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	* '''Type I Deiodinase (D1)''':		* '''Type I Deiodinase (D1)''':
	* Found primarily in the [[liver]], [[kidney]], and [[thyroid gland]].		** 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.		** 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).		** Also capable of converting reverse T3 (rT3) to diiodothyronine (T2).

	* '''Type II Deiodinase (D2)''':		* '''Type II Deiodinase (D2)''':
	* Predominantly located in the [[brain]], [[pituitary gland]], [[brown adipose tissue]], and [[skeletal muscle]].		** Predominantly located in the [[brain]], [[pituitary gland]], [[brown adipose tissue]], and [[skeletal muscle]].
	* Converts T4 to T3, thus playing a critical role in maintaining local T3 levels in tissues.		** Converts T4 to T3, thus playing a critical role in maintaining local T3 levels in tissues.
	* Important for the feedback regulation of the [[hypothalamic-pituitary-thyroid axis]].		** Important for the feedback regulation of the [[hypothalamic-pituitary-thyroid axis]].

	* '''Type III Deiodinase (D3)''':		* '''Type III Deiodinase (D3)''':
	* Expressed in the [[placenta]], [[central nervous system]], and [[skin]].		** Expressed in the [[placenta]], [[central nervous system]], and [[skin]].
	* Inactivates T4 and T3 by converting them to rT3 and T2, respectively.		** Inactivates T4 and T3 by converting them to rT3 and T2, respectively.
	* Protects tissues from excessive thyroid hormone action.		** Protects tissues from excessive thyroid hormone action.

	==Function and Importance==		==Function and Importance==
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	* [[Hypothyroidism]]		* [[Hypothyroidism]]
	* [[Hyperthyroidism]]		* [[Hyperthyroidism]]
			{{stub}}
	[[Category:Endocrinology]]		[[Category:Endocrinology]]
	[[Category:Enzymes]]		[[Category:Enzymes]]
	[[Category:Thyroid]]		[[Category:Thyroid]]

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{{Infobox diagnostic
| name = Sum activity of peripheral deiodinases
| image =
| alt =
| caption =
| pronounce =
| purpose =
| test of = Maximum amount of T3 produced from T4 by peripheral deiodinases
| based on =
| synonyms = SPINA-GD, GD, deiodination capacity, total deiodinase activity
| calculator =
| DiseasesDB =
| ICD10 = 
| ICD9 =
| ICDO =
| MedlinePlus =
| eMedicine =
| MeshID =
| LOINC = 82367-4
| reference_range = 20–40 nmol/s
}}
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.<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 ==
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.

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]].

''In vivo'', it may therefore be beneficial to estimate GD from equilibrium levels of T4 and T3. It is obtained with

<math>\hat G_D = {{\beta _{31} (K_{M1} + [FT_4 ])(1 + K_{30} [TBG])[FT_3 ]} \over {\alpha _{31} [FT_4 ]}}</math>

or

<math>\hat G_D = {{\beta _{31} (K_{M1} + [FT_4 ])[TT_3 ]} \over {\alpha _{31} [FT_4 ]}}</math>

<math>\alpha _{31}</math>: [[Concentration#Qualitative description|Dilution]] factor for T3 (reciprocal of apparent volume of distribution, 0.026 l−1) 
<math>\beta _{31}</math>: [[Clearance (medicine)|Clearance]] exponent for T3 (8e-6 sec−1) 
''K''''M''1: [[Dissociation constant]] of type-1-deiodinase (5e-7 mol/l) 
''K''30: 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===
{| class="wikitable"
|'''Lower limit'''||'''Upper limit'''||'''Unit'''
|-
| 20<ref name=dietrich2002/> || 40<ref name=dietrich2002/> || 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.<ref name=dietrich2002/>

== 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 <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>

=== Clinical utility ===

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>.

=== 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<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"/>.

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"/>.

== See also ==
* [[Thyroid function tests]]
* [[Thyroid's secretory capacity]]
* [[Jostel's TSH index]]
* [[Thyrotroph Thyroid Hormone Sensitivity Index]]
* [[SimThyr]]

== References ==
{{Reflist|2}}
{{Use dmy dates|date=April 2017}}
== External links ==
* [http://spina.sf.net SPINA Thyr: Open source software for calculating GT and GD]
* Package "[https://cran.r-project.org/package=SPINA SPINA]" for the statistical environment [[R (software)|R]]

[[Category:Chemical pathology]]
[[Category:Blood tests]]
[[Category:Endocrine procedures]]
[[Category:Thyroidological methods]]
[[Category:Thyroid homeostasis]]
[[Category:Structure parameters of thyroid function]]
{{dictionary-stub1}}

Sum activity of peripheral deiodinases - Revision history

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