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.
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]
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]
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 SPINA-GD significantly decreases due to low-dose
radioiodine therapy 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]
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).[42] In the general population it is, however, positively associated with the bone mineral density of the femoral neck and with reduced risk of osteoporosis.[43] 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.[44]
Deiodination capacity proved to be an independent predictor of substitution dose in several trials that included persons on replacement therapy with
levothyroxine.[45][46]
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)[50] and urine concentrations of
cadmium and
phthalate metabolites[51][52][53] and negative correlation to
paraben,
mercury and
bisphenol A concentration.[54][51][52] In a cohort of manganese-exposed workers, SPINA-GD responded to a tenfold increase in concentrations of titanium, nickel, selenium and strontium.[55]
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