Thyroid's secretory capacity

Thyroid's secretory capacity (G_T, 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^[a]) is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit (e.g. one second).^[2][3]

Thyroid's secretory capacity
Reference ranges for SPINA-GT and other thyroid function tests
Synonyms	SPINA-GT, GT, T4 output, thyroid hormone output, thyroid's incretory capacity, functional thyroid capacity[1]
Reference range	1.41–8.67 pmol/s
Test of	Maximum amount of T4 produced by the thyroid in one second
MeSH	D013960
LOINC	82368-2

How to determine GT

Experimentally, G_T 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, costly and accompanied by significant exposure to radiation.^[5]

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

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

or

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

[TSH]: Serum thyrotropin concentration (in mIU/L or μIU/mL)
[FT4]: Serum free T4 concentration (in pmol/L)
[TT4]: Serum total T4 concentration (in nmol/L)
${\displaystyle {\hat {G}}_{T}}$: Theoretical (apparent) secretory capacity (SPINA-GT)
${\displaystyle \alpha _{T}}$: Dilution factor for T4 (reciprocal of apparent volume of distribution, 0.1 L⁻¹)
${\displaystyle \beta _{T}}$: Clearance exponent for T4 (1.1e-6 sec⁻¹), i. e., reaction rate constant for degradation
K₄₁: Binding constant T4-TBG (2e10 L/mol)
K₄₂: Binding constant T4-TBPA (2e8 L/mol)
D_T: EC₅₀ for TSH (2.75 mU/L)^[2][6]

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 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.^{[citation needed]}

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.

Lower limit	Upper limit	Unit
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^[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]

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.^[18]

Clinical utility

In clinical trials SPINA-GT was significantly elevated in patients with Graves' disease and toxic adenoma compared to normal subjects.^[2][8][19] 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).^[20] For this purpose, its usage has been recommended in sociomedical assessment.^[21]

Pathophysiological and therapeutic implications

In patients suffering from toxic adenoma, toxic multinodular goitre and Graves’ disease radioiodine therapy leads to a significant decrease of the initially elevated SPINA-GT.^[19]

Correlation of SPINA-GT with creatinine clearance suggests a negative influence of uremic toxins on thyroid biology.^[22][23] In the initial phase of major non-thyroidal illness syndrome (NTIS) SPINA-GT may be temporarily elevated.^[24][25] In chronic NTIS^[26] as well as in certain non-critical chronic diseases, e.g. chronic fatigue syndrome^[27][28] or asthma^[29] 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.^[30] 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.^[30] 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.^[31][32] This doesn't seem to be the case, however, in Western populations.^[33]

In women, therapy with Metformin results in increased SPINA-GT, in parallel to improved insulin sensitivity.^[34][35] This observation was reproducible in men with hypogonadism, but not in men with normal testosterone concentrations,.^[36] In postmenopausal women this effect was only observed in subjects on oestradiol replacement therapy.^[37] Therefore, the described phenomenon seems to depend on an interaction of metformin with sex hormones.^[36][38] 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.^[39] 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.^[40] In a large study from mainland China, SPINA-GT was elevated in certain psychiatric diseases including bipolar disorder and schizophrenia.^[41] In bipolar disorder with manic or mixed episodes it was higher than in cases with depressive episodes.^[41]

SPINA-GT is reduced in persons suffering from hidradenitis suppurativa compared to healthy controls with the same sex and age distribution.^[42] This phenomenon has been ascribed to B-cell-mediated hypothyroidism, i.e. hypothyroid Graves' disease due to inhibiting TSH receptor autoantibodies (iTRAb).^[42]

In patients with autoimmune thyroiditis a gluten-free diet results in increased SPINA-GT (in parallel to sinking autoantibody titres).^[43] Statin therapy has the same effect, but only if supply with vitamin D is sufficient.^[44] Accordingly, substitution therapy with 25-hydroxyvitamin D leads to rising secretory capacity.^{[45][46][47][48]} This effect is potentiated by substitution therapy with myo-inositol^[49] and selenomethionine^[45][46][50] or, in women, with dehydroepiandrosterone,^[51] but impaired in males with early-onset androgenic alopecia.^[52] The effects of vitamin D and selenomethionine are attenuated in hyperprolactinaemia, suggesting an inhibitory effect of prolactin.^[53] 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.^[54]

On the other hand, men treated with spironolactone are faced with decreasing SPINA-GT (in addition to rising thyroid antibody titres).^[55] It has, therefore, been concluded that spironolactone may aggravate thyroid autoimmunity in men.^[55]

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.^[56] 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.^[57] In both diabetic and non-diabetic persons it correlates (negatively) with age and (positively) with the concentrations of troponin T and HbA1c.^[58]

SPINA-GT correlates to mechanical pain sensitivity (MPS) in quantitative sensory testing (QST) and to measures of respiratory arrhythmia in the analysis of heart rate variability, indicating a potential link to both sensorimotor and autonomic neuropathy.^[59]

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.^[60] This applies to both incidence and event-free survival.^[60] Likewise, SPINA-GT is elevated in a significant subgroup of patients with takotsubo syndrome,^[61] especially in non-survivors.^[62] A stress-mediated effect on SPINA-GT is also suggested by the observation that it is increased in persons with a history of psychological trauma.^[63] 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.^[64][9]

Among subjects with Parkinson's disease, SPINA-GT is significantly elevated in tremor-dominant and mixed subtypes compared to the akinetic-rigid type.^[65]

Specific secretory capacity (SPINA-GTs) is reduced in obesity^[2] and autoimmune thyroiditis.^[7][66]

Endocrine disruptors may affect stimulated thyroid output, as demonstrated by a positive correlation of SPINA-GT with exposure to 2-hydroxynaphthalene (2-NAP),^[67] urinary mercury concentration^[68] and the excretion of certain phthalate metabolites,^[69] and negative correlation with combined exposure to polycyclic aromatic hydrocarbons (PAHs)^[67] and nickel.^[70] Additionally, SPINA-GT is altered in persons exposed to butylparaben and propylparaben.^[71][72]

In a longitudinal evaluation of a large sample of the general US population over 10 years, reduced SPINA-GT significantly predicted all-cause mortality.^[73]

See also

• Thyroid function tests
• Sum activity of peripheral deiodinases
• Jostel's TSH index
• Thyrotroph Thyroid Hormone Sensitivity Index
• Thyroid Feedback Quantile-based Index
• SimThyr
• SPINA-GBeta
• SPINA-GR

Notes

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