Thyroid's secretory capacity

Thyroid's secretory capacity
Reference ranges for TSH, FT4, JTI and SPINA-GT
Reference ranges for SPINA-GT and other thyroid function tests
SynonymsSPINA-GT, GT, T4 output, thyroid hormone output, thyroid's incretory capacity, functional thyroid capacity[1]
Reference range1.41–8.67 pmol/s
Test ofMaximum amount of T4 produced by the thyroid in one second
MeSHD013960
LOINC82368-2

Thyroid's secretory capacity (GT, also referred to as thyroid's incretory capacity, maximum thyroid hormone output, T4 output or, if calculated from serum levels of thyrotropin and thyroxine, as SPINA-GT) is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit (e.g. one second).[2][3]

How to determine GT

Experimentally, GT can be determined by stimulating the thyroid with a high thyrotropin concentration (e.g. by means of rhTSH, i.e. recombinant human thyrotropin) and measuring its output in terms of T4 production, or by measuring the serum concentration of protein-bound iodine-131 after administration of radioiodine.[4] These approaches are, however, either costly or accompanied by significant exposure to radiation.

In vivo, GT can also be estimated from equilibrium levels of TSH and T4 or free T4. In this case it is calculated with

or

: Theoretical (apparent) secretory capacity (SPINA-GT)
: Dilution factor for T4 (reciprocal of apparent volume of distribution, 0.1 L−1)
: Clearance exponent for T4 (1.1e-6 sec−1)
K41: Binding constant T4-TBG (2e10 L/mol)
K42: Binding constant T4-TBPA (2e8 L/mol)
DT: EC50 for TSH (2.75 mU/L)[2][5]

The method is based on mathematical models of thyroid homeostasis.[2][3] Calculating the secretory capacity with one of these equations is an inverse problem. Therefore, certain conditions (e.g. stationarity) have to be fulfilled to deliver a reliable result.

Specific secretory capacity

The ratio of SPINA-GT and thyroid volume VT (as determined e.g. by ultrasonography)

,

i.e.

or

is referred to as specific thyroid capacity (SPINA-GTs).[6] It is a measure for how much one millilitre of thyroid tissue can produce under conditions of maximum stimulation. Thereby, SPINA-GTs is an estimate for the endocrine quality of thyroid tissue.

Reference Range

SPINA-GT percentiles
Percentiles for thyroid's secretory capacity (SPINA-GT) along with reference ranges for Jostel's TSH index (TSHI or JTI) and univariable reference ranges for thyrotropin (TSH) and free thyroxine (FT4), shown in the two-dimensional phase plane defined by serum concentrations of TSH and FT4.
Lower limitUpper limitUnit
1.41[2]8.67[2]pmol/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.[2]

Clinical significance

Validity

SPINA-GT is elevated in primary hyperthyroidism[7] and reduced in both primary hypothyroidism[8][9][10] and untreated autoimmune thyroiditis.[11] It has been observed to correlate (with positive direction) to resting energy expenditure,[12] resting heart rate[13] and thyroid volume,[2][6] and (with negative direction) to thyroid autoantibody titres, which reflect organ destruction due to autoimmunity.[14] Elevated SPINA-GT in Graves' disease is reversible with antithyroid treatment.[12] While SPINA-GT is significantly altered in primary thyroid disorders, it is insensitive to disorders of secondary nature (e.g. pure pituitary diseases).[3]

Reliability

In silico experiments with Monte Carlo simulations demonstrated that both SPINA-GT and SPINA-GD can be estimated with sufficient reliability, even if laboratory assays have limited accuracy.[3] This was confirmed by longitudinal in vivo studies that showed that GT has lower intraindividual variation (i.e. higher reliability) than TSH, FT4 or FT3.[15]

Clinical utility

In clinical trials SPINA-GT was significantly elevated in patients suffering from Graves' disease and toxic adenoma compared to normal subjects.[2][7] It is also elevated in diffuse and nodular goiters, and reduced in untreated autoimmune thyroiditis.[2][11] In patients with toxic adenoma it has higher specificity and positive likelihood ratio for diagnosis of thyrotoxicosis than serum concentrations of thyrotropin, free T4 or free T3.[2] GT's specificity is also high in thyroid disorders of secondary or tertiary origin.[3]

Pathophysiological and therapeutic implications

Correlation of SPINA-GT with creatinine clearance suggests a negative influence of uremic toxins on thyroid biology.[16][17] In the initial phase of major non-thyroidal illness syndrome (NTIS) SPINA-GT may be temporarily elevated.[18][19] In chronic NTIS[20] as well as in certain non-critical chronic diseases, e.g. chronic fatigue syndrome[21] or asthma[22] SPINA-GT is slightly reduced.

According to the results of a community-based study in China it was associated to sleep duration and exercise habits.[23] With respect to iodine supply, it showed a complex U-shaped pattern, being reduced in subjects consuming iodine-rich food, but elevated in situations of iodine excess.[23] In another study from China, SPINA-GT correlated with negative direction to markers of obesity including body mass index, waist circumference and waist to hip ratio.[24] This doesn't seem to be the case, however, in Western populations.[25]

In women, therapy with Metformin results in increased SPINA-GT, in parallel to improved insulin sensitivity.[26] This observation was reproducible in men with hypogonadism, but not in men with normal testosterone concentrations,[27]. In postmenopausal women this effect was only observed in subjects on oestradiol replacement therapy.[28] Therefore, the described phenomenon seems to depend on an interaction of metformin with sex hormones.[27][29] In hyperthyroid[7] men both SPINA-GT and SPINA-GD negatively correlate to erectile function, intercourse satisfaction, orgasmic function and sexual desire. Likewise, in women suffering from thyrotoxicosis elevated thyroid's secretory capacity predicts depression and sexual dysfunction.[30] Conversely, in androgen-deficient men with concomitant autoimmune thyroiditis, substitution therapy with testosterone leads to a decrease in thyroid autoantibody titres and an increase in SPINA-GT.[31]

In patients with autoimmune thyroiditis a gluten-free diet results in increased SPINA-GT (in parallel to sinking autoantibody titres).[32] Statin therapy has the same effect, but only if supply with vitamin D is sufficient.[33] Accordingly, substitution therapy with 25-hydroxyvitamin D leads to rising secretory capacity.[34][35][36] This effect is potentiated by substitution therapy with selenomethionine[34][35][37] or, in women, with dehydroepiandrosterone,[38] but impaired in males with early-onset androgenic alopecia.[39] The effects of vitamin D and selenomethionine are attenuated in hyperprolactinaemia, suggesting an inhibitory effect of prolactin.[40]

On the other hand, men treated with spironolactone are faced with decreasing SPINA-GT (in addition to rising thyroid antibody titres).[41] It has, therefore, been concluded that spironolactone may aggravate thyroid autoimmunity in men.[41]

A study in euthyroid subjects with structural heart disease found that increased SPINA-GT predicts the risk of malignant arrhythmia including ventricular fibrillation and ventricular tachycardia.[42] This applies to both incidence and event-free survival.[42] Likewise, SPINA-GT is elevated in a significant subgroup of patients with takotsubo syndrome.[43] On the other hand, two studies found negative correlation between SPINA-GT and markers of dispersion in cardiac repolarisation, including Tp-e interval, JT interval, Tp-e/ QT ratio and Tp-e/QTc ratio. These results suggest that reduced thyroid function may trigger cardiovascular mortality as well.[44][45]

Among subjects with Parkinson's disease, SPINA-GT is significantly eleveated in tremor-dominant and mixed subtypes compared to the akinetic-rigid type.[46]

Specific secretory capacity (SPINA-GTs) is reduced in obesity[2] and autoimmune thyroiditis.[6][47]

Endocrine disruptors may affect stimulated thyroid output, as demonstrated by a positive correlation of SPINA-GT with urinary mercury concentration[48] and the excretion of certain phthalate metabolites.[49]

See also

References

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