Sum activity of peripheral deiodinases

Sum activity of peripheral deiodinases
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Reference Range	20–40 nmol/s
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The sum activity of peripheral deiodinases (G_D, 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">,

 Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research, 
 Frontiers in Endocrinology, 
 
 Vol. 7,
 pp. 57,
 DOI: 10.3389/fendo.2016.00057,
 PMID: 27375554,
 PMC: 4899439,</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.

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.

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

${\hat{G}}_D=\frac{{\beta }_{31}(K_{M1}+[F{T}_4])(1+K_{30}[TBG])[F{T}_3]}{{\alpha }_{31}[F{T}_4]}$

or

${\hat{G}}_D=\frac{{\beta }_{31}(K_{M1}+[F{T}_4])[T{T}_3]}{{\alpha }_{31}[F{T}_4]}$

${\alpha }_{31}$: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 l⁻¹)
${\beta }_{31}$: Clearance exponent for T3 (8e-6 sec⁻¹)
K_M1: Dissociation constant of type-1-deiodinase (5e-7 mol/l)
K₃₀: Dissociation constant T3-TBG (2e9 l/mol)<ref name=dietrich2002>,

 Der Hypophysen-Schilddrüsen-Regelkreis, 
  
 Berlin, Germany:Logos-Verlag Berlin, 
  
  
  
 ISBN 978-3-89722-850-4,</ref>

Reference range

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">,

 Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves' Disease, 
 International Journal of Endocrinology, 
 
 Vol. 2018,
 pp. 9863050,
 DOI: 10.1155/2018/9863050,
 PMID: 29853888,
 PMC: 5960571,</ref>, body mass index<ref name=dietrich2002/><ref name="Liu2012">, 
 Nonthyroidal illness syndrome: is it far away from Crohn's disease?, 
 Journal of Clinical Gastroenterology, 
 
 Vol. 47(Issue: 2),
 pp. 153–9,
 DOI: 10.1097/MCG.0b013e318254ea8a,
 PMID: 22874844,</ref><ref>, 
 TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis, 
 Journal of Thyroid Research, 
 2012,
 Vol. 2012,
 pp. 1–29,
 DOI: 10.1155/2012/351864,
 PMID: 23365787,
 PMC: 3544290,</ref> and thyrotropin levels in humans,<ref>, 
 Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?, 
 European Journal of Endocrinology, 
 
 Vol. 168(Issue: 2),
 pp. 271–80,
 DOI: 10.1530/EJE-12-0819,
 PMID: 23184912,</ref><ref name="Hoermann2014">, 
 Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment, 
 Clinical Endocrinology, 
 
 Vol. 81(Issue: 6),
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 Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure, 
 Endocrine, 
 
 Vol. 27(Issue: 3),
 pp. 283–8,
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 Nonthyroidal illness syndrome in enterocutaneous fistulas, 
 American Journal of Surgery, 
 
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 PMID: 23809674,</ref><ref name="dietrich2015">, 
 Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling, 
 European Thyroid Journal, 
 
 Vol. 4(Issue: 2),
 pp. 129–37,
 DOI: 10.1159/000381543,
 PMID: 26279999,
 PMC: 4521060,</ref><ref name=Fan2016>, 
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 PMID: 26871787,
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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 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"/>. SPINA-GD is significantly reduced in euthyroid sick syndrome<ref name="Dietrich_2019">,

 Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata, 
 Trauma und Berufskrankheit, 
 
 
 
 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">,

 Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine, 
 PLOS ONE, 
 
 Vol. 12(Issue: 11),
 pp. e0187232,
 DOI: 10.1371/journal.pone.0187232,
 PMID: 29155897,
 PMC: 5695809,</ref> SPINA-GD is also reduced in low-T3 syndrome<ref name="Xu_2019">, 
 Low T3 Syndrome as a Predictor of Poor Prognosis in Patients With Pyogenic Liver Abscess., 
 Frontiers in Endocrinology, 
 
 Vol. 10,
 pp. 541,
 DOI: 10.3389/fendo.2019.00541,
 PMID: 31447784,</ref> and certain chronic diseases, e.g. chronic fatigue syndrome<ref>, 
 Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case–Control Study, 
 Frontiers in Endocrinology, 
 
 Vol. 9,
 pp. 97,
 DOI: 10.3389/fendo.2018.00097,
 PMID: 29615976,
 PMC: 5869352,</ref> or geriatric asthma<ref>, 
 Impact of thyroid hormones on asthma in older adults, 
 Journal of International Medical Research, 
 
 
 pp. 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">,

 Sexual function and depressive symptoms in men with overt hyperthyroidism., 
 Endokrynologia Polska, 
 
 Vol. 70(Issue: 1),
 pp. 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, orgasmic function and sexual desire. Substitution with selenomethionine results in increased SPINA-GD in subjects with autoimmune thyroiditis<ref name="Krysiak_Selenomethionine_Men_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, 
 
 Vol. 71(Issue: 2),
 pp. 243–7,
 DOI: 10.1016/j.pharep.2018.10.012,
 PMID: 30818086,</ref><ref name="Krysiak_Selenomethionine_Women_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, 
 
 Vol. 71(Issue: 2),
 pp. 367–73,
 DOI: 10.1016/j.pharep.2018.12.006,
 PMID: 30844687,</ref><ref name="Krysiak_Selenomethionine_2019">, 
 The Effect of Selenomethionine on Thyroid Autoimmunity in Euthyroid Men With Hashimoto Thyroiditis and Testosterone Deficiency., 
 Journal of Clinical Pharmacology, 
 
 
 
 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">,

 Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency, 
 Endocrine Connections, 
 
 Vol. 4(Issue: 4),
 pp. 196–205,
 DOI: 10.1530/EC-15-0056,
 PMID: 26335522,
 PMC: 4557078,</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"/>. Correlations were also shown to age, total atrial conduction time and concentrations of 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

External links

• SPINA Thyr: Open source software for calculating GT and GD
• Package "SPINA" for the statistical environment R

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