Sum activity of peripheral deiodinases

{{cs1 config|name-list-style=vanc}} {{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 = D013960 | 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'''{{efn|''SPINA'' is an acronym for "structure parameter inference approach".}}) 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 | s2cid = 14210899 | title = Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research | journal = Frontiers in Endocrinology | volume = 7 | page = 57 | date = 9 June 2016 | pmid = 27375554 | pmc = 4899439 | doi = 10.3389/fendo.2016.00057 | doi-access = free }}</ref> 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.

''GD'' is both a theoretical concept that is used in physiological theories of thyroid function and (as a calculated parameter) a biomarker for advanced diagnosis of thyroid disorders.<ref>{{cite book |last1=Hoermann |first1=Rudolf |last2=Dietrich |first2=Johannes W. |chapter=Diagnosis of Hypothyroidism |title=Hypothyroidism |date=2025 |pages=111–132 |doi=10.1007/978-981-96-3682-2_10|isbn=978-981-96-3681-5 }}</ref>

== 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.<ref name="Bianco_2014">{{cite journal |last1=Bianco |first1=AC |last2=Anderson |first2=G |last3=Forrest |first3=D |last4=Galton |first4=VA |last5=Gereben |first5=B |last6=Kim |first6=BW |last7=Kopp |first7=PA |last8=Liao |first8=XH |last9=Obregon |first9=MJ |last10=Peeters |first10=RP |last11=Refetoff |first11=S |last12=Sharlin |first12=DS |last13=Simonides |first13=WS |last14=Weiss |first14=RE |last15=Williams |first15=GR |title=American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. |journal=Thyroid |date=January 2014 |volume=24 |issue=1 |pages=88–168 |doi=10.1089/thy.2013.0109 |pmc=3887458 |pmid=24001133}}</ref>

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.<ref name="Bianco_2014"/>

''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>

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

[''FT4'']: Serum free T4 concentration (in pmol/L) [''FT3'']: Serum free T3 concentration (in pmol/L) [''TT3'']: Serum total T3 concentration (in nmol/L) <math>\alpha _{31}</math>: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 L−1) <math>\beta _{31}</math>: Clearance exponent for T3 (8e-6 sec−1) (i. e., reaction rate constant for degradation) ''K''''M''1: Binding constant of type-1-deiodinase (5e-7 mol/L) ''K''30: Binding 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>

The method is based on mathematical models of thyroid homeostasis.<ref name = "Dietrich_2016"/><ref name=dietrich2002/> 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.

The product of SPINA-GD times the urinary iodine excretion can be used to assess iodine-independent factors affecting deiodinase activity, e.g. selenium deficiency.<ref name="Sun_2023">{{cite journal |last1=Sun |first1=Q |last2=Oltra |first2=E |last3=Dijck-Brouwer |first3=DAJ |last4=Chillon |first4=TS |last5=Seemann |first5=P |last6=Asaad |first6=S |last7=Demircan |first7=K |last8=Espejo-Oltra |first8=JA |last9=Sánchez-Fito |first9=T |last10=Martín-Martínez |first10=E |last11=Minich |first11=WB |last12=Muskiet |first12=FAJ |last13=Schomburg |first13=L |title=Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone. |journal=Redox Biology |date=3 July 2023 |volume=65 |article-number=102796 |doi=10.1016/j.redox.2023.102796 |pmid=37423160|pmc=10338150 }}</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 === Unlike FT3-FT4 or T3-T4 ratios, the equation for SPINA-GD accounts for nonlinear enyzme kinetics according to the Monod equation and Michaelis-Menten kinetics. It is therefore assumed to be more accurate than the simpler ratios.<ref>{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JE |last3=Larisch |first3=R |last4=Dietrich |first4=JW |title=Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease. |journal=European Thyroid Journal |date=September 2016 |volume=5 |issue=3 |pages=171–179 |doi=10.1159/000447967 |pmid=27843807 |pmc=5091265 }}</ref><ref>{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JEM |last3=Larisch |first3=R |last4=Dietrich |first4=JW |title=The role of functional thyroid capacity in pituitary thyroid feedback regulation. |journal=European Journal of Clinical Investigation |date=October 2018 |volume=48 |issue=10 |article-number=e13003 |doi=10.1111/eci.13003 |pmid=30022470}}</ref><ref name="Hoermann_et_al_JCTE_2020">{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JEM |last3=Larisch |first3=R |last4=Dietrich |first4=JW |title=Heterogenous biochemical expression of hormone activity in subclinical/overt hyperthyroidism and exogenous thyrotoxicosis. |journal=Journal of Clinical & Translational Endocrinology |date=March 2020 |volume=19 |article-number=100219 |doi=10.1016/j.jcte.2020.100219 |pmid=32099819 |pmc=7031309 }}</ref>

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 |s2cid=44088904 |title=Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves' Disease |journal=International Journal of Endocrinology |date=2018 |volume=2018 |article-number=9863050 |doi=10.1155/2018/9863050|pmid=29853888 |pmc=5960571 |doi-access=free }}</ref> thyroglobulin concentration<ref>{{cite journal |last1=Sazumi |first1=Yosuke |last2=Soejima |first2=Yoshiaki |last3=Otsuka |first3=Yuki |last4=Nakano |first4=Yasuhiro |last5=Yamamoto |first5=Koichiro |last6=Suyama |first6=Atsuhito |last7=Takase |first7=Ryosuke |last8=Oguni |first8=Kohei |last9=Yasuda |first9=Miho |last10=Furukawa |first10=Masanori |last11=Otsuka |first11=Fumio |title=Behavior of serum thyroglobulin in relation to thyroid function under low-thyrotropin conditions in general practice |journal=Frontiers in Endocrinology |date=15 May 2026 |volume=17 |article-number=1756863 |doi=10.3389/fendo.2026.1756863 |doi-access=free }}</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 | s2cid = 35344744 | 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 | s2cid = 15996441 | title = TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis | journal = Journal of Thyroid Research | volume = 2012 | pages = 1–29 | year = 2012 | pmid = 23365787 | pmc = 3544290 | doi = 10.1155/2012/351864 | doi-access = free }}</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 | doi-access = free }}</ref><ref name="Hoermann2014">{{cite journal | vauthors = Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R | s2cid = 19341039 | 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 | doi-access = free }}</ref> and that it is reduced in nonthyroidal illness with hypodeiodination.<ref name=Liu2012 /><ref name=Rosolowska-Huszcz2005>{{cite journal | vauthors = Rosolowska-Huszcz D, Kozlowska L, Rydzewski A | s2cid = 25630198 | 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 | s2cid = 207639541 | 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 | s2cid = 14016461 | title = Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study | journal = Medicine | volume = 95 | issue = 6 | article-number = e2640 | date = February 2016 | pmid = 26871787 | pmc = 4753882 | doi = 10.1097/MD.0000000000002640 }}</ref> 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.<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|s2cid=73481267 }}</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|s2cid=73486105 }}</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 |volume=59 |issue=11 |pages=1477–1484 |date=20 May 2019 |doi=10.1002/jcph.1447 |pmid=31106856|s2cid=159040151 }}</ref><ref name = "Krysiak_JCPT_2020">{{cite journal |last1=Krysiak |first1=R |last2=Kowalcze |first2=K |last3=Okopień |first3=B |title=Hyperprolactinaemia attenuates the inhibitory effect of vitamin D/selenomethionine combination therapy on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis: A pilot study. |journal=Journal of Clinical Pharmacy and Therapeutics |date=10 July 2020 |volume=45 |issue=6 |pages=1334–1341 |doi=10.1111/jcpt.13214 |pmid=32649802|s2cid=220485158 |doi-access=free }}</ref><ref>{{cite journal |last1=Krysiak |first1=Robert |last2=Kowalcze |first2=Karolina |last3=Szkróbka |first3=Witold |last4=Okopień |first4=Bogusław |title=Sexual Function and Depressive Symptoms in Young Women with Euthyroid Hashimoto's Thyroiditis Receiving Vitamin D, Selenomethionine and Myo-Inositol: A Pilot Study |journal=Nutrients |date=20 June 2023 |volume=15 |issue=12 |page=2815 |doi=10.3390/nu15122815 |pmid=37375719 |pmc=10304218 |doi-access=free }}</ref><ref name="Krysiak_et_al_2026">{{cite journal |last1=Krysiak |first1=Robert |last2=Kowalcze |first2=Karolina |last3=Ott |first3=Johannes |last4=Cangelosi |first4=Giovanni |last5=Zaami |first5=Simona |last6=Okopień |first6=Bogusław |title=Vitamin E Intake Modulates the Effect of Selenomethionine on Sexual Function and Depressive Symptoms in Reproductive-Age Women with Euthyroid Autoimmune Thyroiditis: A Pilot Study |journal=Antioxidants |date=26 April 2026 |volume=15 |issue=5 |pages=549 |doi=10.3390/antiox15050549 |doi-access=free }}</ref> Conversely, it was observed that SPINA-GD is reduced in persons positive for autoantibodies to selenoprotein P, which is assumed to be involved in transport and storage of selenium.<ref name="Sun_2023"/>

=== 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.<ref name = "dietrich2002"/> These measures of diagnostic utility are also high in nodular goitre, where SPINA-GD is elevated.<ref name = "dietrich2002"/> 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).<ref name="Hoermann_et_al_JCTE_2020"/> SPINA-GD may therefore be an effective biomarker for the differential diagnosis of thyrotoxicosis.<ref>{{cite web |last1=Dietrich |first1=Johannes W. |title=SPINA in Science and Research: Year in Review: 2020 |url=https://sourceforge.net/p/spina/discussion/2256842/thread/b696b0d969/ |website=sourceforge.net |access-date=2 January 2021 |language=en}}</ref><ref>{{cite journal |last1=Pattarawongpaiboon |first1=Chidchanok |last2=Srisawat |first2=Nattachai |last3=Tungsanga |first3=Kriang |last4=Champunot |first4=Ratapum |last5=Somboonjun |first5=Jukrin |last6=Srichomkwun |first6=Panudda |title=Clinical characteristics and outcomes of an exogenous thyrotoxicosis epidemic in prison |journal=BMJ Nutrition, Prevention & Health |date=20 November 2023 |volume=6 |issue=2 |pages=318–325 |doi=10.1136/bmjnph-2023-000789|doi-access=free |pmid=38618547 |pmc=11009531 }}</ref>

Compared to healthy subjects, 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. |s2cid=202673793 |title=Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata |journal=Trauma und Berufskrankheit |volume=21 |issue=4 |pages=260–267 |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<ref name=Aweimer_2021>{{cite journal |last1=Aweimer |first1=Assem |last2=Schiedat |first2=Fabian |last3=Schöne |first3=Dominik |last4=Landgrafe-Mende |first4=Gabi |last5=Bogossian |first5=Harilaos |last6=Mügge |first6=Andreas |last7=Patsalis |first7=Polykarpos C. |last8=Gotzmann |first8=Michael |last9=Akin |first9=Ibrahim |last10=El-Battrawy |first10=Ibrahim |last11=Dietrich |first11=Johannes W. |title=Abnormal Cardiac Repolarization in Thyroid Diseases: Results of an Observational Study |journal=Frontiers in Cardiovascular Medicine |date=23 November 2021 |volume=8 |article-number=738517 |doi=10.3389/fcvm.2021.738517 |pmid=34888359 |pmc=8649843|doi-access=free }}</ref><ref>{{cite journal |last1=Ağbaht |first1=K |last2=Pişkinpaşa |first2=SV |title=Serum TSH, 25(OH) D and phosphorus levels predict weight loss in individuals with diabetes/prediabetes and morbid obesity: a single-center retrospective cohort analysis. |journal=BMC Endocrine Disorders |date=18 November 2022 |volume=22 |issue=1 |page=282 |doi=10.1186/s12902-022-01202-4 |pmid=36401211 |pmc=9673446 |doi-access=free }}</ref> 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 | s2cid = 6407766 | title = Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine | journal = PLOS ONE | volume = 12 | issue = 11 | article-number = e0187232 | date = 2017 | pmid = 29155897 | doi = 10.1371/journal.pone.0187232 | pmc=5695809| bibcode = 2017PLoSO..1287232H | doi-access = free }}</ref> In patients suffering from toxic adenoma, toxic multinodular goitre and Graves' disease low-dose radioiodine therapy leads to a significant reduction of SPINA-GD as well.<ref name="Larisch_et_al_2024">{{cite journal |last1=Larisch |first1=R |last2=Midgley |first2=JEM |last3=Dietrich |first3=JW |last4=Hoermann |first4=R |title=Effect of Radioiodine Treatment on Quality of Life in Patients with Subclinical Hyperthyroidism: A Prospective Controlled Study. |journal=Nuklearmedizin. Nuclear Medicine |date=23 January 2024 |volume=63 |issue=3 |pages=176–187 |doi=10.1055/a-2240-8087 |pmid=38262472|s2cid=267198748 }}</ref>

SPINA-GD correlates in positive direction with type 2 allostatic load<ref>{{cite journal |last1=Zhuolin |first1=D |last2=Chun |first2=H |last3=Su |first3=X |title=Association between allostatic load and thyroid function in U.S. adults: a cross-sectional study based on NHANES data. |journal=Stress (Amsterdam, Netherlands) |date=2026 |volume=29 |issue=1 |article-number=2653858 |doi=10.1080/10253890.2026.2653858 |pmid=41941533}}</ref>. Accordingly, it is elevated in obesity. This applies to both the metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO) phenotypes.<ref>{{cite journal |last1=Wang Zixiao |first1=Wang Zixiao |last2=Yang Sijue |first2=Yang Sijue |last3=Guan Haixia |first3=Guan Haixia |last4=Wang Wei |first4=Wang Wei |title=甲状腺功能正常人群中甲状腺激素敏感性与肥胖表型的关系 |journal=中华内分泌代谢杂志 |date=2023 |volume=39 |issue=5 |pages=426–429 |doi=10.3760/cma.j.cn311282-20221012-00579}}</ref> 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,<ref name=Ittermann2021>{{cite journal |last1=Ittermann |first1=T |last2=Markus |first2=MRP |last3=Bahls |first3=M |last4=Felix |first4=SB |last5=Steveling |first5=A |last6=Nauck |first6=M |last7=Völzke |first7=H |last8=Dörr |first8=M |title=Low serum TSH levels are associated with low values of fat-free mass and body cell mass in the elderly. |journal=Scientific Reports |date=2021-05-18 |volume=11 |issue=1 |page=10547 |doi=10.1038/s41598-021-90178-7 |pmid=34006958|pmc=8131378 |bibcode=2021NatSR..1110547I |doi-access=free }}</ref> confirming observations in the NHANES dataset<ref>{{cite journal |last1=Chatzitomaris |first1=A |last2=Hoermann |first2=R |last3=Midgley |first3=JE |last4=Hering |first4=S |last5=Urban |first5=A |last6=Dietrich |first6=B |last7=Abood |first7=A |last8=Klein |first8=HH |last9=Dietrich |first9=JW |title=Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. |journal=Frontiers in Endocrinology |date=2017 |volume=8 |article-number=163 |doi=10.3389/fendo.2017.00163 |pmid=28775711|pmc=5517413 |doi-access=free }}</ref> and in a Chinese study.<ref>{{cite journal |last1=Yang |first1=L |last2=Sun |first2=X |last3=Tao |first3=H |last4=Zhao |first4=Y |title=The association between thyroid homeostasis parameters and obesity in subjects with euthyroidism. |journal=Journal of Physiology and Pharmacology |date=February 2023 |volume=74 |issue=1 |doi=10.26402/jpp.2023.1.07 |pmid=37245234}}</ref> 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.<ref name=Ittermann2021/> Generally, SPINA-GD seems to be upregulated in metabolic syndrome, as demonstrated by a significant correlation to the triglyceride-glucose index, a marker of insulin resistance.<ref>{{cite journal |last1=Cheng |first1=H |last2=Hu |first2=Y |last3=Zhao |first3=H |last4=Zhou |first4=G |last5=Wang |first5=G |last6=Ma |first6=C |last7=Xu |first7=Y |title=Exploring the association between triglyceride-glucose index and thyroid function. |journal=European Journal of Medical Research |date=10 November 2023 |volume=28 |issue=1 |page=508 |doi=10.1186/s40001-023-01501-z |pmid=37946276 |pmc=10636949 |doi-access=free }}</ref>

In type 1 allostatic load, SPINA-GD is reduced. This applies to low-T3 syndrome<ref name="Xu_2019">{{cite journal |last1=Xu |first1=J |last2=Wang |first2=L |s2cid=199435315 |title=Low T3 Syndrome as a Predictor of Poor Prognosis in Patients With Pyogenic Liver Abscess. |journal=Frontiers in Endocrinology |date=2019 |volume=10 |article-number=541 |doi=10.3389/fendo.2019.00541 |pmid=31447784|pmc=6691090 |doi-access=free }}</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.|s2cid=4550317|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|article-number=97|doi=10.3389/fendo.2018.00097|pmid=29615976|pmc=5869352|doi-access=free}}</ref><ref name="Sun_2023"/> acute<ref name="Filipczyk2025">{{cite journal |last1=Filipczyk |first1=Alicja |last2=Wujtewicz |first2=Magdalena A. |last3=Okrągły |first3=Michał |last4=Steckiewicz |first4=Karol P. |title=Impact of Continuous Veno-Venous Hemodiafiltration on Thyroid Homeostasis in Critically Ill Patients |journal=Journal of Clinical Medicine |date=6 August 2025 |volume=14 |issue=15 |page=5542 |doi=10.3390/jcm14155542 |doi-access=free |pmid=40807165 |pmc=12347796 }}</ref> and chronic kidney disease,<ref>{{cite journal |last1=Chen |first1=Y |last2=Zhang |first2=W |last3=Wang |first3=N |last4=Wang |first4=Y |last5=Wang |first5=C |last6=Wan |first6=H |last7=Lu |first7=Y |title=Thyroid Parameters and Kidney Disorder in Type 2 Diabetes: Results from the METAL Study. |journal=Journal of Diabetes Research |date=2020 |volume=2020 |article-number=4798947 |doi=10.1155/2020/4798947 |pmid=32337292|pmc=7149438 |doi-access=free }}</ref><ref>{{cite journal |last1=Yang |first1=S |last2=Lai |first2=S |last3=Wang |first3=Z |last4=Liu |first4=A |last5=Wang |first5=W |last6=Guan |first6=H |title=Thyroid Feedback Quantile-based Index correlates strongly to renal function in euthyroid individuals. |journal=Annals of Medicine |date=December 2021 |volume=53 |issue=1 |pages=1945–1955 |doi=10.1080/07853890.2021.1993324 |pmid=34726096|pmc=8567884 }}</ref> short bowel syndrome<ref>{{cite journal |last1=Wan |first1=S |last2=Yang |first2=J |last3=Gao |first3=X |last4=Zhang |first4=L |last5=Wang |first5=X |title=Nonthyroidal Illness Syndrome in Patients With Short-Bowel Syndrome. |journal=Journal of Parenteral and Enteral Nutrition |date=22 July 2020 |volume=45 |issue=5 |pages=973–981 |doi=10.1002/jpen.1967 |pmid=32697347|s2cid=220698496 }}</ref> or geriatric asthma.<ref>{{cite journal |last1=Bingyan |first1=Zhan |last2=Dong |first2=Wei |s2cid=195830014 |title=Impact of thyroid hormones on asthma in older adults |journal=Journal of International Medical Research |volume=47 |issue=9 |date=7 July 2019 |pages=4114–4125 |doi=10.1177/0300060519856465 |pmid=31280621|pmc=6753544 }}</ref> Six months after the primary infection, it correlates negatively to the FS-14 score for fatigue in patients affected by Long COVID (PASC).<ref>{{cite journal |last1=Dong |first1=S |last2=Ding |first2=F |last3=Wang |first3=Y |last4=Liu |first4=S |last5=Bai |first5=R |last6=Liu |first6=Y |last7=Zhao |first7=Y |last8=Zhu |first8=Y |last9=Liu |first9=M |last10=Liu |first10=Y |last11=Xing |first11=Q |title=The relation between FT(3) and long-term fatigue in patients with COVID-19. |journal=Frontiers in Endocrinology |date=2024 |volume=15 |article-number=1411262 |doi=10.3389/fendo.2024.1411262 |doi-access=free |pmid=39247915|pmc=11377235 }}</ref> In Graves' disease, SPINA-GD is initially elevated but decreases with antithyroid treatment in parallel to declining TSH receptor autoantibody titres.<ref name="Kim_2018"/> 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.<ref>{{cite journal |last1=Aweimer |first1=A |last2=El-Battrawy |first2=I |last3=Akin |first3=I |last4=Borggrefe |first4=M |last5=Mügge |first5=A |last6=Patsalis |first6=PC |last7=Urban |first7=A |last8=Kummer |first8=M |last9=Vasileva |first9=S |last10=Stachon |first10=A |last11=Hering |first11=S |last12=Dietrich |first12=JW |title=Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study. |journal=Journal of Internal Medicine |date=12 November 2020 |volume=289 |issue=5 |pages=675–687 |doi=10.1111/joim.13189 |pmid=33179374|doi-access=free }}</ref> This may result from concomitant non-thyroidal illness syndrome, so that the clinical phenotype represents overlapping type 1 and type 2 allostatic response. In a large register-based study, reduced SPINA-GD predicted a poor outcome of Takotsubo syndrome.<ref name="Aweimer_2024">{{cite journal |last1=Aweimer |first1=A |last2=Dietrich |first2=JW |last3=Santoro |first3=F |last4=Fàbregas |first4=MC |last5=Mügge |first5=A |last6=Núñez-Gil |first6=IJ |last7=Vazirani |first7=R |last8=Vedia |first8=O |last9=Pätz |first9=T |last10=Ragnatela |first10=I |last11=Arcari |first11=L |last12=Volpe |first12=M |last13=Corbì-Pascual |first13=M |last14=Martinez-Selles |first14=M |last15=Almendro-Delia |first15=M |last16=Sionis |first16=A |last17=Uribarri |first17=A |last18=Thiele |first18=H |last19=Brunetti |first19=ND |last20=Eitel |first20=I |last21=Stiermaier |first21=T |last22=Hamdani |first22=N |last23=Abumayyaleh |first23=M |last24=Akin |first24=I |last25=El-Battrawy |first25=I |title=Takotsubo syndrome outcomes predicted by thyroid hormone signature: insights from cluster analysis of a multicentre registry. |journal=eBioMedicine |date=18 March 2024 |volume=102 |article-number=105063 |doi=10.1016/j.ebiom.2024.105063 |pmid=38502972|pmc=10963195 }}</ref>

In certain psychiatric diseases, including major depression, bipolar disorder and schizophrenia SPINA-GD is reduced compared to healthy controls.<ref name="Cui2024">{{cite journal |last1=Cui |first1=T |last2=Qi |first2=Z |last3=Wang |first3=M |last4=Zhang |first4=X |last5=Wen |first5=W |last6=Gao |first6=S |last7=Zhai |first7=J |last8=Guo |first8=C |last9=Zhang |first9=N |last10=Zhang |first10=X |last11=Guan |first11=Y |last12=Retnakaran |first12=R |last13=Hao |first13=W |last14=Zhai |first14=D |last15=Zhang |first15=R |last16=Zhao |first16=Y |last17=Wen |first17=SW |title=Thyroid allostasis in drug-free affective disorder patients. |journal=Psychoneuroendocrinology |date=April 2024 |volume=162 |article-number=106962 |doi=10.1016/j.psyneuen.2024.106962 |pmid=38277991}}</ref> This observation is supported by negative correlation of SPINA-GD with the depression percentiles in the Hospital Anxiety and Depression Scale (HADS).<ref name="BazikaGerasch_2024">{{cite journal |last1=Bazika-Gerasch |first1=B |last2=Kumowski |first2=N |last3=Enax-Krumova |first3=E |last4=Kaisler |first4=M |last5=Eitner |first5=LB |last6=Maier |first6=C |last7=Dietrich |first7=JW |title=Impaired autonomic function and somatosensory disturbance in patients with treated autoimmune thyroiditis. |journal=Scientific Reports |date=29 May 2024 |volume=14 |issue=1 |page=12358 |doi=10.1038/s41598-024-63158-w |pmid=38811750|pmc=11137073 |bibcode=2024NatSR..1412358B }}</ref>

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|doi-access=free }}</ref> 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.<ref name="Krysiak_Selenomethionine_Men_2018"/><ref name="Krysiak_Selenomethionine_Women_2018"/><ref name="Krysiak_Selenomethionine_2019"/><ref name = "Krysiak_JCPT_2020"/>

In subjects with diabetes mellitus SPINA-GD is positively correlated to several bone resorption markers including the N-mid fragment of osteocalcin and procollagen type I N-terminal propeptide (P1NP), as well as, however in men only, the β-C-terminal cross-linked telopeptides of type I collagen (β-CTX).<ref>{{cite journal |last1=Chen |first1=Y |last2=Zhang |first2=W |last3=Chen |first3=C |last4=Wang |first4=Y |last5=Wang |first5=N |last6=Lu |first6=Y |title=Thyroid and bone turnover markers in type 2 diabetes: results from the METAL study. |journal=Endocrine Connections |date=31 March 2022 |volume=11 |issue=3 |doi=10.1530/EC-21-0484 |pmid=35196256|pmc=9010813 }}</ref> In the general population it is, however, positively associated with the bone mineral density of the femoral neck and with reduced risk of osteoporosis.<ref>{{cite journal |last1=Liu |first1=C |last2=Hua |first2=L |last3=Liu |first3=K |last4=Xin |first4=Z |title=Impaired sensitivity to thyroid hormone correlates to osteoporosis and fractures in euthyroid individuals. |journal=Journal of Endocrinological Investigation |date=16 February 2023 |volume=46 |issue=10 |pages=2017–2029 |doi=10.1007/s40618-023-02035-1 |pmid=36795243|s2cid=256899701 }}</ref> In both diabetic and non-diabetic subsjects it correlates (negatively) with age and concentrations of c-reactive protein, troponin T and B-type natriuretic peptide, and (positively) with the concentrations of total cholesterol, low-density lipoprotein and triglycerides.<ref>{{cite journal |last1=Li |first1=W |last2=He |first2=Q |last3=Zhang |first3=H |last4=Shu |first4=S |last5=Wang |first5=L |last6=Wu |first6=Y |last7=Yuan |first7=Z |last8=Zhou |first8=J |title=Thyroid-stimulating hormone within the normal reference range has a U-shaped association with the severity of coronary artery disease in nondiabetic patients but is diluted in diabetic patients. |journal=Journal of Investigative Medicine |date=20 January 2023 |volume=71 |issue=4 |pages=350–360 |doi=10.1177/10815589221149187 |pmid=36680358|s2cid=256055662 }}</ref>

Deiodination capacity proved to be an independent predictor of substitution dose in several trials that included persons 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><ref>{{cite journal |last1=Le Moli |first1=R |last2=Malandrino |first2=P |last3=Russo |first3=M |last4=Tumino |first4=D |last5=Piticchio |first5=T |last6=Naselli |first6=A |last7=Rapicavoli |first7=V |last8=Belfiore |first8=A |last9=Frasca |first9=F |title=Levothyroxine therapy, calculated deiodinases activity and basal metabolic rate in obese or nonobese patients after total thyroidectomy for differentiated thyroid cancer, results of a retrospective observational study. |journal=Endocrinology, Diabetes & Metabolism |date=March 2023 |volume=6 |issue=2 |article-number=e406 |doi=10.1002/edm2.406 |pmid=36722311|pmc=10000637 }}</ref>

Probably as a consequence of non-thyroidal illness syndrome, SPINA-GD predicts mortality in trauma<ref name="Dietrich_2019"/> and postoperative atrial fibrillation in patients undergoing cardiac surgery.<ref name="dietrich2015"/> The association to mortality is retained even after adjustment for other established risk factors, including age, APACHE II score and plasma protein binding of thyroid hormones.<ref name="Dietrich_2019"/> Correlations were also shown to age, total atrial conduction time, and concentrations of 3,5-diiodothyronine and B-type natriuretic peptide.<ref name="dietrich2015"/> SPINA-GD also correlates with several components of the kynurenine pathway, which might mirror an assosication to a pro-inflammatory milieu.<ref>{{cite journal |last1=Krupa |first1=A |last2=Łebkowska |first2=A |last3=Kondraciuk |first3=M |last4=Kaminski |first4=KA |last5=Kowalska |first5=I |title=Alteration in kynurenine pathway metabolites in young women with autoimmune thyroiditis. |journal=Scientific Reports |date=21 March 2024 |volume=14 |issue=1 |page=6851 |doi=10.1038/s41598-024-57154-3 |pmid=38514790|pmc=10957988 |bibcode=2024NatSR..14.6851K }}</ref> Accordingly, in a population suffering from pyogenic liver abscess SPINA-GD correlated to markers of malnutrition, inflammation and liver failure.<ref name="Xu_2019"/> 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.<ref>{{cite journal |last1=Tan |first1=Y |last2=Gao |first2=L |last3=Yin |first3=Q |last4=Sun |first4=Z |last5=Man |first5=X |last6=Du |first6=Y |last7=Chen |first7=Y |title=Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with Parkinson's disease. |journal=The International Journal of Neuroscience |date=April 2021 |volume=131 |issue=4 |pages=346–356 |doi=10.1080/00207454.2020.1744595 |pmid=32186220|s2cid=212752563 }}</ref> Euthyroid sick syndrome may be the reason for variations of SPINA-GD in subjects treated with immune checkpoint inhibitors for cancer as well.<ref>{{cite journal |last1=Verelst |first1=FR |last2=Beyens |first2=MMJ |last3=Vandenbroucke |first3=E |last4=Forceville |first4=K |last5=Th B Twickler |first5=M |title=A decrease in peripheral thyroid hormone conversion efficiency in patients treated with immune checkpoint inhibitors and L-T3 as a possible alternative therapeutic escape option. |journal=European Journal of Clinical Investigation |date=15 April 2022 |volume=52 |issue=7 |article-number=e13790 |doi=10.1111/eci.13790 |pmid=35428986|s2cid=248203797 }}</ref>

Endocrine disruptors may have pronounced effects on step-up deiodinases, as suggested by positive correlation of SPINA-GD to combined exposure to polycyclic aromatic hydrocarbons (PAHs)<ref>{{cite journal |last1=Yang |first1=S |last2=Sun |first2=J |last3=Wang |first3=S |last4=E |first4=L |last5=Zhang |first5=S |last6=Jiang |first6=X |title=Association of exposure to polycyclic aromatic hydrocarbons with thyroid hormones in adolescents and adults, and the influence of the iodine status. |journal=Environmental Science: Processes & Impacts |date=9 August 2023 |volume=25 |issue=9 |pages=1449–1463 |doi=10.1039/d3em00135k |pmid=37555279|s2cid=259916981 }}</ref> and urine concentrations of cadmium and phthalate metabolites,<ref name="Choi2020">{{cite journal |last1=Choi |first1=Sohyeon |last2=Kim |first2=Min Joo |last3=Park |first3=Young Joo |last4=Kim |first4=Sunmi |last5=Choi |first5=Kyungho |last6=Cheon |first6=Gi Jeong |last7=Cho |first7=Yoon Hee |last8=Jeon |first8=Hye Li |last9=Yoo |first9=Jiyoung |last10=Park |first10=Jeongim |title=Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population |journal=Environment International |date=July 2020 |volume=140 |article-number=105783 |doi=10.1016/j.envint.2020.105783|pmid=32464474 |doi-access=free |bibcode=2020EnInt.14005783C }}</ref><ref name="Kim2020">{{cite journal |last1=Kim |first1=Min Joo |last2=Kim |first2=Sunmi |last3=Choi |first3=Sohyeon |last4=Lee |first4=Inae |last5=Moon |first5=Min Kyong |last6=Choi |first6=Kyungho |last7=Park |first7=Young Joo |last8=Cho |first8=Yoon Hee |last9=Kwon |first9=Young Min |last10=Yoo |first10=Jiyoung |last11=Cheon |first11=Gi Jeong |last12=Park |first12=Jeongim |title=Association of exposure to polycyclic aromatic hydrocarbons and heavy metals with thyroid hormones in general adult population and potential mechanisms |journal=Science of the Total Environment |date=December 2020 |volume=762 |article-number=144227 |pmid=33373756 |doi=10.1016/j.scitotenv.2020.144227|s2cid=229722026 }}</ref><ref>{{cite journal |last1=Chen |first1=Y |last2=Zhang |first2=W |last3=Chen |first3=J |last4=Wang |first4=N |last5=Chen |first5=C |last6=Wang |first6=Y |last7=Wan |first7=H |last8=Chen |first8=B |last9=Lu |first9=Y |title=Association of Phthalate Exposure with Thyroid Function and Thyroid Homeostasis Parameters in Type 2 Diabetes. |journal=Journal of Diabetes Research |date=2021 |volume=2021 |article-number=4027380 |doi=10.1155/2021/4027380 |pmid=34746318|pmc=8566079 |doi-access=free }}</ref><ref>{{cite journal |last1=Lee |first1=I |last2=Kim |first2=MJ |last3=Park |first3=YJ |last4=Moon |first4=MK |last5=Choi |first5=S |last6=Park |first6=J |last7=Kim |first7=E |last8=Lee |first8=G |last9=Choi |first9=K |title=Effect of fasting status on association between exposure to phthalate and phenolics, and thyroid hormones in adult women of reproductive age. |journal=Environmental Research |date=17 January 2025 |volume=269 |article-number=120880 |doi=10.1016/j.envres.2025.120880 |pmid=39826653|bibcode=2025ER....26920880L }}</ref> negative correlation to paraben, mercury and bisphenol A concentration<ref>{{cite journal |last1=Huang |first1=PC |last2=Chen |first2=HC |last3=Leung |first3=SH |last4=Lin |first4=YJ |last5=Huang |first5=HB |last6=Chang |first6=WT |last7=Huang |first7=HI |last8=Chang |first8=JW |title=Associations between paraben exposure, thyroid capacity, homeostasis and pituitary thyrotropic function in the general Taiwanese: Taiwan Environmental Survey for Toxicants (TEST) 2013 | journal=Environmental Science and Pollution Research | date=1 December 2023 |volume=31 |issue=1 |pages=1288–1303 | doi=10.1007/s11356-023-31277-y |pmid=38038926|s2cid=265514578 }}</ref><ref name="Choi2020"/><ref name="Kim2020"/><ref name="Huang_2025">{{cite journal |last1=Huang |first1=PC |last2=Chen |first2=H |last3=Kuo |first3=PL |last4=Chen |first4=HC |last5=Chang |first5=WT |last6=Chang |first6=JW |title=Associations between urinary parabens and thyroid hormone homeostasis across trimesters in Taiwanese pregnant women. |journal=Ecotoxicology and Environmental Safety |date=30 January 2025 |volume=291 |article-number=117818 |doi=10.1016/j.ecoenv.2025.117818 |pmid=39889471|doi-access=free |bibcode=2025EcoES.29117818H }}</ref> and a nonlinear association to the concentrations of per- and polyfluoroalkyl substances (PFAS).<ref>{{cite journal |last1=Yu |first1=X |last2=Liu |first2=Y |last3=Wang |first3=M |last4=Jia |first4=P |last5=Yang |first5=S |last6=Sun |first6=F |last7=Jin |first7=Y |last8=Wang |first8=X |last9=Guo |first9=Z |last10=Zhao |first10=G |last11=Gao |first11=B |title=Association between per- and polyfluoroalkyl substance exposures and thyroid homeostasis parameters. |journal=The Journal of Clinical Endocrinology and Metabolism |date=18 November 2024 |volume=110 |issue=8 |pages=e2723–e2736 |doi=10.1210/clinem/dgae798 |pmid=39556482}}</ref> In a cohort of manganese-exposed workers, SPINA-GD responded to a tenfold increase in concentrations of titanium, nickel, selenium and strontium.<ref>{{cite journal |last1=Ge |first1=X |last2=He |first2=J |last3=Lin |first3=S |last4=Bao |first4=Y |last5=Zheng |first5=Y |last6=Cheng |first6=H |last7=Cai |first7=H |last8=Feng |first8=X |last9=Yang |first9=W |last10=Hu |first10=S |last11=Wang |first11=L |last12=Liao |first12=Q |last13=Wang |first13=F |last14=Liu |first14=C |last15=Chen |first15=X |last16=Zou |first16=Y |last17=Yang |first17=X |title=Associations of metal mixtures with thyroid function and potential interactions with iodine status: results from a cross-sectional study in MEWHC. |journal=Environmental Science and Pollution Research International |date=16 September 2023 |volume=30 |issue=48 |pages=105665–105674 |doi=10.1007/s11356-023-29682-4 |pmid=37715904|bibcode= 2023ESPR...3005665G|s2cid=262013667 }}</ref>

SPINA-GD is significantly elevated in residents of circumpolar regions<ref>{{cite journal |last1=Nikanorova |first1=A.A. |last2=Borisova |first2=T.V. |last3=Pshennikova |first3=V.G. |last4=Nakhodkin |first4=S.S. |last5=Fedorova |first5=S.A. |last6=Barashkov |first6=N.A. |title=АЛЛОСТАЗ ЩИТОВИДНОЙ ЖЕЛЕЗЫ 2 ТИПА У ЖИТЕЛЕЙ ЯКУТИИ [Type 2 Thyroid Allostasis in the residents of Yakutia] |journal=Yakut Medical Journal |date=30 June 2024 |volume=86 |issue=1 |pages=80–84 |doi=10.25789/YMJ.2024.86.19}}</ref> and carriers of the TT genotype of the rs3811787 polymorphism of the UCP1 gene.<ref name="Nikanorova_et_al_2025">{{cite journal |last1=Nikanorova |first1=Alena A. |last2=Barashkov |first2=Nikolay A. |last3=Pshennikova |first3=Vera G. |last4=Nakhodkin |first4=Sergey S. |last5=Romanov |first5=Georgii P. |last6=Solovyev |first6=Aisen V. |last7=Fedorova |first7=Sardana A. |title=The Evaluation of Significance of Uncoupling Protein Genes UCP1, UCP2, UCP3, UCP4, UCP5, and UCP6 in Human Adaptation to Cold Climates |journal=Biology |date=23 April 2025 |volume=14 |issue=5 |page=454 |doi=10.3390/biology14050454|doi-access=free |pmid=40427644 |pmc=12108989 }}</ref> Since this genotype is more prevalent in geographical regions near the North Pole, it is assumed that the variations of SPINA-GD are part of a natural selection mechanism for adaptation to a cold climate.<ref name = "Nikanorova_et_al_2025"/>

In a longitudinal evaluation of a large sample of the general US population over 10 years, reduced SPINA-GD significantly predicted worse overall survival.<ref>{{cite journal |last1=Dietrich |first1=Johannes W. |title=P4-Endokrinologie – Kybernetische Perspektiven eines neuen Ansatzes |journal=Leibniz Online |date=2024 |volume=54 |doi=10.53201/LEIBNIZONLINE54 |url=https://leibnizsozietaet.de/wp-content/uploads/2024/12/03_03_Kybernetik-2024_DietrichLeibniz-Online-Fachbeitrag.pdf |language=de}}</ref>

==Notes== {{notelist | colwidth = | notes = }}

== References == {{Reflist|2}} {{Use dmy dates|date=April 2017}}

== External links == {{Library resources box|by=no|onlinebooks=no|about=yes|wikititle=SPINA-GD}}{{Authority control}}

Category:Clinical chemistry Category:Blood tests Category:Endocrine procedures Category:Thyroidological methods Category:Thyroid homeostasis Category:Structure parameters of thyroid function Category:Static endocrine function tests