Sum activity of peripheral deiodinases

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Sum activity of peripheral deiodinases
Synonyms SPINA-GD, GD, deiodination capacity, total deiodinase activity
Reference range 20–40 nmol/s
Test ofMaximum amount of T3 produced from T4 by peripheral deiodinases
MeSH D013960
LOINC 82367-4

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 [a] ) 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.

Contents

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

[FT4]: Serum free T4 concentration (in pmol/L)
[FT3]: Serum free T3 concentration (in pmol/L)
[TT3]: Serum total T3 concentration (in nmol/L)
: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 L−1)
: Clearance exponent for T3 (8e-6 sec−1) (i. e., reaction rate constant for degradation)
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.

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. [4]

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, [5] body mass index [3] [6] [7] and thyrotropin levels in humans, [8] [9] and that it is reduced in nonthyroidal illness with hypodeiodination. [6] [10] [11] [12] [13] 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. [14] [15] [16] [17] [18] 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. [4]

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). [19] SPINA-GD may therefore be an effective biomarker for the differential diagnosis of thyrotoxicosis. [20] [21]

Compared to healthy subjects, SPINA-GD is significantly reduced in euthyroid sick syndrome. [22]

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. [9] 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 [23] [24] and the correlation of SPINA-GD to thyrotropin concentration is lost. [25] 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. [26]

SPINA-GD is elevated in obesity. This applies to both the metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO) phenotypes. [27] 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, [28] confirming observations in the NHANES dataset [29] and in a Chinese study. [30] 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. [28] 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. [31]

SPINA-GD is reduced in low-T3 syndrome [32] and certain chronic diseases, e.g. chronic fatigue syndrome, [33] [4] chronic kidney disease, [34] [35] short bowel syndrome [36] or geriatric asthma. [37] In Graves' disease, SPINA-GD is initially elevated but decreases with antithyroid treatment in parallel to declining TSH receptor autoantibody titres. [5] 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. [38] 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. [39]

In certain psychiatric diseases, including major depression, bipolar disorder and schizophrenia SPINA-GD is reduced compared to healthy controls. [40] This observation is supported by negative correlation of SPINA-GD with the depression percentiles in the Hospital Anxiety and Depression Scale (HADS). [41]

In hyperthyroid [42] 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. [14] [15] [16] [17]

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). [43] In the general population it is, however, positively associated with the bone mineral density of the femoral neck and with reduced risk of osteoporosis. [44] 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. [45]

Deiodination capacity proved to be an independent predictor of substitution dose in several trials that included persons on replacement therapy with levothyroxine. [46] [47]

Probably as a consequence of non-thyroidal illness syndrome, SPINA-GD predicts mortality in trauma [22] and postoperative atrial fibrillation in patients undergoing cardiac surgery. [12] 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. [22] Correlations were also shown to age, total atrial conduction time, and concentrations of 3,5-diiodothyronine and B-type natriuretic peptide. [12] SPINA-GD also correlates with several components of the kynurenine pathway, which might mirror an assosication to a pro-inflammatory milieu. [48] Accordingly, in a population suffering from pyogenic liver abscess SPINA-GD correlated to markers of malnutrition, inflammation and liver failure. [32] 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. [49] Euthyroid sick syndrome may be the reason for variations of SPINA-GD in subjects treated with immune checkpoint inhibitors for cancer as well. [50]

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) [51] and urine concentrations of cadmium and phthalate metabolites [52] [53] [54] , negative correlation to paraben, mercury and bisphenol A concentration [55] [52] [53] and a nonlinear association to the concentrations of per- and polyfluoroalkyl substances [56] . In a cohort of manganese-exposed workers, SPINA-GD responded to a tenfold increase in concentrations of titanium, nickel, selenium and strontium. [57]

In a longitudinal evaluation of a large sample of the general US population over 10 years, reduced SPINA-GD significantly predicted reduced overall survival [58] .

See also

Notes

  1. ↑ SPINA is an acronym for "structure parameter inference approach".

Related Research Articles

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

<span class="mw-page-title-main">Iodothyronine deiodinase</span> Class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease, and autoimmune thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed.

<span class="mw-page-title-main">Thyroid hormone resistance</span> Medical condition

Thyroid hormone resistance (also resistance to thyroid hormone (RTH), and sometimes Refetoff syndrome) describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, or not completely suppressed as would be expected. The first report of the condition appeared in 1967. Essentially this is decreased end organ responsiveness to thyroid hormones. A new term "impaired sensitivity to thyroid hormone" has been suggested in March 2014 by Refetoff et al.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when an overactive thyroid leads to hypermetabolism, which can cause death from cardiac arrest or multiple organ failure.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

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<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine, also known as rT3, is an isomer of triiodothyronine (T3).

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<span class="mw-page-title-main">Allan–Herndon–Dudley syndrome</span> Medical condition

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<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

Deiodinase (monodeiodinase) is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

<span class="mw-page-title-main">Thyroid's secretory capacity</span> Medical diagnostic method

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

<span class="mw-page-title-main">3,5-Diiodothyronine</span> Chemical compound

3,5-Diiodothyronine (3,5-T2) is an active thyroid hormone within the class of iodothyronines. It has two iodine atoms at positions 3 and 5 of its inner ring.

<span class="mw-page-title-main">Jostel's TSH index</span> Medical diagnostic method

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI), is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial. It is also recommended for purposes of differential diagnosis in the sociomedical expert assessment.

<span class="mw-page-title-main">SimThyr</span> Medical research simulation software

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