The sum activity of peripheral deiodinases (''G
D'', also referred to as deiodination capacity, total deiodinase activity or, if calculated from levels of thyroid hormones, as SPINA-GD) is the maximum amount of
triiodothyronine
Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.
Production of T3 and its prohormone thyroxine ( ...
produced per time-unit under conditions of substrate saturation.
It is assumed to reflect the activity of
deiodinase
Deiodinase (or "Monodeiodinase") is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.
Types
Types of deiodinases include:
Iodothyronine deiodinases catalyze release of iodine directly from the thyron ...
s outside the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and other isolated compartments. GD is therefore expected to reflect predominantly the activity of
type I deiodinase.
How to determine GD
''G
D'' can be determined experimentally by exposing a
cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
system to saturating concentrations of
T4 and measuring the
T3 production. Whole body deiodination activity can be assessed by measuring production of radioactive iodine after loading the organism with marked thyroxine.
However, both approaches are faced with draw-backs. Measuring deiodination in cell culture delivers little, if any, information on total deiodination activity. Using marked thyroxine exposes the body to
thyrotoxicosis
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 radioactivity. Additionally, it is not possible to differentiate step-up reactions resulting in T3 production from the step-down reaction catalyzed by type 3 deiodination, which mediates production of
reverse T3
Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).
Reverse T3 is the third-most common iodothyronine the thyroid gland releases into the bloodstream, at 0.9 ...
. Distinguishing the contribution of distinct deiodinases is possible, however, by sequential approaches using deiodinase-specific blocking agents, but this approach is cumbersome and time-consuming.
''In vivo'', it may therefore be beneficial to estimate ''G
D'' from equilibrium levels of T4 and T3. It is obtained with
or
:
Dilution
Dilution may refer to:
* Reducing the concentration of a chemical
* Serial dilution, a common way of going about this reduction of concentration
* Homeopathic dilution
* Dilution (equation), an equation to calculate the rate a gas dilutes
*Tradema ...
factor for T3 (reciprocal of apparent volume of distribution, 0.026 L
−1)
:
Clearance exponent for T3 (8e-6 sec
−1)
''K''
''M''1:
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 li ...
of type-1-deiodinase (5e-7 mol/L)
''K''
30: Binding constant T3-TBG (2e9 L/mol)
The method is based on mathematical models of thyroid homeostasis.
[ Calculating deiodinase activity 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.
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-GD correlates to the T4-T3 conversion rate in slow tissue pools, as determined with isotope-based measurements in healthy volunteers. It was also shown that GD correlates with resting energy expenditure Resting metabolic rate (RMR) is whole-body mammal (and other vertebrate) metabolism during a time period of strict and steady ''resting conditions'' that are defined by a combination of assumptions of physiological homeostasis and biological equili ...
, body mass index
Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
and thyrotropin levels in humans, and that it is reduced in nonthyroidal illness with hypodeiodination. Multiple studies demonstrated SPINA-GD to rise after initiation of substitution therapy with selenium, a trace element that is essential for the synthesis of deiodinases.
Clinical utility
Compared to both healthy volunteers and subjects with 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 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 ...
, SPINA-GD is reduced in subacute thyroiditis
Subacute thyroiditis is a form of thyroiditis that can be a cause of both thyrotoxicosis and hypothyroidism. It is uncommon and can affect individuals of both sexes, occurring three times as often in women than in men. and people of all ages. The m ...
. In this condition, it has a higher specificity, positive
Positive is a property of positivity and may refer to:
Mathematics and science
* Positive formula, a logical formula not containing negation
* Positive number, a number that is greater than 0
* Plus sign, the sign "+" used to indicate a posi ...
and negative likelihood ratio
In evidence-based medicine, likelihood ratios are used for assessing the value of performing a diagnostic test. They use the sensitivity and specificity of the test to determine whether a test result usefully changes the probability that a cond ...
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 metabolism of ...
, free T4 or free T3. These measures of diagnostic utility are also high in nodular goitre
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 ...
, where SPINA-GD is elevated. Among subjects with subclinical thyrotoxicosis, calculated deiodinase activity is significantly lower in exogenous thyrotoxicosis (resulting from therapy with levothyroxine) than in true hyperthyroidism (ensuing from toxic adenoma
A thyroid adenoma is a benign tumor of the thyroid gland, that may be inactive or active (functioning autonomously) as a toxic adenoma.
Signs and symptoms
A thyroid adenoma may be clinically silent ("cold" adenoma), or it may be a functional tumor ...
, toxic multinodular goitre
Toxic multinodular goiter (TMNG), also known as multinodular toxic goiter (MNTG), is an active multinodular goiter associated with hyperthyroidism.
It is a common cause of hyperthyroidism in which there is excess production of thyroid hormones fr ...
or 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 thyr ...
). SPINA-GD may therefore be an effective biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for the differential diagnosis of thyrotoxicosis.
Compared to healthy subjects, SPINA-GD is significantly reduced in euthyroid sick syndrome
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 ...
.
Pathophysiological and therapeutic implications
Recent research revealed total deiodinase activity to be higher in untreated hypothyroid patients as long as thyroid tissue is still present. This effect may ensue from the existence of an effective TSH-deiodinase axis or TSH-T3 shunt. After total thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. In general surgery, endocrine or head and neck surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other conditi ...
or high-dose radioiodine
There are 37 known isotopes of iodine (53I) from 108I to 144I; all undergo radioactive decay except 127I, which is stable. Iodine is thus a monoisotopic element.
Its longest-lived radioactive isotope, 129I, has a half-life of 15.7 million year ...
therapy (e.g. in treated thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...
) as well as after initiation of substitution therapy with levothyroxine the activity of step-up deiodinases decreases and the correlation of SPINA-GD to thyrotropin concentration is lost.
In two large population-based cohorts within the Study of Health in Pomerania SPINA-GD was positively correlated to some markers of body composition
In physical fitness, body composition is used to describe the percentages of fat, bone, water, and muscle in human bodies. Because muscular tissue takes up less space in the body than fat tissue, body composition, as well as weight, determines ...
including body mass index
Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
(BMI), waist circumference
The waist is the part of the Human abdomen, abdomen between the rib cage and Hip (anatomy), hips. On people with slim bodies, the waist is the narrowest part of the torso.
''Waistline'' refers to the horizontal line where the waist is narrowe ...
, fat-free mass and body cell mass, confirming earlier observations in the NHANES
The National Health and Nutrition Examination Survey (NHANES) is a survey research program conducted by the National Center for Health Statistics (NCHS) to assess the health and nutritional status of adults and children in the United States, and t ...
dataset. This positive association was age-dependent and with respect to BMI significant in young subjects only, but with respect to body cell mass stronger in elderly persons.[
SPINA-GD is reduced in low-T3 syndrome] and certain 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 causes and mechanisms of the disease are not fully understood. Distinguishing core symptoms are ...
, chronic kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
, short bowel syndrome
Short bowel syndrome (SBS, or simply short gut) is a rare malabsorption disorder caused by a lack of functional small intestine. The primary symptom is diarrhea, which can result in dehydration, malnutrition, and weight loss. Other symptoms may in ...
or geriatric 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, cou ...
. 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 thyr ...
, SPINA-GD is initially elevated but decreases with antithyroid treatment in parallel to declining TSH receptor autoantibody titres. Although takotsubo syndrome (TTS) results in most cases from psychosocial stressors, thereby reflecting type 2 allostatic load
Allostatic load is "the wear and tear on the body" which accumulates as an individual is exposed to repeated or chronic stress. The term was coined by Bruce McEwen and Eliot Stellar in 1993. It represents the physiological consequences of chro ...
, SPINA-GD has been described to be reduced in TTS. This may result from concomitant non-thyroidal illness syndrome, so that the clinical phenotype represents overlapping type 1 and type 2 allostatic response.
In hyperthyroid men both SPINA-GT and SPINA-GD negatively correlate to erectile function
An erection (clinically: penile erection or penile tumescence) is a physiological phenomenon in which the penis becomes firm, engorged, and enlarged. Penile erection is the result of a complex interaction of psychological, neural, vascular, a ...
, 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 ...
. Substitution with 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-gluta ...
results in increased SPINA-GD in subjects with autoimmune thyroiditis.
In subjects with diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
SPINA-GD is positively correlated to several bone resorption markers including the N-mid fragment of osteocalcin and procollagen type I N-terminal propeptide (P1NP), as well as, however in men only, the β-C-terminal cross-linked telopeptides of type I collagen (β-CTX).
Deiodination capacity proved to be an independent predictor of substitution dose in a trial with over 300 patients on replacement therapy with levothyroxine
Levothyroxine, also known as -thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat hypothyroidism, thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also ...
.
Probably as a consequence of non-thyroidal illness syndrome, SPINA-GD predicts mortality
Mortality is the state of being mortal, or susceptible to death; the opposite of immortality.
Mortality may also refer to:
* Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...
in trauma
Trauma most often refers to:
* Major trauma, in physical medicine, severe physical injury caused by an external source
* Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event
*Traumatic i ...
and postoperative atrial fibrillation in patients undergoing cardiac surgery. The association to mortality is retained even after adjustment for other established risk factors, including age, APACHE II
APACHE II ("Acute Physiology and Chronic Health Evaluation II") is a severity-of-disease classification system, one of several ICU scoring systems. It is applied within 24 hours of admission of a patient to an intensive care unit (ICU): an int ...
score and plasma protein binding of thyroid hormones. Correlations were also shown to age, total atrial conduction time, and concentrations of 3,5-diiodothyronine
3,5-Diiodothyronine (3,5-T2) is an active thyroid hormone within the class of iodothyronines. It has two iodine atoms at positions 3 and 5 of its inner ring.
Biological effects
3,5-T2 is an active thyroid hormone. It stimulates the TR-beta re ...
and B-type natriuretic peptide. In a population suffering from pyogenic liver abscess SPINA-GD correlated to markers of malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues a ...
, inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and liver failure. A study on 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 becom ...
found SPINA-GD to be significantly decreased 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, fa ...
-dominant and mixed subtypes compared to the akinetic-rigid type. Euthyroid sick syndrome
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 ...
may be the reason for variations of SPINA-GD in subjects treated with immune checkpoint inhibitor
Cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer im ...
s for cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
as well.
Endocrine disruptors
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 ca ...
may have pronounced effects on step-up deiodinases, as suggested by positive correlation of SPINA-GD to urine concentrations of cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Like zinc, it demonstrates oxidation state +2 in most of ...
and 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 and negative correlation to mercury
Mercury commonly refers to:
* Mercury (planet), the nearest planet to the Sun
* Mercury (element), a metallic chemical element with the symbol Hg
* Mercury (mythology), a Roman god
Mercury or The Mercury may also refer to:
Companies
* Merc ...
and bisphenol A
Bisphenol A (BPA) is a chemical compound primarily used in the manufacturing of various plastics. It is a colourless solid which is soluble in most common organic solvents, but has very poor solubility in water. BPA is produced on an industrial s ...
concentration.
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 lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
* Thyroid's secretory capacity
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) is the maximum stimulated amount of thy ...
* Jostel's TSH index
* Thyrotroph Thyroid Hormone Sensitivity Index
* Thyroid Feedback Quantile-based Index
The Thyroid Feedback Quantile-based Index (TFQI) is a calculated parameter for thyrotropic pituitary function. It was defined to be more robust to distorted data than established markers including Jostel's TSH index (JTI) and the thyrotroph thyr ...
* SimThyr
* SPINA-GBeta
SPINA-GBeta is a calculated biomarker for pancreatic beta cell function. It represents the maximum amount of insulin that beta cells can produce per time-unit (e.g. in one second).
How to determine GBeta
The index is derived from a mathematical ...
* SPINA-GR
SPINA-GR is a calculated biomarker for insulin sensitivity. It represents insulin receptor gain.
How to determine GR
The index is derived from a mathematical model of insulin-glucose homeostasis. For diagnostic purposes, it is calculated from fast ...
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