Thyroid's 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).[7] 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.

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]

SPINA-GT is elevated in primary hyperthyroidism[8][9] and reduced in both primary hypothyroidism[10][11][12][9] and untreated autoimmune thyroiditis.[13] It has been observed to correlate (with positive direction) to resting energy expenditure,[14] resting heart rate,[15] the colour Doppler ultrasound pattern[16] and thyroid volume,[2][7] and (with negative direction) to thyroid autoantibody titres, which reflect organ destruction due to autoimmunity.[17] Elevated SPINA-GT in Graves' disease is reversible with antithyroid treatment.[14] While SPINA-GT is significantly altered in primary thyroid disorders, it is insensitive to disorders of secondary nature (e.g. pure pituitary diseases).[3]

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.[18]

In clinical trials SPINA-GT was significantly elevated in patients with Graves' disease and toxic adenoma compared to normal subjects.[2][8] It is also elevated in diffuse and nodular goiters, and reduced in untreated autoimmune thyroiditis.[2][13] 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]

Calculating SPINA-GT has proved to be useful in challenging clinical situations, e.g. for differential diagnosis of subclinical hypothyroidism and elevated TSH concentration due to type 2 allostatic load (as it is typical for obesity and certain psychiatric diseases). For this purpose, its usage has been recommended in sociomedical assessment.[19]

Correlation of SPINA-GT with creatinine clearance suggests a negative influence of uremic toxins on thyroid biology.[20][21] In the initial phase of major non-thyroidal illness syndrome (NTIS) SPINA-GT may be temporarily elevated.[22][23] In chronic NTIS[24] as well as in certain non-critical chronic diseases, e.g. chronic fatigue syndrome[25][26] or asthma[27] 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.[28] 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.[28] In two other studies from China, SPINA-GT correlated with negative direction to markers of obesity including body mass index, waist circumference and waist to hip ratio.[29][30] This doesn't seem to be the case, however, in Western populations.[31]

In women, therapy with Metformin results in increased SPINA-GT, in parallel to improved insulin sensitivity.[32] This observation was reproducible in men with hypogonadism, but not in men with normal testosterone concentrations,.[33] In postmenopausal women this effect was only observed in subjects on oestradiol replacement therapy.[34] Therefore, the described phenomenon seems to depend on an interaction of metformin with sex hormones.[33][35] In hyperthyroid[8] men both SPINA-GT and SPINA-GD negatively correlate to erectile function, intercourse satisfaction, orgasmic function and sexual desire. Likewise, in women with thyrotoxicosis elevated thyroid's secretory capacity predicts depression and sexual dysfunction.[36] 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.[37]

In patients with autoimmune thyroiditis a gluten-free diet results in increased SPINA-GT (in parallel to sinking autoantibody titres).[38] Statin therapy has the same effect, but only if supply with vitamin D is sufficient.[39] Accordingly, substitution therapy with 25-hydroxyvitamin D leads to rising secretory capacity.[40][41][42][43] This effect is potentiated by substitution therapy with myo-inositol[44] and selenomethionine[40][41][45] or, in women, with dehydroepiandrosterone,[46] but impaired in males with early-onset androgenic alopecia.[47] The effects of vitamin D and selenomethionine are attenuated in hyperprolactinaemia, suggesting an inhibitory effect of prolactin.[48] Although both vitamin D supplementation and gluten-free diet result in increased SPINA-GT, there seems to be a complex interaction between both therapeutic measures, since vitamin D treatment is only able to elevate the thyroid's secretory capacity in subjects not following any dietary recommendation.[49]

On the other hand, men treated with spironolactone are faced with decreasing SPINA-GT (in addition to rising thyroid antibody titres).[50] It has, therefore, been concluded that spironolactone may aggravate thyroid autoimmunity in men.[50]

In subjects with type 2 diabetes, treatment with beta blockers resulted in decreased SPINA-GT, suggesting sympathetic innervation to contribute to the control of thyroid function.[51] In diabetic women, but not in men, SPINA-GT shows a positive correlation to the β-C-terminal cross-linked telopeptides of type I collagen (β-CTX), a marker of bone resorption.[52] In both diabetic and non-diabetic persons it correlates (negatively) with age and (positively) with the concentrations of troponin T and HbA1c.[53]

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.[54] This applies to both incidence and event-free survival.[54] Likewise, SPINA-GT is elevated in a significant subgroup of patients with takotsubo syndrome.[55] 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.[56][9]

Among subjects with Parkinson's disease, SPINA-GT is significantly elevated in tremor-dominant and mixed subtypes compared to the akinetic-rigid type.[57]

Specific secretory capacity (SPINA-GTs) is reduced in obesity[2] and autoimmune thyroiditis.[7][58]

Endocrine disruptors may affect stimulated thyroid output, as demonstrated by a positive correlation of SPINA-GT with exposure to 2-hydroxynaphthalene (2-NAP),[59] urinary mercury concentration[60] and the excretion of certain phthalate metabolites,[61] and negative correlation with combined exposure to polycyclic aromatic hydrocarbons (PAHs)[59] and nickel.[62]