Thyroid's secretory capacity

Specific secretory capacity

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

${\displaystyle {\hat {G}}_{TS}={\frac {{\hat {G}}_{T}}{{V}_{T}}}}$,

i.e.

${\displaystyle {\hat {G}}_{TS}={\frac {\beta _{T}(D_{T}+[TSH])(1+K_{41}[TBG]+K_{42}[TBPA])[FT_{4}]}{\alpha _{T}[TSH]{V}_{T}}}}$

or

${\displaystyle {\hat {G}}_{TS}={\frac {\beta _{T}(D_{T}+[TSH])[TT_{4}]}{\alpha _{T}[TSH]{V}_{T}}}}$

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

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.

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]

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]