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) is the maximum stimulated amount of
thyroxine
File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4
rect 376 268 820 433 Thyroid-stimulating hormone
rect 411 200 849 266 Thyrotropin-releasing hormone
rect 297 168 502 200 Hypothalamus
rect 66 216 386 25 ...
that the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
can produce in a given time-unit (e.g. one second).
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
Iodine-131 (131I, I-131) is an important radioisotope of iodine discovered by Glenn Seaborg and John Livingood in 1938 at the University of California, Berkeley. It has a radioactive decay half-life of about eight days. It is associated with nuc ...
after administration of
radioiodine. These approaches are, however, costly and accompanied by significant exposure to radiation.
''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
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)
''K''
41:
Binding constant
The binding constant, or affinity constant/association constant, is a special case of the equilibrium constant ''K'', and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and lig ...
T4-TBG (2e10 L/mol)
''K''
42: Binding constant T4-TBPA (2e8 L/mol)
''D''
''T'':
EC50 for TSH (2.75 mU/L)
[
The method is based on mathematical models of thyroid homeostasis.] Calculating the secretory capacity with one of these equations is an inverse problem
An inverse problem in science is the process of calculating from a set of observations the causal factors that produced them: for example, calculating an image in X-ray computed tomography, source reconstruction in acoustics, or calculating the ...
. 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
Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies fr ...
)
,
i.e.
or
is referred to as ''specific thyroid capacity'' (SPINA-GTs). It is a measure for how much one millilitre
The litre (international spelling) or liter (American English spelling) (SI symbols L and l, other symbol used: ℓ) is a metric unit of volume. It is equal to 1 cubic decimetre (dm3), 1000 cubic centimetres (cm3) or 0.001 cubic metre (m3). ...
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
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.[
]
Clinical significance
Validity
SPINA-GT is elevated in primary hyperthyroidism
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 ...
and reduced in both primary hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
[ and untreated autoimmune thyroiditis.] It has been observed to correlate (with positive direction) to resting energy expenditure, resting heart rate, the colour Doppler ultrasound pattern and thyroid volume, and (with negative direction) to thyroid autoantibody titres, which reflect organ destruction due to autoimmunity. Elevated SPINA-GT in Graves' disease
Graves' disease (german: Morbus Basedow), 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 thyro ...
is reversible with antithyroid treatment. While SPINA-GT is significantly altered in primary thyroid disorders, it is insensitive to disorders of secondary nature (e.g. pure pituitary diseases).
Reliability
In silico
In biology and other experimental sciences, an ''in silico'' experiment is one performed on computer or via computer simulation. The phrase is pseudo-Latin for 'in silicon' (correct la, in silicio), referring to silicon in computer chips. It ...
experiments with Monte Carlo simulation
Monte Carlo methods, or Monte Carlo experiments, are a broad class of computational algorithms that rely on repeated random sampling to obtain numerical results. The underlying concept is to use randomness to solve problems that might be determini ...
s demonstrated that both SPINA-GT and SPINA-GD can be estimated with sufficient reliability, even if laboratory assays have limited accuracy. 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.
Clinical utility
In clinical trials SPINA-GT was significantly elevated in patients with Graves' disease
Graves' disease (german: Morbus Basedow), 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 thyro ...
and toxic adenoma compared to normal subjects. It is also elevated in diffuse and nodular goiter
A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.
Worldwide, over 90% of goitre cases are caused by iodine deficiency. The term is ...
s, and reduced in untreated autoimmune thyroiditis. In patients with toxic adenoma it has higher specificity and positive likelihood ratio for diagnosis of thyrotoxicosis than serum concentrations of thyrotropin
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 metabolis ...
, free T4 or free T3. GT's specificity is also high in thyroid disorders of secondary or tertiary origin.
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.
Pathophysiological and therapeutic implications
Correlation of SPINA-GT with creatinine clearance suggests a negative influence of uremic toxins on thyroid biology. In the initial phase of major non-thyroidal illness syndrome (NTIS) SPINA-GT may be temporarily elevated. In chronic NTIS as well as in certain non-critical chronic diseases, e.g. chronic fatigue syndrome
Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The Pathophysiology, causes and mechanisms of the disease are not fully understood. Distinguishing c ...
or asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, ...
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. 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. 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. This doesn't seem to be the case, however, in Western populations.
In women, therapy with Metformin
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
results in increased SPINA-GT, in parallel to improved insulin sensitivity. This observation was reproducible in men with hypogonadism, but not in men with normal testosterone concentrations,. In postmenopausal women this effect was only observed in subjects on oestradiol replacement therapy. Therefore, the described phenomenon seems to depend on an interaction of metformin with sex hormones. In hyperthyroid men both SPINA-GT and SPINA-GD negatively correlate to erectile function, intercourse satisfaction, orgasmic function and sexual desire
Sexual desire is an emotion and motivational state characterized by an interest in sexual objects or activities, or by a drive to seek out sexual objects or to engage in sexual activities. It is an aspect of sexuality, which varies significantly ...
. Likewise, in women with thyrotoxicosis elevated thyroid's secretory capacity predicts depression and sexual dysfunction. Conversely, in androgen-deficient men with concomitant autoimmune thyroiditis
Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...
, substitution therapy with testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristic ...
leads to a decrease in thyroid autoantibody titres and an increase in SPINA-GT.
In patients with autoimmune thyroiditis a gluten-free diet
A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of proteins found in wheat (and all of its species and hybrids, such as spelt, kamut, and triticale), as well as barley, rye, and oats. The inclu ...
results in increased SPINA-GT (in parallel to sinking autoantibody titres). Statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
L ...
therapy has the same effect, but only if supply with vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 ...
is sufficient. Accordingly, substitution therapy with 25-hydroxyvitamin D leads to rising secretory capacity. This effect is potentiated by substitution therapy with myo-inositol and selenomethionine
Selenomethionine (SeMet) is a naturally occurring amino acid. The L-selenomethionine enantiomer is the main form of selenium found in Brazil nuts, cereal grains, soybeans, and grassland legumes, while ''Se''-methylselenocysteine, or its γ-glu ...
or, in women, with dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functi ...
, but impaired in males with early-onset androgenic alopecia. The effects of vitamin D and selenomethionine are attenuated in hyperprolactinaemia, suggesting an inhibitory effect of prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the p ...
. 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.
On the other hand, men treated with spironolactone
Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressur ...
are faced with decreasing SPINA-GT (in addition to rising thyroid antibody titres). It has, therefore, been concluded that spironolactone may aggravate thyroid autoimmunity in men.
In subjects with type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
, treatment with beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack (secondary prevention). They are al ...
s resulted in decreased SPINA-GT, suggesting sympathetic innervation to contribute to the control of thyroid function. 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.
A study in euthyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
subjects with structural heart disease Structural heart disease, also known as structural cardiac disease, is a collection of heart diseases that includes heart failure, coronary artery disease, hypertrophic cardiomyopathy, and congenital heart disease
A congenital heart defect (CHD), ...
found that increased SPINA-GT predicts the risk of malignant arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
including ventricular fibrillation
Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no ...
and ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
. This applies to both incidence and event-free survival.[ Likewise, SPINA-GT is elevated in a significant subgroup of patients with takotsubo syndrome. 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.][
Among subjects with ]Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms bec ...
, SPINA-GT is significantly eleveated in tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...
-dominant and mixed subtypes compared to the akinetic-rigid type.
Specific secretory capacity (SPINA-GTs) is reduced in obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
[ and ]autoimmune thyroiditis
Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...
.
Endocrine disruptor
Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause c ...
s may affect stimulated thyroid output, as demonstrated by a positive correlation of SPINA-GT with urinary mercury concentration and the excretion of certain phthalate
Phthalates (, ), or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften ...
metabolites.
See also
* Thyroid function tests
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes are connected by a thin band of Connective tissue, tissue cal ...
* 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
References
External links
SPINA Thyr: Open source software for calculating GT and GD
* Package
SPINA
for the statistical environment R
{{Authority control
Chemical pathology
Blood tests
Endocrine procedures
Thyroidological methods
Thyroid homeostasis
Structure parameters of thyroid function
Static endocrine function tests