "Impact of thyroid hormones on asthma in older adults". Journal of International Medical Research. 47 (9): 4114–4125. doi:10.1177/0300060519856465. PMC 6753544. PMID 31280621. S2CID 195830014.
  29. ↑ Aweimer, A; El-Battrawy, I; Akin, I; Borggrefe, M; Mügge, A; Patsalis, PC; Urban, A; Kummer, M; Vasileva, S; Stachon, A; Hering, S; Dietrich, JW (12 November 2020). "Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study". Journal of Internal Medicine. 289 (5): 675–687. doi:10.1111/joim.13189. PMID 33179374.
  30. ↑ Krysiak, R; Marek, B; Okopień, B (2019). "Sexual function and depressive symptoms in men with overt hyperthyroidism". Endokrynologia Polska. 70 (1): 64–71. doi:10.5603/EP.a2018.0069. PMID 30307028.
  31. ↑ Midgley JE, Larisch R, Dietrich JW, Hoermann R (December 2015). "Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency". Endocrine Connections. 4 (4): 196–205. doi:10.1530/EC-15-0056. PMC 4557078. PMID 26335522.
  32. ↑ Tan, Y; Gao, L; Yin, Q; Sun, Z; Man, X; Du, Y; Chen, Y (April 2021). "Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with Parkinson's disease". The International Journal of Neuroscience. 131 (4): 346–356. doi:10.1080/00207454.2020.1744595. PMID 32186220. S2CID 212752563.
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  35. ↑ Chen, Y; Zhang, W; Chen, J; Wang, N; Chen, C; Wang, Y; Wan, H; Chen, B; Lu, Y (2021). "Association of Phthalate Exposure with Thyroid Function and Thyroid Homeostasis Parameters in Type 2 Diabetes". Journal of Diabetes Research. 2021: 4027380. doi:10.1155/2021/4027380. PMC 8566079. PMID 34746318.

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