The '''sum activity of peripheral deiodinases''' ('''''G<sub>D</sub>''''', 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.<ref name = "Dietrich_2016">{{cite journal | vauthors = Dietrich JW, Landgrafe-Mende G, Wiora E, Chatzitomaris A, Klein HH, Midgley JE, Hoermann R | title = Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research | journal = Frontiers in Endocrinology | volume = 7 | pages = 57 | date = 9 June 2016 | pmid = 27375554 | pmc = 4899439 | doi = 10.3389/fendo.2016.00057 }}</ref> It is assumed to reflect the activity of [[deiodinase]]s outside the [[central nervous system]] and other isolated compartments. GD is therefore expected to reflect predominantly the activity of [[Iodothyronine deiodinase|type I deiodinase]].
== How to determine GD ==
==Sum Activity of Peripheral Deiodinases==
GD can be determined experimentally by exposing a [[cell culture]] system to saturating concentrations of [[thyroxine|T4]] and measuring the [[Triiodothyronine|T3]] production. Whole body deiodination activity can be assessed by measuring production of radioactive iodine after loading the organism with marked thyroxine.
The '''sum activity of peripheral deiodinases''' refers to the collective function of enzymes known as [[deiodinases]] that are responsible for the activation and deactivation of [[thyroid hormones]] in peripheral tissues. These enzymes play a crucial role in the regulation of [[metabolism]], [[growth]], and [[development]] by modulating the levels of active thyroid hormones available to tissues.
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]].
==Types of Deiodinases==
There are three main types of deiodinases, each with distinct roles and tissue distributions:
''In vivo'', it may therefore be beneficial to estimate GD from equilibrium levels of T4 and T3. It is obtained with
* '''Type I Deiodinase (D1)''':
** Found primarily in the [[liver]], [[kidney]], and [[thyroid gland]].
** Converts [[thyroxine]] (T4) to the more active [[triiodothyronine]] (T3) by removing an iodine atom from the outer ring.
** Also capable of converting reverse T3 (rT3) to diiodothyronine (T2).
The sum activity of peripheral deiodinases is essential for the fine-tuning of thyroid hormone action in various tissues. By converting T4 to T3, deiodinases ensure that tissues receive the appropriate amount of active hormone necessary for their specific metabolic needs. This local regulation is crucial for:
<math>\alpha _{31}</math>: [[Concentration#Qualitative description|Dilution]] factor for T3 (reciprocal of apparent volume of distribution, 0.026 l<sup>−1</sup>)<br />
* '''Metabolic Rate Regulation''': T3 is the active form of thyroid hormone that influences the [[basal metabolic rate]].
<math>\beta _{31}</math>: [[Clearance (medicine)|Clearance]] exponent for T3 (8e-6 sec<sup>−1</sup>)<br />
* '''Development''': Proper levels of T3 are vital for [[fetal development]] and [[neurodevelopment]].
''K''<sub>''M''1</sub>: [[Dissociation constant]] of type-1-deiodinase (5e-7 mol/l)<br />
* '''Thermogenesis''': In [[brown adipose tissue]], D2-mediated conversion of T4 to T3 is important for heat production.
''K''<sub>30</sub>: Dissociation constant T3-TBG (2e9 l/mol)<ref name=dietrich2002>{{cite book | vauthors = Dietrich JW | title = Der Hypophysen-Schilddrüsen-Regelkreis | publisher = Logos-Verlag Berlin | isbn = 978-3-89722-850-4 | location = Berlin, Germany | date = 2002 | oclc = 50451543 | ol = 24586469M }}</ref>
===Reference range===
==Clinical Significance==
{| class="wikitable"
Alterations in the activity of deiodinases can lead to various clinical conditions:
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.<ref name=dietrich2002/>
* '''Hypothyroidism''': Reduced deiodinase activity can lead to decreased T3 levels, contributing to symptoms of hypothyroidism.
* '''Hyperthyroidism''': Increased deiodinase activity may result in excessive T3 production, exacerbating hyperthyroid conditions.
* '''Non-thyroidal Illness Syndrome''': Changes in deiodinase activity are observed in critical illnesses, affecting thyroid hormone levels and metabolism.
== Clinical significance ==
==Related Pages==
=== Validity ===
* [[Thyroid hormone]]
SPINA-GD correlates to the T4-T3 conversion rate in slow tissue pools, as determined with isotope-based measurements in healthy volunteers <ref name = "Dietrich_2016"/>. It was also shown that GD correlates with [[resting energy expenditure]]<ref name="Kim_2018">{{cite journal |last1=Kim |first1=Min Joo |last2=Cho |first2=Sun Wook |last3=Choi |first3=Sumin |last4=Ju |first4=Dal Lae |last5=Park |first5=Do Joon |last6=Park |first6=Young Joo |title=Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves' Disease |journal=International Journal of Endocrinology |date=2018 |volume=2018 |pages=9863050 |doi=10.1155/2018/9863050|pmid=29853888 |pmc=5960571 }}</ref>, [[body mass index]]<ref name=dietrich2002/><ref name="Liu2012">{{cite journal | vauthors = Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J | title = Nonthyroidal illness syndrome: is it far away from Crohn's disease? | journal = Journal of Clinical Gastroenterology | volume = 47 | issue = 2 | pages = 153–9 | date = February 2013 | pmid = 22874844 | doi = 10.1097/MCG.0b013e318254ea8a }}</ref><ref>{{cite journal | vauthors = Dietrich JW, Landgrafe G, Fotiadou EH | title = TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis | journal = Journal of Thyroid Research | volume = 2012 | issue = | pages = 1–29 | year = 2012 | pmid = 23365787 | pmc = 3544290 | doi = 10.1155/2012/351864 }}</ref> and thyrotropin levels in humans,<ref>{{cite journal | vauthors = Hoermann R, Midgley JE, Larisch R, Dietrich JW | title = Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? | journal = European Journal of Endocrinology | volume = 168 | issue = 2 | pages = 271–80 | date = February 2013 | pmid = 23184912 | doi = 10.1530/EJE-12-0819 }}</ref><ref name="Hoermann2014">{{cite journal | vauthors = Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R | title = Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment | journal = Clinical Endocrinology | volume = 81 | issue = 6 | pages = 907–15 | date = December 2014 | pmid = 24953754 | doi = 10.1111/cen.12527 }}</ref> and that it is reduced in [[Euthyroid sick syndrome|nonthyroidal illness]] with hypodeiodination.<ref name=Liu2012 /><ref name=Rosolowska-Huszcz2005>{{cite journal | vauthors = Rosolowska-Huszcz D, Kozlowska L, Rydzewski A | title = Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure | journal = Endocrine | volume = 27 | issue = 3 | pages = 283–8 | date = August 2005 | pmid = 16230785 | doi = 10.1385/ENDO:27:3:283 }}</ref><ref>{{cite journal | vauthors = Han G, Ren J, Liu S, Gu G, Ren H, Yan D, Chen J, Wang G, Zhou B, Wu X, Yuan Y, Li J | title = Nonthyroidal illness syndrome in enterocutaneous fistulas | journal = American Journal of Surgery | volume = 206 | issue = 3 | pages = 386–92 | date = September 2013 | pmid = 23809674 | doi = 10.1016/j.amjsurg.2012.12.011 }}</ref><ref name="dietrich2015">{{cite journal | vauthors = Dietrich JW, Müller P, Schiedat F, Schlömicher M, Strauch J, Chatzitomaris A, Klein HH, Mügge A, Köhrle J, Rijntjes E, Lehmphul I | title = Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling | journal = European Thyroid Journal | volume = 4 | issue = 2 | pages = 129–37 | date = June 2015 | pmid = 26279999 | pmc = 4521060 | doi = 10.1159/000381543 }}</ref><ref name=Fan2016>{{cite journal | vauthors = Fan S, Ni X, Wang J, Zhang Y, Tao S, Chen M, Li Y, Li J | title = Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study | journal = Medicine | volume = 95 | issue = 6 | pages = e2640 | date = February 2016 | pmid = 26871787 | pmc = 4753882 | doi = 10.1097/MD.0000000000002640 }}</ref>
* [[Thyroxine]]
* [[Triiodothyronine]]
=== Clinical utility ===
* [[Hypothyroidism]]
* [[Hyperthyroidism]]
Compared to both healthy volunteers and subjects with [[hypothyroidism]] and [[thyrotoxicosis]], SPINA-GD is reduced in [[subacute thyroiditis]]. In this condition, it has a higher [[Sensitivity and specificity|specificity]], [[positive likelihood ratio|positive]] and [[negative likelihood ratio]] than serum concentrations of [[thyrotropin]], free T4 or free T3<ref name = "dietrich2002"/>. These measures of diagnostic utility are also high in nodular [[goitre]], where SPINA-GD is elevated<ref name = "dietrich2002"/>. SPINA-GD is significantly reduced in [[euthyroid sick syndrome]]<ref name="Dietrich_2019">{{cite journal |last1=Dietrich |first1=J. W. |last2=Ackermann |first2=A. |last3=Kasippillai |first3=A. |last4=Kanthasamy |first4=Y. |last5=Tharmalingam |first5=T. |last6=Urban |first6=A. |last7=Vasileva |first7=S. |last8=Schildhauer |first8=T. A. |last9=Klein |first9=H. H. |last10=Stachon |first10=A. |last11=Hering |first11=S. |title=Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata |journal=Trauma und Berufskrankheit |date=19 September 2019 |doi=10.1007/s10039-019-00438-z}}</ref>.
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[[Category:Endocrinology]]
=== Pathophysiological and therapeutic implications ===
[[Category:Enzymes]]
Recent research revealed total deiodinase activity to be higher in untreated hypothyroid patients as long as thyroid tissue is still present<ref name="Hoermann2014"/>. 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.<ref name="Hoermann_PLoS_2017">{{cite journal | vauthors = Hoermann R, Midgley JE, Larisch R, Dietrich JW | title = Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine | journal = PLOS ONE | volume = 12 | issue = 11 | pages = e0187232 | date = 2017 | pmid = 29155897 | doi = 10.1371/journal.pone.0187232 | pmc=5695809| bibcode = 2017PLoSO..1287232H }}</ref> SPINA-GD is also reduced in [[Low t3 syndrome|low-T3 syndrome]]<ref name="Xu_2019">{{cite journal |last1=Xu |first1=J |last2=Wang |first2=L |title=Low T3 Syndrome as a Predictor of Poor Prognosis in Patients With Pyogenic Liver Abscess. |journal=Frontiers in Endocrinology |date=2019 |volume=10 |pages=541 |doi=10.3389/fendo.2019.00541 |pmid=31447784}}</ref> and certain chronic diseases, e.g. [[chronic fatigue syndrome]]<ref>{{cite journal|last1=Ruiz-Núñez|first1=Begoña|last2=Tarasse|first2=Rabab|last3=Vogelaar|first3=Emar F.|last4=Janneke Dijck-Brouwer|first4=D. A.|last5=Muskiet|first5=Frits A. J.|title=Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case–Control Study|journal=Frontiers in Endocrinology|date=20 March 2018|volume=9|pages=97|doi=10.3389/fendo.2018.00097|pmid=29615976|pmc=5869352}}</ref> or geriatric [[asthma]]<ref>{{cite journal |last1=Bingyan |first1=Zhan |last2=Dong |first2=Wei |title=Impact of thyroid hormones on asthma in older adults |journal=Journal of International Medical Research |date=7 July 2019 |pages=030006051985646 |doi=10.1177/0300060519856465 |pmid=31280621}}</ref>. In [[Graves's disease]], initially elevated SPINA-GD decreaes with antithyroid treatment in parallel to declining TSH receptor autoantibody titres<ref name="Kim_2018"/>.
[[Category:Thyroid]]
In hyperthyroid<ref name="Krysiak_2019_EndPol">{{cite journal |last1=Krysiak |first1=R |last2=Marek |first2=B |last3=Okopień |first3=B |title=Sexual function and depressive symptoms in men with overt hyperthyroidism. |journal=Endokrynologia Polska |date=2019 |volume=70 |issue=1 |pages=64–71 |doi=10.5603/EP.a2018.0069 |pmid=30307028}}</ref> men both [[SPINA-GT]] and SPINA-GD negatively correlate to [[erectile function]], intercourse satisfaction, [[Orgasm|orgasmic function]] and [[sexual desire]]. Substitution with [[selenomethionine]] results in increased SPINA-GD in subjects with autoimmune thyroiditis<ref name="Krysiak_Selenomethionine_Men_2018">{{cite journal |last1=Krysiak |first1=Robert |last2=Szkróbka |first2=Witold |last3=Okopień |first3=Bogusław |title=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 |journal=Pharmacological Reports |date=October 2018 |volume=71 |issue=2 |pages=243–7 |doi=10.1016/j.pharep.2018.10.012 |pmid=30818086}}</ref><ref name="Krysiak_Selenomethionine_Women_2018">{{cite journal |last1=Krysiak |first1=Robert |last2=Kowalcze |first2=Karolina |last3=Okopień |first3=Bogusław |title=Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis and low vitamin D status |journal=Pharmacological Reports |date=December 2018 |volume = 71 |issue = 2 |pages = 367–73 |doi=10.1016/j.pharep.2018.12.006 |pmid=30844687}}</ref><ref name="Krysiak_Selenomethionine_2019">{{cite journal |last1=Krysiak |first1=R |last2=Kowalcze |first2=K |last3=Okopień |first3=B |title=The Effect of Selenomethionine on Thyroid Autoimmunity in Euthyroid Men With Hashimoto Thyroiditis and Testosterone Deficiency. |journal=Journal of Clinical Pharmacology |date=20 May 2019 |doi=10.1002/jcph.1447 |pmid=31106856}}</ref>.
Deiodination capacity proved to be an independent predictor of substitution dose in a trial with over 300 patients on replacement therapy with [[levothyroxine]].<ref name="midgley2015">{{cite journal | vauthors = Midgley JE, Larisch R, Dietrich JW, Hoermann R | title = Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency | journal = Endocrine Connections | volume = 4 | issue = 4 | pages = 196–205 | date = December 2015 | pmid = 26335522 | pmc = 4557078 | doi = 10.1530/EC-15-0056 }}</ref>
Probably as a consequence of [[non-thyroidal illness syndrome]], SPINA-GD predicts [[Mortality rate|mortality]] in [[Polytrauma|trauma]]<ref name="Dietrich_2019"/> and postoperative [[atrial fibrillation]] in patients undergoing cardiac surgery<ref name="dietrich2015"/>. Correlations were also shown to age, total atrial conduction time and concentrations of [[3,5-Diiodothyronine|3,5-diiodothyronine]] and [[B-type natriuretic peptide]]<ref name="dietrich2015"/>. In a population suffering from pyogenic liver abscess SPINA-GD correlated to markers of [[malnutrition]], [[inflammation]] and [[liver failure]]<ref name="Xu_2019"/>.
The sum activity of peripheral deiodinases refers to the collective function of enzymes known as deiodinases that are responsible for the activation and deactivation of thyroid hormones in peripheral tissues. These enzymes play a crucial role in the regulation of metabolism, growth, and development by modulating the levels of active thyroid hormones available to tissues.
The sum activity of peripheral deiodinases is essential for the fine-tuning of thyroid hormone action in various tissues. By converting T4 to T3, deiodinases ensure that tissues receive the appropriate amount of active hormone necessary for their specific metabolic needs. This local regulation is crucial for:
Metabolic Rate Regulation: T3 is the active form of thyroid hormone that influences the basal metabolic rate.
