Sum Activity Of Peripheral Deiodinases
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The sum activity of peripheral deiodinases (''GD'', 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 thyroxi ...
produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of
deiodinase Deiodinase (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 thyronine ...
s outside the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase. ''GD'' is both a theoretical concept that is used in physiological theories of thyroid function and (as a calculated parameter) a biomarker for advanced diagnosis of thyroid disorders.


How to determine GD

''GD'' can be determined experimentally by exposing a
cell culture Cell culture or tissue culture is the process by which cell (biology), cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been Cell isolation, isolated from living tissue, ...
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 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. 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 ''GD'' from equilibrium levels of T4 and T3. It is obtained with \hat G_D = or \hat G_D = 'FT4'' Serum free T4 concentration (in pmol/L)
'FT3'' Serum free T3 concentration (in pmol/L)
'TT3'' Serum total T3 concentration (in nmol/L)
\alpha _: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 L−1)
\beta _: Clearance exponent for T3 (8e-6 sec−1) (i. e.,
reaction rate constant In chemical kinetics, a reaction rate constant or reaction rate coefficient () is a proportionality constant which quantifies the rate and direction of a chemical reaction by relating it with the concentration of reactants. For a reaction between ...
for degradation)
''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, sound source reconstruction, source reconstruction in ac ...
. Therefore, certain conditions (e.g. stationarity) have to be fulfilled to deliver a reliable result. The product of SPINA-GD times the urinary
iodine Iodine is a chemical element; it has symbol I and atomic number 53. The heaviest of the stable halogens, it exists at standard conditions as a semi-lustrous, non-metallic solid that melts to form a deep violet liquid at , and boils to a vi ...
excretion can be used to assess iodine-independent factors affecting deiodinase activity, e.g. selenium deficiency.


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,
body mass index Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...
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 Selenium is a chemical element; it has symbol (chemistry), symbol Se and atomic number 34. It has various physical appearances, including a brick-red powder, a vitreous black solid, and a grey metallic-looking form. It seldom occurs in this elem ...
, a trace element that is essential for the synthesis of deiodinases. Conversely, it was observed that SPINA-GD is reduced in persons positive for autoantibodies to selenoprotein P, which is assumed to be involved in transport and storage of selenium.


Clinical utility

Compared to both healthy volunteers and subjects with
hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
and
hyperthyroidism Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...
, SPINA-GD is reduced in subacute thyroiditis. In this condition, it has a higher specificity, positive and negative likelihood ratio than serum concentrations of thyrotropin, free T4 or free T3. These measures of diagnostic utility are also high in nodular
goitre A goitre (British English), or goiter (American English), 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 ...
, 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, toxic multinodular goitre or
Graves' disease Graves' disease, also known as toxic diffuse goiter or Basedow's disease, 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 ...
). 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.


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 surgery, 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 ...
or high-dose
radioiodine There are 40 known isotopes of iodine (53I) from 108I to 147I; 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 16.14 million ye ...
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, ...
) 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 patients suffering from toxic adenoma, toxic multinodular goitre and Graves’ disease low-dose
radioiodine therapy 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 nu ...
leads to a significant reduction of SPINA-GD as well. SPINA-GD is elevated in obesity. This applies to both the metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO) phenotypes. 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 refers to quantifying the different components (or "compartments") of a human body. The selection of compartments varies by model but may include fat, bone, water, and muscle. Two people of the same gender, h ...
including
body mass index Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...
(BMI),
waist circumference The waist is the part of the Human abdomen, abdomen between the rib cage and Hip (anatomy), hips. Normally, it is the narrowest part of the torso. ''Waistline'' refers to the horizontal line where the waist is narrowest, or to the general appe ...
, fat-free mass and body cell mass, confirming observations in the NHANES dataset and in a Chinese study. 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. Generally, SPINA-GD seems to be upregulated in
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...
, as demonstrated by a significant correlation to the triglyceride-glucose index, a marker of
insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...
. SPINA-GD is reduced in low-T3 syndrome and certain chronic diseases, e.g.
chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...
,
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
,
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 i ...
or geriatric
asthma Asthma is a common 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 wh ...
. Six months after the primary infection, it correlates negatively to the FS-14 score for
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
in patients affected by
Long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
(PASC). In
Graves' disease Graves' disease, also known as toxic diffuse goiter or Basedow's disease, 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 ...
, 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 (biology), stress. The term was coined by Bruce McEwen and Eliot Stellar in 1993. It represents the physiological conseq ...
, 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 a large register-based study, reduced SPINA-GD predicted a poor outcome of Takotsubo syndrome. In certain psychiatric diseases, including major depression, bipolar disorder and schizophrenia SPINA-GD is reduced compared to healthy controls. This observation is supported by negative correlation of SPINA-GD with the depression percentiles in the Hospital Anxiety and Depression Scale (HADS). 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 results in increased SPINA-GD in subjects with autoimmune thyroiditis. In subjects with
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
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). In the general population it is, however, positively associated with the bone mineral density of the femoral neck and with reduced risk of osteoporosis. In both diabetic and non-diabetic subsjects it correlates (negatively) with age and concentrations of
c-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...
,
troponin T Troponin T (shortened TnT or TropT) is a part of the troponin complex, which are proteins integral to the contraction of skeletal and heart muscles. They are expressed in skeletal and cardiac myocytes. Troponin T binds to tropomyosin and help ...
and B-type natriuretic peptide, and (positively) with the concentrations of total
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
,
low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
and
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
s. Deiodination capacity proved to be an independent predictor of substitution dose in several trials that included persons on replacement therapy with levothyroxine. Probably as a consequence of non-thyroidal illness syndrome, SPINA-GD predicts mortality in trauma and postoperative
atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
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 in ...
score and plasma protein binding of thyroid hormones. Correlations were also shown to age, total atrial conduction time, and concentrations of 3,5-diiodothyronine and B-type natriuretic peptide. SPINA-GD also correlates with several components of the kynurenine pathway, which might mirror an assosication to a pro-inflammatory milieu. Accordingly, 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 ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and
liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...
. A study on subjects with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
found SPINA-GD to be significantly decreased in
tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
-dominant and mixed subtypes compared to the akinetic-rigid type. Euthyroid sick syndrome may be the reason for variations of SPINA-GD in subjects treated with immune checkpoint inhibitors for
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
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 n ...
may have pronounced effects on step-up deiodinases, as suggested by positive correlation of SPINA-GD to combined exposure to polycyclic aromatic hydrocarbons (PAHs) and urine concentrations of
cadmium Cadmium is a chemical element; it has chemical symbol, symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12 element, group 12, zinc and mercury (element), mercury. Like z ...
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, negative correlation to
paraben Parabens are organic compounds that are commonly used as preservatives in cosmetic and pharmaceutical products. They are esters of parahydroxybenzoic acid (also known as 4-hydroxybenzoic acid). Chemistry Structure and structure Parabens a ...
, mercury 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 Solubility, soluble in most common organic solvents, but has very poor solubility in water. BPA is produced on a ...
concentration and a nonlinear association to the concentrations of
per- and polyfluoroalkyl substances Per- and polyfluoroalkyl substances (also PFAS, PFASs, and informally referred to as "forever chemicals") are a group of synthetic organofluorine chemical compounds that have multiple fluorine atoms attached to an alkyl chain; there are 7 milli ...
. In a cohort of manganese-exposed workers, SPINA-GD responded to a tenfold increase in concentrations of titanium, nickel, selenium and strontium. SPINA-GD is significantly elevated in residents of circumpolar regions and carriers of the TT genotype of the rs3811787 polymorphism of the UCP1 gene. Since this genotype is more prevalent in geographical regions near the North Pole, it is assumed that the variations of SPINA-GD are part of a natural selection mechanism for adaptation to a cold climate. In a longitudinal evaluation of a large sample of the general US population over 10 years, reduced SPINA-GD significantly predicted worse overall survival.


See also

*
Thyroid function tests 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 (overactive thyroid) or hypothyroidism (underactive thyroid) ...
*
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 t ...
* 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