Thyroid's secretory capacity

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Thyroid's secretory capacity
Reference ranges for TSH, FT4, JTI and SPINA-GT.svg
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 ofMaximum amount of T4 produced by the thyroid in one second
MeSH D013960
LOINC 82368-2

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 [lower-alpha 1] ) is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit (e.g. one second). [2] [3]

Contents

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

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

[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)
: 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), i. e., reaction rate constant for degradation
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] [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 VT (as determined e.g. by ultrasonography)

,

i.e.

or

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. SPINA-GT percentiles.svg
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 [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). For this purpose, its usage has been recommended in sociomedical assessment. [20]

Pathophysiological and therapeutic implications

In patients suffering from toxic adenoma, toxic multinodular goitre and Graves’ disease SPINA-GT significantly decreases due to radioiodine therapy. [19]

Correlation of SPINA-GT with creatinine clearance suggests a negative influence of uremic toxins on thyroid biology. [21] [22] In the initial phase of major non-thyroidal illness syndrome (NTIS) SPINA-GT may be temporarily elevated. [23] [24] In chronic NTIS [25] as well as in certain non-critical chronic diseases, e.g. chronic fatigue syndrome [26] [27] or asthma [28] 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. [29] 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. [29] 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. [30] [31] This doesn't seem to be the case, however, in Western populations. [32]

In women, therapy with Metformin results in increased SPINA-GT, in parallel to improved insulin sensitivity. [33] [34] This observation was reproducible in men with hypogonadism, but not in men with normal testosterone concentrations,. [35] In postmenopausal women this effect was only observed in subjects on oestradiol replacement therapy. [36] Therefore, the described phenomenon seems to depend on an interaction of metformin with sex hormones. [35] [37] 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. [38] 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. [39] In a large study from mainland China, SPINA-GT was elevated in certain psychiatric diseases including bipolar disorder and schizophrenia. [40] In bipolar disorder with manic or mixed episodes it was higher than in cases with depressive episodes. [40]

SPINA-GT is reduced in persons suffering from hidradenitis suppurativa compared to healthy controls with the same sex and age distribution. [41] This phenomenon has been ascribed to B-cell-mediated hypothyroidism, i.e. hypothyroid Graves' disease due to inhibiting TSH receptor autoantibodies (iTRAb). [41]

In patients with autoimmune thyroiditis a gluten-free diet results in increased SPINA-GT (in parallel to sinking autoantibody titres). [42] Statin therapy has the same effect, but only if supply with vitamin D is sufficient. [43] Accordingly, substitution therapy with 25-hydroxyvitamin D leads to rising secretory capacity. [44] [45] [46] [47] This effect is potentiated by substitution therapy with myo-inositol [48] and selenomethionine [44] [45] [49] or, in women, with dehydroepiandrosterone, [50] but impaired in males with early-onset androgenic alopecia. [51] The effects of vitamin D and selenomethionine are attenuated in hyperprolactinaemia, suggesting an inhibitory effect of prolactin. [52] 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. [53]

On the other hand, men treated with spironolactone are faced with decreasing SPINA-GT (in addition to rising thyroid antibody titres). [54] It has, therefore, been concluded that spironolactone may aggravate thyroid autoimmunity in men. [54]

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. [55] 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. [56] In both diabetic and non-diabetic persons it correlates (negatively) with age and (positively) with the concentrations of troponin T and HbA1c. [57]

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. [58] This applies to both incidence and event-free survival. [58] Likewise, SPINA-GT is elevated in a significant subgroup of patients with takotsubo syndrome, [59] especially in non-survivors. [60] 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. [61] 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. [62] [9]

Among subjects with Parkinson's disease, SPINA-GT is significantly elevated in tremor-dominant and mixed subtypes compared to the akinetic-rigid type. [63]

Specific secretory capacity (SPINA-GTs) is reduced in obesity [2] and autoimmune thyroiditis. [7] [64]

Endocrine disruptors may affect stimulated thyroid output, as demonstrated by a positive correlation of SPINA-GT with exposure to 2-hydroxynaphthalene (2-NAP), [65] urinary mercury concentration [66] and the excretion of certain phthalate metabolites, [67] and negative correlation with combined exposure to polycyclic aromatic hydrocarbons (PAHs) [65] and nickel. [68] Additionally, SPINA-GT was altered in young people exposed to butylparaben. [69]

See also

Notes

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

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Endocrine neck-gland secretes excess hormones affecting metabolism

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. A slightly broader term is autoimmune thyroiditis, identical other than that it is also used to describe a similar condition without a goiter.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">De Quervain's thyroiditis</span> Medical condition

De Quervain's thyroiditis, also known as subacute granulomatous thyroiditis or giant cell thyroiditis, is a member of the group of thyroiditis conditions known as resolving thyroiditis. People of all ages and genders may be affected.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

Postpartum thyroiditis refers to thyroid dysfunction occurring in the first 12 months after pregnancy and may involve hyperthyroidism, hypothyroidism or the two sequentially. According to the National Institute of Health, postpartum thyroiditis affects about 8% of pregnancies. There are, however, different rates reported globally. This is likely due to the differing amounts of average postpartum follow times around the world, and due to humans' own innate differences. For example, in Bangkok, Thailand the rate is 1.1%, but in Brazil it is 13.3%. The first phase is typically hyperthyroidism. Then, the thyroid either returns to normal or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Hashimoto's encephalopathy</span> Human disease (neurological condition)

Hashimoto's encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to corticosteroids. It is associated with Hashimoto's thyroiditis, and was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the condition's relationship to the endocrine system is widely disputed. It is recognized as a rare disease by the NIH Genetic and Rare Diseases Information Center.

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

Myxedema coma is an extreme or decompensated form of hypothyroidism and while uncommon, is potentially lethal. A person may have laboratory values identical to a "normal" hypothyroid state, but a stressful event precipitates the myxedema coma state, usually in the elderly. Primary symptoms of myxedema coma are altered mental status and low body temperature. Low blood sugar, low blood pressure, hyponatremia, hypercapnia, hypoxia, slowed heart rate, and hypoventilation may also occur. Myxedema, although included in the name, is not necessarily seen in myxedema coma. Coma is also not necessarily seen in myxedema coma, as patients may be obtunded without being comatose.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

Antithyroid autoantibodies (or simply antithyroid antibodies) are autoantibodies targeted against one or more components on the thyroid. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (anti-TPO antibodies, TPOAb), thyrotropin receptor antibodies (TRAb) and thyroglobulin antibodies (TgAb). TRAb's are subdivided into activating, blocking and neutral antibodies, depending on their effect on the TSH receptor. Anti-sodium/iodide (Anti–Na+/I) symporter antibodies are a more recent discovery and their clinical relevance is still unknown. Graves' disease and Hashimoto's thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-TPO antibodies are most commonly associated with Hashimoto's thyroiditis and activating TRAb's are most commonly associated with Graves' disease. Thyroid microsomal antibodies were a group of anti-thyroid antibodies; they were renamed after the identification of their target antigen (TPO).

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. 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.

<span class="mw-page-title-main">Jostel's TSH index</span>

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI), is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial. It is also recommended for purposes of differential diagnosis in the sociomedical expert assessment.

<span class="mw-page-title-main">SimThyr</span> Medical research simulation software

SimThyr is a free continuous dynamic simulation program for the pituitary-thyroid feedback control system. The open-source program is based on a nonlinear model of thyroid homeostasis. In addition to simulations in the time domain the software supports various methods of sensitivity analysis. Its simulation engine is multi-threaded and supports multiple processor cores. SimThyr provides a GUI, which allows for visualising time series, modifying constant structure parameters of the feedback loop, storing parameter sets as XML files and exporting results of simulations in various formats that are suitable for statistical software. SimThyr is intended for both educational purposes and in-silico research.

The Thyrotroph Thyroid Hormone Sensitivity Index is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. Today it is also used to get an estimate for the set point of thyroid homeostasis, especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses.

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