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A Study of Extrathyroidal Conversion of Thyroxine (T 4 ) to 3,3′,5-Triiodothyronine (T 3 ) in Vitro*
Abstract
An in vitro model has been employed to study the nature of the process of peripheral monodeiodination of thyroxine to triiodothyronine (T3) and the factors capable of modulating it. Thyroxine (T4, 5 μg/ml, 6 x 10-6M) was incubated in 0.15M phosphate buffer (pH 7.35) with various rat tissue homogenates (approximately 0.13 g-equivalent) for 2 h at 37 C, and the T3 generated during incubation was measured by a specific immunoassay of an ethanol extract of the homogenate. The liver and kidney homogenates produced more T3 than various other tissues; the kidney was more active than the liver. The T4 to T3 converting activity in the liver homogenates was influenced by the concentration of the homogenate, duration of incubation, substrate (T4) concentration, pH of incubation and temperature of incubation. It was unaffected by large concentrations of several agents including methimazole, hydrocortisone, sodium iodide, mono- or diiodotyrosine, 3,5-diidothyronine, thyronine and methylated and halogenated analogues of 3,3',5'-triidothyronine (reverse T3, rT3). However, various other agents including several thyroid analogues and propylthiouracil (PTU) inhibited T4 to T3 conversion in a dose-dependent manner. Inhibitory thyroid analogues, in order of their potency, were rT3, 3',5'-diiodothyronine, tetraiodothyroacetic acid, 3,3'-diiodothyronine and 3-monoiodothyronine; on a molar basis, the relative potency of these agents was approximately 100:100:5:1:1. PTU was about 3% as potent as rT3 on a weight basis and only 1% as potent as rT3 on a molar basis. Analyses of the data by Lineweaver-Burk plot suggested that rT3 is a competitive inhibitor and PTU, an uncompetitive inhibitor of conversion of T4 to T3. The various data suggest that: a) monodeiodination of T4 to T3 is enzymic in nature, and b) rT3 is a very potent inhibitor of conversion of T4 to T3.
... Protein content was measured by Bradford's method (15). Basic characterization of enzyme activity included the analysis of the effects of protein concentration (15-600 g), time (15-60 min), and temperature of incubation (12,24, and 37 C). Subsequent analysis included substrate and cofactor dependency and effect of inhibitors. ...
... This suggests fundamental differences in the deiodinative pathways of these two substrates. Based on these results, we examined rT 3 deiodination between 0.5 and 2000 nm at various temperatures (12,24, and 37 C) and at high DTT concentrations (25 mm) with the idea of distinguishing more than one enzymatic pathway. As shown in Fig. 3A, the enzyme seems to be more efficient around the physiological temperature (24 C). ...
... Thus, it has been demonstrated previously that T 4 -ORD can be detected in trout liver at higher substrate concentrations if the activity is measured by the production of T 3 by RIA (7, 21, 22), which would not be possible if the activity were measured by the release of 125 I, because, at high substrate concentrations, the fractional rate deiodination is very low (Fig. 2). In the rat liver, in contrast, type I-mediated T 4 ORD can be demonstrated both by isotopic 5Ј-deiodination and by T 3 RIA (23,24). Nonetheless, as measured here, ORD of T 4 is dependent on DTT and is resistant to PTU, as reported for mammalian type II in pituitary and brain (18 -20, 25). ...
Deiodinases are major determinants of thyroid hormone tissue availability and disposal. The knowledge of the expression of these enzymes in lower species is important to understand evolutionary and ontogenetic aspects of thyroid hormone action and metabolism. Here we have studied outer ring deiodination in the trout liver using both reverse T3 (rT3) and T4 as substrates. The use of rT3 disclosed two enzymatic components with the characteristics of mammalian types I and II 5′-deiodinases. The high rT3-Km type I 5′-deiodinase activity (180 nm) has a low cofactor requirement (5 mm dithiothreitol) and is relatively sensitive to propylthiouracil inhibition, whereas the low rT3-Km activity was akin to the outer ring deiodination of T4 in these regards. The use of T4 exhibited only a single type of activity with a low Km (0.63 nm), a relatively high cofactor requirement (25 mm dithiothreitol), and propylthiouracil-resistance. Teleosts constitute a unique example of type II activity expression in the liver of an adult vertebrate. Furthermore, the Vmax of this enzyme is as high as that found in comparable homogenates from hypothyroid mammalian tissues, whereas the Vmax of the type I activity is lower than that of mammalian liver. These findings are in consonance with the peculiar kinetics of T3 in trout liver, kinetics remarkably similar to those of the mammalian pituitary, cerebral cortex, and brown adipose tissue, which also preferentially express type II deiodinase.
... Soon after the discovery of T 3 (4,5), conversion of T 4 into T 3 was demonstrated in rat kidney slices by Albright et al (53). This deiodination reaction has now been demonstrated in many tissues and cell preparations, including cultured human liver cells (54), isolated rat liver cells (55), rat liver homogenate (55)(56)(57)(58)(59)(60) and microsomes (55,57), cultured human kidney cells (54), rat kidney homogenate (59,61,62) and isolated rat renal tubules (63), cultured human fibroblasts (64), human polymorphonuclear leukocytes (65,66), isolated perfused rat heart (67) and dog heart homogenate (68), homogenates of rat cerebellumand cerebral cortex (69,70), rat skeletal muscle homogenate (59,71) and perfused rat skeletal muscle (72), rat thyroid tissue (73,74), isolated human thyroid cells (75), human thyroid homogenate (76), rat thyroid particulate fraction (77), human and dog thyroid microsomes (78), rat pituitary homogenate (79,80) and human placenta and fetal membranes (81). ...
... Soon after the discovery of T 3 (4,5), conversion of T 4 into T 3 was demonstrated in rat kidney slices by Albright et al (53). This deiodination reaction has now been demonstrated in many tissues and cell preparations, including cultured human liver cells (54), isolated rat liver cells (55), rat liver homogenate (55)(56)(57)(58)(59)(60) and microsomes (55,57), cultured human kidney cells (54), rat kidney homogenate (59,61,62) and isolated rat renal tubules (63), cultured human fibroblasts (64), human polymorphonuclear leukocytes (65,66), isolated perfused rat heart (67) and dog heart homogenate (68), homogenates of rat cerebellumand cerebral cortex (69,70), rat skeletal muscle homogenate (59,71) and perfused rat skeletal muscle (72), rat thyroid tissue (73,74), isolated human thyroid cells (75), human thyroid homogenate (76), rat thyroid particulate fraction (77), human and dog thyroid microsomes (78), rat pituitary homogenate (79,80) and human placenta and fetal membranes (81). ...
... Soon after the discovery of T 3 (4,5), conversion of T 4 into T 3 was demonstrated in rat kidney slices by Albright et al (53). This deiodination reaction has now been demonstrated in many tissues and cell preparations, including cultured human liver cells (54), isolated rat liver cells (55), rat liver homogenate (55)(56)(57)(58)(59)(60) and microsomes (55,57), cultured human kidney cells (54), rat kidney homogenate (59,61,62) and isolated rat renal tubules (63), cultured human fibroblasts (64), human polymorphonuclear leukocytes (65,66), isolated perfused rat heart (67) and dog heart homogenate (68), homogenates of rat cerebellumand cerebral cortex (69,70), rat skeletal muscle homogenate (59,71) and perfused rat skeletal muscle (72), rat thyroid tissue (73,74), isolated human thyroid cells (75), human thyroid homogenate (76), rat thyroid particulate fraction (77), human and dog thyroid microsomes (78), rat pituitary homogenate (79,80) and human placenta and fetal membranes (81). ...
Rat liver cells contain iodothyronine deiodinating enzymes (iodothyronine-5 and 5′-deiodinases), which are associated with the endoplasmic reticulum. In the present study, the iodothyronine deiodinases have been solubilized from the microsomal fraction of rat liver with 1.0% cholate and 0.25% of the polyoxyethylene ether W-1. Cholate can be effectively removed from the cholate extract with a mixture of the polystyrene beads XAD-2 and XAD-7. However, after some time, aggregation of proteins occurred.Cholate solubilized iodothyronine-5′-deiodinase has an apparent molecular weight of 65 000 and a Stokes radius of 36–37 Å. The sedimentation coefficient is 4.3 S in 0.4–0.6% cholate, 7.6 S in 0.05% W-1 ether and 12.8 S in the absence of detergent. The enzyme solubilized with W-1 ether has an apparent molecular weight of approx. 200 000 and a Stokes radius of 52–56 Å in 0.025% W-1 ether. In the latter extract, the sedimentation coefficient of the deiodinase is 4.3–5.2 S under different conditions.On DEAE-Sepharose chromatography, 70% of the bound deiodinases eluted with 0.1 M NaCl. The purification of this fraction was only 2-fold. Covalent chromatography, using activated thiol-Sepharose, resulted in approximately 3-fold purification of the deiodinases solubilized with W-1 ether, whereas in case of the cholate extract, no purification at all was obtained. Glutathione-Sepharose affinity chromatography resulted in no enrichment of the deiodinases.
... T 3 and T 4 thyroid hormone (TH) are produced in the thyroid, though the thyroid primarily produces T 4 and less than 20% of the TH it releases is T 3 (Abdalla and Bianco 2014). Triiodothyronine (T 3 ) is primarily produced peripherally in the body via the monodeiodination of thyroxine (T 4 ) (Chopra 1977). THs typically act as transcription factors by binding to thyroid hormone receptors (TRs). ...
µ-Crystallin is a NADPH-regulated thyroid hormone binding protein encoded by the CRYM gene in humans. It is primarily expressed in the brain, muscle, prostate, and kidney, where it binds thyroid hormones, which regulate metabolism and thermogenesis. It also acts as a ketimine reductase in the lysine degradation pathway when it is not bound to thyroid hormone. Mutations in CRYM can result in non-syndromic deafness, while its aberrant expression, predominantly in the brain but also in other tissues, has been associated with psychiatric, neuromuscular, and inflammatory diseases. CRYM expression is highly variable in human skeletal muscle, with 15% of individuals expressing ≥13 fold more CRYM mRNA than the median level. Ablation of the Crym gene in murine models results in the hypertrophy of fast twitch muscle fibers and an increase in fat mass of mice fed a high fat diet. Overexpression of Crym in mice causes a shift in energy utilization away from glycolysis towards an increase in the catabolism of fat via β-oxidation, with commensurate changes of metabolically involved transcripts and proteins. The history, attributes, functions, and diseases associated with CRYM, an important modulator of metabolism, are reviewed.
... It is also notable that the preferred substrate of D1 for 5′D is not T4, but rT3. D1 activity is most abundant in the liver, kidney, and thyroid, but it is also expressed at a relatively low level in many other tissues (38). It has been widely accepted that the D1 is responsible for the generation of most of the extrathyroidal T3. ...
In this minireview we provide an historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the three deiodinase genes. The story starts in 1820 when it was first determined that elemental iodine was important for normal thyroid function. Almost a hundred years later it was found that the primary active principle of the gland, thyroxine (T4), contains iodine. Once radioactive iodine became available in the 1940s it was demonstrated that the metabolism of the T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of 3,5,3’-triiodothyronine in 1952. We then discuss in some detail the events of the next twenty years, that included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the three deiodinases were identified and characterized and their genes cloned.
... In fact, studies have demonstrated that, mercury exposed mice developed a conspicuously damaged and degenerative liver tissue with necrotic changes as well as significant increase in serum ALT and AST and a decrease in serum ALP [36]. There is abundant evidence of mercury mediated deiodinase activity inhibition in adult rat liver [37][38][39]. ...
Background
Mercury can be very toxic to human health even at low dose of exposure. Artisanal small-scale miners (ASGMs) use mercury in gold production, hence are at risk of mercury-induced organ dysfunction.
Aim
We determined the association between mercury exposure, thyroid function and work-related factors among artisanal small-scale gold miners in Bibiani- Ghana.
Method
We conveniently recruited 137 consenting male gold miners at their work site in Bibiani-Ghana, in a comparative cross-sectional study. Occupational activities and socio-demographic data of participants were collected using a questionnaire. Blood sample was analysed for total mercury and thyroid hormones.
Results
Overall, 58.4% (80/137) of the participants had blood mercury exceeding the occupational exposure threshold (blood mercury ≥5μg/L). T3(P<0.0001) and T4(P<0.0001) were significantly reduced among the exposed group compared to the non-exposed. TSH showed no significant variation between the exposed and non-exposed groups. Longer work duration (≥5years), gold amalgamation, gold smelting and sucking of excess mercury with the mouth were associated with increased odds of mercury exposure. Blood mercury showed negative correlation with T3(r = -0.29, P<0.0001), and T4(r = -0.69, P<0.0001) and positive correlation with work duration (r = 0.88, P<0.001). Even though a positive trend of association between blood mercury and TSH levels was recorded, it was not significant (r = 0.07, P = 0.4121)
Conclusion
Small scale miners in Bibiani are exposed to mercury above the occupational threshold which may affect thyroid hormone levels.
... However, excessive taurine supplementation caused excessive loss of free amino acids and reduced the utilization efficiency of amino acids in fish Zhou et al., 2015). In addition, thyroid hormones such as triiodothyronine (T 3 ) and thyroxine (T 4 ) are involved in metabolic regulation, growth and development and especially modulating protein synthesis (Chopra, 1977;Wang, 2013). In the present study, the inclusion of 50 and 10 g/kg taurine significantly increased the T 3 and T 4 contents, respectively, in turbot serum. ...
The effects of dietary taurine on growth performance, liver and intestine morphology, serum physiological and antioxidant parameters, serum thyroid hormone level, muscle taurine content and fatty acid composition of turbot were first evaluated, for the safe utilization in marine fish feed and for human food safety. Four experimental diets were formulated to contain 0, 10, 50 and 100 g/kg taurine. Each diet was randomly assigned to six replicates of 30 juvenile turbot (initial mean weight of 7.46 g). The feeding trial lasted for 10 weeks. The growth performance of fish was significantly enhanced by 10 g/kg dietary taurine. The integrity of the distal intestine was impaired and the absorptive surface was found to be significantly reduced by 100 g/kg dietary taurine. The obvious pathological changes in liver were observed in fish fed 100 g/kg taurine. Dietary taurine with 10 and 50 g/kg significantly increased the activities of serum superoxide dismutase, lysozyme and thyroid hormone. The taurine content in muscle was found to be significantly increased by dietary taurine; however, no significant differences were observed among taurine-supplemented treatments. This study suggested that 10 g/kg taurine was safe in turbot feed, and fivefold of safety margin was obtained.
... (1985), who first stated an interaction of rT, with the hypermetabolic effect of T,. A possible mechanism has been postulated by Chopra (1977), who suggested that rT, interacts with the binding site of T, in target cells. Such a suggestion is strengthened by the possibility of binding several iodothyronines by one receptor (Cutten et al., 1984). ...
The effect of 3,3’,5’-triiodothyronine (rT,) and 3,5,3’-triiodothyronine (T,) on O2 consumption
in I-day-old chickens was studied. The birds were divided into five groups, each
of six chickens: (1) control-without injection; (2) control-injected with 100 JLI of solvent
(0.01 N NaOH in saline); (3) injected with 10 p,g rT,/chicken; (4) injected with 0.5 pg
T,/chicken; and (5) injected with 10 pg rT, + 0.5 pg T,/chicken. 0, consumption was
measured using a Kipp & Zonen diaferometer at neutral temperature (30”) 0, 1, 2, 3, and 4
hr after injection of hormones. Corresponding groups of other chickens served only for
blood collection. rT, and T, were measured by radioimmunoassay. Reverse T, decreased 0,
consumption by 10.87%. Contrary to this, T, increased O2 consumption by 29.41%. Reverse
T,. injected together with T,, interacted with the hypermetabolic effect of T, up to 2 hr after
injection; then, 0: consumption started to increase, and was about 16.7% higher compared
with the basal level 3 hr after injection. The blood plasma level of rT, increased about 29-fold
at the first hour after injection, without changes in the basal level of T,. Administration of
T, increased its level 6-fold 2 hr after injection, which was accompanied by a gradual
decrease in the basal level of rT, (3.7-fold) 4 hr after injection. Administration of rT, + T,
increased the rT, level 30.fold at 2 hr and the T, level 1.7-fold at the first hour after injection.
Thus, rT, acts hypometabolically and interacts with the hypermetabolic effect of T,; administration
of T, lowered the basal level of rT,; and the plasma level of T, did not change
... Many depressed and bipolar patients have undiagnosed thyroid dysfunction as the underlying cause or major contributor to their depression. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] The dysfunction present with these conditions includes down regulation of D1 (reduced T4 to T3 conversion) and reduced uptake of T4 into the cell, resulting in increased serum T4 levels with low intracellular T3 levels 24-26, 30, 31, 35, 39-45 and upregulated D3, resulting in elevated reverse T3, 23,24,30,31 which blocks the thyroid effect 145,[176][177][178][179][180][181][182][183][184][185][186] and is an indicator of reduced transport of T4 into the cell. 175,185 Additionally, studies show that depressed patients have reduced T4 transport across the blood brain barrier due to a defective transport protein, transthyretin, resulting in significantly reduced thyroid levels in the brains of depressed patients despite "normal" serum levels and standard thyroid tests 23, 39, 40 as well as a reduced TSH response to TRH. [28][29][30][31][43][44][45][46][47][48][49][50] It is not surprising that T4 and T4/T3 combinations may have some benefit in depression; but due to the suppressed T4 to T3 conversion from suppressed D1 [24][25][26]30 and reduced uptake of T4 into the cell and brain, 25,31,39,40 timed-released T3 is significantly more beneficial than T4 or T4/T3 combination supplementation. ...
There have been recent advances in understanding of the local control of thyroid activity and metabolism, including deiodinase activity and thyroid hormone membrane transport. The goal of this review is to increase the understanding of the clinical relevance of cellular
deiodinase activity. The physiologic significance of types 1, 2 and 3 deiodinase (D1, D2 and D3, respectively) on the intracellular production of T3 are discussed along with the importance and significance of the production of reverse T3. The difference in the pituitary and peripheral activity
of these deidoidinases under a wide range of common physiologic conditions results in different intracellular T3 levels in the pituitary and peripheral tissues, resulting in the inability to detect low tissue levels of thyroid hormone in peripheral tissues with TSH testing. This review demonstrates
that extreme caution should be used in relying on TSH or serum thyroid levels to rule out hypothyroidism in the presence of a wide range of conditions, including physiologic and emotional stress, depression, dieting, obesity, leptin insulin resistance, diabetes, chronic fatigue syndrome, fibromyalgia,
inflammation, autoimmune disease, or systemic illness, as TSH levels will often be normal despite the presence of significant hypothyroidism. The review discusses the significant clinical benefits of thyroid replacement in such conditions despite having normal TSH levels and the superiority
of T3 replacement instead of standard T4 therapy.
... Thyroid hormone, specifically triiodothyronine (T,), is important for glucose absorption, protein synthesis and lipid metabolism. The production of T, from thyroxine (T,) in nonthyroidal tissues is an important regulator of thyroid action (Chopra 1977) and diet is one of several factors controlling the deiodination of T, to T,. Although not investigated in the horse, human (Davidson and Chopra 1979) and rat (Glass et al. 1978) studies have proved the role of T, in the control of substrate metabolism to be dependent upon the amount of peripheral hormone available which can be regulated by diet composition and caloric amount (Katzeff et al. 1988;Danforth and Burger 1989). ...
Eight Thoroughbred horses were used to determine the effects of long-term calorie restriction and diet composition on serum T4 and T3 concentrations and metabolic responses with exercise. Horses were randomly assigned to 2 treatment groups (n = 4): Group 1, horses were fed a calorie-restricted diet designed to have 70% of the calories from the roughage source (RHR); Group 2, horses were fed a calorie-restricted diet designed to have 70% of the calories from the concentrate source (RHC). Horses then completed 2 step-wise exercise tests; one following a 12 h fast and one 2 h after a meal of 2 kg of a grain mix. Glucose concentrations declined (P<.01) in fed horses on the RHR diet but did not change in fed horses on the RHC diet Fasted horses receiving the RHR diet had a more rapid increase in glucose concentration during exercise compared to fasted horses receiving the RHC diet (P<.01) as well as the highest glucose concentration at fatigue (P<.05). Insulin concentrations were higher (P<.05) at fatigue in fed horses on the RHR diet Fasted horses receiving the RHR diet had higher (P<.01) pre-exercise FFA concentrations and a more rapid decline (P<.01) in FFA during exercise. Serum T3 concentrations increased (P<.01) in response to exercise within all treatments. The differences in thyroid hormone, glucose and FFA responses to exercise suggest that calorie source may be important in the hormonal regulation and energy metabolism of horses consuming calorie deficient diets.
Ghrelin, classically known as a central appetite-stimulating hormone, has recently been recognized to play an important role in peripheral tissue energy metabolism. In chicken, contrary to mammal, ghrelin acts as an anorexia signal, increased by fasting and further elevated after refed. In the present study, the effect of ghrelin on glucose/lipid utilization by peripheral tissues was investigated. Injection of exogenous acyl ghrelin reduced plasma triglyceride and glucose levels of chickens at both fasting and fed status. In the in vitro cultured chicken primary hepatocytes, adipocytes, and myoblasts, ghrelin suppressed glucose uptake, stimulated fatty acids uptake and oxidation, and decreased TG content. In hepatocyte, ghrelin increased the activities of LPL and HL, and upregulated the expression levels of gene ACC, CPT1, and PPARα. Ghrelin treatment markedly increased the protein level of p-ACC, PPARγ, PGC1α, and CPT1 in hepatocytes, adipocytes and myoblasts. Inhibition of AMPK activity by Compound C had no influence on glucose uptake by hepatocyte, adipocyte, and myoblast, but further amplified the stimulated fatty acid uptake of adipocyte by ghrelin. The present result demonstrates that ghrelin facilitates the uptake and oxidation of fatty acid and cut down the utilization of glucose by the liver, muscle, and adipose tissues. The result suggests that ghrelin functions as a signal of fatty acid oxidation. The study provides a vital framework for understanding the intrinsic role of ghrelin as a crucial factor in the concerted regulation of metabolic substrate of hepatocytes, adipocytes, and myoblasts.
The problem of acute respiratory tract infections (including acute bronchitis) remains urgent in the whole world independent of human age, especially when disease rates are considered. The World Health Organization reports annually on 1.5 billion cases of acute respiratory diseases. In Ukraine, the disease rate is 3.6 times higher among children than among adults (totally, it is equal to 67,000 cases per 100,000 individuals). The highest rate is observed among under-6-year-old children. In contrast to the average bronchopulmonary disease rate in Europe, the same Ukrainian index remains slightly higher for the last decades. Among children, the acute bronchitis rate is 6.2–25.0% within all bronchopulmonary diseases, reaching 50.0–90.0% if there are recurrences.
Our literature review aims to compare different researchers’ perspectives, selecting articles and analyzing data as to how thyroid hormones and cortisol influence immune response in children’s bronchopulmonary diseases. In the literature review, the modern perspective of children’s hormonal state in bronchopulmonary diseases is studied. The hypothalamus-hypophysis-thyroid and hypothalamus-hypophysis-paranephros interaction roles in bronchopulmonary adaptive responses are explained. The thyroid hormone and cortisol importance for organism resistance are regarded. The manifestation, pathogenetic progress mechanisms, diagnosing methods, and treatment of different subclinical hormonal shifts (particularly euthyroid sick syndrome) are researched. The interconnection of hormonal and immunological indicators is covered (whose change is a predictively significant marker – that can foresee the disease progress, its duration and consequences for patients). Therefore, the relevance consists in researching the influence of thyroid hormones and cortisol on immune response by different pathological states of children’s bronchopulmonary diseases.
Artisanal small-scale mining is widely operated in various countries serving as a livelihood to many rural communities. However, it is a significant source of environmental mercury contamination which affects human health. Amalgamation and amalgam smelting, two significant steps in the artisanal small-scale mining operations generate lots of mercury vapors, leading to chronic exposure among miners. Thus, this article seeks to provide a topical review of recent findings on organ damage and metabolic disorders among mercury-exposed artisanal small-scale miners with emphasis on the contributing factors such as personal protective equipment usage and artisanal small-scale gold mining-specific occupational activities. Also, insights into the effect of mercury intoxication and mechanisms of action on organ and metabolic systems among exposed individuals are provided.
Canonical thyroid hormone (TH) signaling results from the interaction of T3 with nuclear receptors and stimulation or repression target genes. Ligand (T3) availability is under tight control of several intracellular checkpoints, which enable target cells to modify their own T3 fingerprint. A crucial step of intracellular T3 metabolism is catalyzed by the deiodinases. These enzymes can, within the single cell, enhance (D1 and D2) or reduce (D3) T3 concentrations. Thyroid hormone transport within the target cells is also a limiting step of thyroid hormone action. Various specific transporters have been isolated for the entrance and the clearance of the iodothyronines and constitute a complex system of active transport of THs inside and outside the cells. Concerted modulation of the different TH regulating factors is responsible for a spatiotemporal precise adaptation of the hormonal signal to the different cell-specific requirements.
Thyroxine (T4) is the major thyroid hormone in the thyroid gland and the circulation. However, it is widely accepted on the basis of abundant evidence that 3,5,3'-triiodothyronine (T3) is responsible for most, if not all, of the physiological effects of TH in extrathyroidal tissues, and T4 functions as the pro-hormone. Whether T4 has any intrinsic activity per se or is merely a pro-hormone that must be converted to T3 in order to exert any TH action has yet to be resolved. Although there are some physiological actions of T4 that are mediated by receptors at the cell membrane (non-genomic effects), the vast majority of the physiological effects of the THs identified to date involve the binding of T3 to specific nuclear receptors to regulate gene expression (genomic effects). This review examines how the role of T4 in genomic TH action has been viewed and debated during the hundred years since it was first isolated in 1914.
Während die Vorstellungen über die Ä tiologie der chronischen Polyarthritis zur Zeit vorwiegend noch spekulativer Natur sind, gibt es eine Vielzahl pathobiochemischer Befunde, die geeignet sind, pathogenetische Teilmechanismen zu erklären (1). Zur besseren Übersicht der pathobiochemischen Mechanismen erscheint eine Einteilung in drei verschiedene Stadien mit zum Teil fließenden Übergängen und gleicbzeitigem Ablauf sinnvoll.
The influence of acidosis on peripheral metabolism of T4. was studied in infants with diarrhea and metabolic acidosis. The serum concentrations of T4, T3, rT3, TSH and TBG were compared to those of healthy control subjects. Significantly lower T3 and T4 and significantly higher rT3 serum concentrations were found in the patients in contrast to the control group. No significant differences were found in TSH and TBG values between infants with metabolic acidosis and control subjects. Initial pH showed a significant correlation with T3 but not with T4 and rT3. Despite the reduced serum T3 and T4 concentrations, TSH values were within the normal range. Our data show that the metabolic acidosis with normal anion gap could result in the abnormal peripheral conversion of T4 to T3 and the significant reduction of T3 serum levels, all of which are characterized by the low T3 syndrome.
Enzymatic T4 5′-monodeiodination has been demonstrated in a variety of rat tissues (1,2) and may be an important factor in the regulation of T3 concentrations in several target sites of thyroid hormone action. As a consequence, under various (patho)physiological conditions, the total T3 content of tissues which exhibit T4 to T3 conversion in vivo may be affected to an extent not disclosed by alterations in circulating T3 levels. In the present study, we evaluated the relationship between T3 in several extrathyroidal tissues and plasma T3 for both euthyroid and hypothyroid rats.
Während die Vorstellungen über die Ätiologie der chronisch-entzündlichen Gelenkerkrankungen z.Zt. vorwiegend noch spekulativer Natur sind, gibt es eine Vielzahl pathobiochemischer Befunde, die geeignet sind, pathogenetische Teilmechanismen zu erklären [1]. Zur besseren Übersicht chronisch-entzündlicher Gelenkprozesse erscheint die Einteilung in 4 verschiedene Stadien sinnvoll, mit zum Teil fließenden Übergängen und gleichzeitigem Ablauf:
1
Primäre Aktivierung des Bindegewebes durch meist unbekannte Mechanismen, die zur Synovitis führen
2
Immunchemische Reaktionen, die den entzündlichen Prozeß unterhalten und verstärken
3
Destruktion der interzellulären Matrixbestandteile (Proteoglykane, Hyaluronat, Kollagen, strukturelle Glykoproteine) vorwiegend durch hydrolytische Enzyme und 02-entstammende Radikale
4
Reparative Stoffwechselprozesse von Synovialzellen und Chondrocyten, um durch Neusynthese der Matrixbestandteile deren Verlust auszugleichen
The bulk of research activity during the past year has been concerned with attempts to define some of the factors that regulate the secretion of thyrotropin-releasing hormone (TRH). Since a reliable radioimmunoassay for measuring TRH in plasma has not yet been developed, effects of various factors on TRH secretion have been inferred from changes in the concentration of thyrotropin (TSH) in plasma. This approach may not be a disadvantage, however. Since TRH is so widespread throughout the brain, changes in plasma concentration need not reflect alterations in the hypothalamic elaboration of this peptide. On the other hand, alterations in TRH that are relevant to TSH secretion should be reflected in alterations in plasma TSH concentration. That endogenous TRH has a role in the regulation of TSH secretion has in the past been inferred from the effects of administered exogenous TRH. Two groups of investigators1–3 have now provided direct evidence to support such a role by observing the effects on serum TSH concentrations in the rat of administering anti-TRH antiserum. In normal rats, administration of anti-TRH antiserum was followed by depression of basal serum TSH concentration and by suppression of the cold-induced surge of TSH secretion. In untreated hypothyroid rats, the anti-TRH antiserum produced a modest decrease in basal serum TSH concentration, but in triiodothyronine (T3)-treated thyroidectomized animals, it did not prevent the rise in serum TSH concentration that occurred when T3 was withdrawn.
Causes of hyperthyroidism and the different entities involved with thyroiditis compose the majority of benign endocrine diseases. These disorders range from the very common chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) and Graves’ disease to the very rare invasive fibrous thyroiditis (Riedel’s thyroiditis). Their presentation is just as diverse, anywhere from an incidental goiter to a life-threatening thyrotoxicosis. This chapter focuses on the evaluation, diagnosis, and management of hyperthyroidism and the various types of thyroiditis, with special attention to laboratory studies, radiologic findings, pathology, and surgical management.
Several experimental and clinical conditions sharing stress as a common factor (i.e., fasting, surgical procedures, severe non-thyroidal systemic illnesses) are known to induce marked alterations on the extrathyroidal metabolism of iodothyronines (1). These alterations, known as the “low T3 syndrome,” are characterized by low 3,5,3’–triiodothyronine (T3), and high 3,3’,5’–triiodothyronine (rT3) serum concentrations, while thyroxine (T4) values in serum may be decreased or unchanged (2).
Selenium status influences a number of endocrine processes, most notably those involved in thyroid hormone synthesis and metabolism. Thyroid follicular cells maintain a highly oxidative environment as required for thyroid hormone synthesis. Glutathione peroxidase expression in the thyroid gland is thus important to prevent oxidation-induced cellular toxicity. In addition, the iodothyronine deiodinases, which catalyze the principal reactions of thyroid hormone metabolism, are selenoproteins. Selenium may also impact carbohydrate metabolism and female reproduction, though these effects are less well characterized.
Proteins have been labeled with halogen isotopes for many years. These tracers have been exploited as probes of protein metabolism and pharmacokinetics in
vivo and have provided invaluable tools for use in radioimmunoassay. Because of this extensive experience with radioiodinated proteins and the direct applicability of in
vitro data obtained with I-125, labeling with halogen isotopes has been an attractive approach to the development of monoclonal antibodies as agents for radioimmunodiagnostic and therapeutic applications.
The ability to receive and process information for initiating metabolic processes and coordinating the activities of the specialized cells comprising an organ is essential to the orchestrated activities of multicellular organisms. Informational molecules can bind at stereospecific receptor sites either on the membrane or within the cell and can start a chain of events eliciting a biochemical response. The endocrine system, with its myriad hormones, provides a level of control of metabolic processes that permits the coordinate responses of many cells, enabling the resultant biochemical response to be expressed at a physiologic level. In this chapter, we will focus on the biochemical activities of hormones.
Aim: To observe the changes of the content of thyroid hormone T3, T4 and activity of T4-5′-deiodinase in brain tissues of rats with chronic cerebral ischemia. Methods: The experiment was carried out in the laboratory of Department of Neurology, Nanfang Hospital of Southern Medical University from March to August 2005. Altogether 28 clean grade male SD rats were selected and randomly divided into sham-operation group (SO, n=8), pure operation group (PO, n=10) and thyroid hormone treatment group (THT, n=10). The animal models with cerebral ischemia were established by permanently bilateral common carotid artery ligation. The rats in the SO group were only subjected to anterior neck cut and passivity separation of bilateral common carotid artery without ligation. The rats in the THT group were given intragastric administration of thyroid hormone 20 mg per rat, once daily for 5 weeks at the next day of operation. Morris Water Maze Test was performed after successful establishment of models. After removing the brain homogenate, the activity of deiodinase (CHOPRA method) and concentrations of T3, T4 were detected by using radioimmunoassay. Results: A total of 20 rats were involved in the result analysis, except 4 rats in the PO and THT groups respectively died during establishment of models. 1The average latent period of the PO group was significantly longer than the other groups during platform orientation test (P < 0.05); the probe time of the SO group was much shorter than the other two groups during spatial probe test (P < 0.05); the results in the working-memory test of the SO and THT groups were superior than the PO group (P < 0.05). 2 The activity of deiodinase in the PO and THT groups were significantly decreased compared with the SO group, which had significant differences [(1.63±0.88), (3.11±0.88), P < 0.05]; [(1.93±0.29), (3.11±0.88), P < 0.05], and the PO group was the lowest; T3 concentration of thc PO and THT groups was lower than the SO group (P < 0.01), and the THT group was higher than the PO group, which had significant differences (P < 0.01); T4 concentration of the PO group was significantly decreased compared with the SO group (P < 0.01), while the THT group was obviously increased compared with the PO group (P < 0.01). Conclusion: The changes of thyroid hormone concentration and its metabolism, which are abnormal in the brain tissues of rats with chronic cerebral ischemia, are correlated with the cognitive function.
Objective: To explore the effect of associated deficiency of selenium, protein and vitamin E (VE) on the thyroid injury and thyroid hormone metabolism of the rats in a long-term. Methods: The Wistar rats were randomly divided into four groups: Group A with selenium deficiency and low protein and VE; Group B with selenium deficiency, low protein but adequate VE; Group C, adequate selenium and protein but low VE; Group D, adequate selenium, protein and VE. The rats were killed at the end of 26th week. Glutathione peroxidase (GSH-Px) activity in the rat blood and type I 5′-deiodinase activity of the rat liver were determined. The content of triiodothyronine (T3), tetraiodothyronine (T4), thyrotropic-stimulating hormone (TSH), activated oxygen (ROS) and malonaldehyde (MDA) were detected in serum. The changes of thyroid histopathology were observed under light microscope. Results: 1 The interactive effect of selenium + protein and VE was not significant on GSH-Px and ID I activity (F = 0.003, 0.871, P > 0.05), but it was significant on MDA and ROS content(F = 13.057, 6.706, P < 0.05 or < 0.01). 2 Selenium + protein and VE could influence T3 and T4 content (F = 431.977, 28.271, 6.570, 41.419, P < 0.05). The interactive effect of selenium + protein and VE was not significant on T3 and T4 content (F = 0.871, 0.136, P > 0.05). Whether in the condition of low selenium and protein or supplementary, T4 contents of supplementary VE group [(79.095 ± 12.199), (64.392 ± 6.261) μg/L] were respectively higher than the low VE group [(61.068 ± 6.648), (44.176 ± 7.090) μg/L], the difference being statistically significant (t = 3.670, 6.045, P < 0.01). In the condition of low VE, T3[(0.718 ± 0.079) μg/L] and T4 [(44.176 ± 7.090 μpg/L] content of supplementary selenium and protein group was lower than that in the low selenium and protein group [(0.966 ± 0.156), (61.068 ± 6.648) μg/L], the difference being statistically significant (t = 4.568, 4.916, P < 0.01). With supplementary VE, T4 content of supplementary selenium and protein group [(64.392 ± 6.261 ) μg/L] was lower than that in the low selenium and protein group [(79.095 ± 12.199) μg/L], the difference being statistically significant (t = 3.033, P < 0.01). 3 Degeneration and necrosis of follicular epithelial cell were induced by diet of low selenium, protein and VE, which could he relieved by supplymentary VE. The sparseness of intracavitary glue was observed occationally in the supplementary selenium and protein but low VE group. Conclusions: Long-term deficiency of selenium, protein and VE results in the decrease of the selenoenzymes of rats, which causes accumulation of the oxidative products, as well as thyroid pathological injury and thyroid hormone metabolism disorder, but supplement of adequate VE can reduce the oxidative damage in rats having low selenium and protein diet.
The effects of thyroid hormones on postnatal growth, differentiation, and metabolism are well known. It is also recognized that thyroid hormones and glucocorticoids have complementary, and sometimes synergistic, effects on specific enzymes in several organs. Given this background information, it is not surprising that thyroid hormones were evaluated for effects on lung maturation and function shortly after recognition of glucocorticoid action. In this chapter I review the action of thyroid hormones in fetal and postnatal lung, describe properties of pulmonary T3 receptors and the correlations between binding and effect, and discuss preliminary information regarding clinical application.
In this study, it was attempted to look for an endogenous stimulatory factor for T4 5′-deiodinase activity in rat liver and to investigate the mechanism of this stimulation by thiol. The TCA extract of rat liver homogenate was subjected to gel chromatography on a Sephadex G-15 column using 0.4M sodium acetate buffer (pH 4.0) as eluate. The collected fractions were examined for stimulatory factors for 3, 3′, 5-triiodothyronine (T3) production from thyroxine (T4). It was found that a stimulatory factor was eluted at the same position as that of a thiol substance. Furthermore, the eluted position corresponded to that of authentic reduced glutathione (GSH). These results indicated that endogenous GSH is responsible for the stimulation of the conversion of T4 to T3. The stimulatory effects of GSH and cysteine on the T4 to T3 conversion in rat liver microsomes were maximum above 8 mM, and maximal stimulation attained was about 3 and 2.5-fold respectively, over basal activity observed in the absence of thiols. Considering the high concentration of GSH in the liver, GSH possibly functions as an endogenous activator in the conversion of T4 to T3. Among the thiol substances examined, dithiothreitol (DTT) showed the most potential activity for enhancing T4 5′-deiodinase. Maximal activity was approximately 9 times that of the basal activity. The mechanism of the activation by thiol was studied using DTT. Rat liver microsomes, pre-treated with 2 mM DTT for 30 min at 0°C, were subjected to Sepharose CL-6B gel chromatography at 4°C, using 20 mM Tris HC1/1 mM EDTA (pH 7.4) as eluate, and the microsomes were separated from DTT in 30 min. When these microsomes were incubated with T4 alone, T3 production was 2.5-fold compared with the original activity of the microsomes eluted from the chromatography. This rate of T3 production was only 10% of that obtained by incubating with T4 in the presence of 2 mM DTT. It was clearly shown from this result that 90% of the enhanced activity was sustained by coexisting with DTT. Furthermore, the same type of experiment was carried out using solubilized rat liver microsomes. The enzyme solubilized with 0.1% deoxycholate was incubated with 1 mM DTT for 30 min at 0°C and then subjected to a Sepharose CL-6B column (1.4 × 65 cm) at 4°C. All of the collected fractions gave only marginal activity of T3 formation when they were incubated with T4 alone. However, when activity was assayed in the presence of 1 mM DTT, there appeared substantial activity in the fractions containing high molecular weight components. In conclusion, one of the effects of thiol for T4 5′-deiodinase is to protect sulfhydryl groups (s) in this enzyme. On the other hand, the present finding, that the separation of the enzyme from thiol resulted in substantial diminution in activity, suggests that thiol compounds may act as cofactors in the T4 to T3 conversion.
Thyroid hormone synthesis occurs within the follicles of the thyroid gland. This chapter describes the following steps involved in thyroid hormone synthesis: (1) inorganic iodide is transported into the gland; (2) intrathyroidal iodide is oxidized to iodine under the influence of H2O2 and peroxidase; (3) iodine is bound in thyroglobulin to tyrosine, forming monoiodotyrosine and diiodotyrosine; (4) the iodotyrosines are enzymatically coupled to form thyroxine (T4) and triiodothyronine (T3); (5) the iodothyronines, T4 and T3, are stored in thyroglobulin until released into the circulation; and (6) the unused iodotyrosines are deiodinated and the iodide is recycled. The thyroid hormone secretion is regulated by the central nervous system. T3-induced changes in specific messenger RNAs lead to the synthesis of particular proteins that mediate the response to thyroid hormone. Thyroid hormone, by inducing protein synthesis, may produce cardiac hypertrophy. Thyroid hormone exerts a major influence on myocardial contractility. Many of the symptoms and signs of hyperthyroidism resemble those of sympathetic stimulation, suggesting that the enhanced hemodynamics of hyperthyroidism may be because of hypersensitivity of the autonomic nervous system.
The effect of 3,3',5'-triiodothyronine (rT3) on angiotensin II (AII)-induced calcium mobilization and formation of inositol 1,4,5-trisphosphate (IP3) in vascular smooth muscle cells (VSMC) was studied in this paper. rT3 at concentrations of 10 and 50,μM inhibited All (1μM)-induced increase in cytosolic calcium concentration ([Ca²⁺]i) and IP3 formation in VSMC dose-dependently.
These results indicate the possibility that rT3 which is regarded as an inactive metabolite of thyroxine (T4) has inhibitory effects on vascular smooth muscle function.
New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and is proving to have considerable clinical significance. Reduced T4
and T3 transport into the cells in peripheral tissues is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic
dieting and aging, while the intracellular T3 level in the pituitary often remains unaffected. The pituitary has different transporters than every other tissue in the body. The thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low
energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected. Because the pituitary remains largely unaffected and is able to maintain intracellular T3 levels while the rest of the body suffers from significantly reduced intracellular T3 levels, there is no elevation
in thyroid-stimulating hormone (TSH) despite the presence of wide-spread tissue hypothyroidism, making the TSH and other standard blood tests a poor marker to determine the presence or absence of hypothyroidism. Because the T4 transporter is more energy dependent than the transporter for T3,
it is also not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial. Thus, if a patient with a normal TSH presents with signs or symptoms consistent with hypothyroidism, which may include low basal body
temperature, fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention, slow reflex relaxation phase or PMS, a combination of both clinical and laboratory assessment, which may include a T3/reverse T3 ratio and
the level of sex hormone binding globulin (SHBG), should be used to determine the likely overall thyroid status and if a therapeutic trail of straight T3 or a T4/T3 combination is indicated and not based solely on standard thyroid function tests.
Aim:
Previous studies in rats have indicated that surgical thyroidectomy represses turnover of serum thyroxine (T4). However, the mechanism of this process has not been identified. To clarify the mechanism, we studied adaptive variation of metabolic enzymes involved in T4 turnover.
Main methods:
We compared serum T4 turnover rates in thyroidectomized (Tx) rats with or without infusion of active thyroid hormone, triiodothyronine (T3). Furthermore, the levels of mRNA expression and activity of the metabolizing enzymes, deiodinase type 1 (D1), type 2 (D2), uridine diphosphate-glucuronosyltransferase (UGT), and sulfotransferase were also compared in several tissues with or without T3 infusion.
Key findings:
After the T3 infusion, the turnover rate of serum T4 in Tx rats returned to normal. Although mRNA expression and activity of D1 decreased significantly in both liver and kidneys without T3 infusion, D2 expression and activity increased markedly in the brain, brown adipose tissue, and skeletal muscle. Surprisingly, hepatic UGT mRNA expression and activity in Tx rats increased significantly in comparison with normal rats, and returned to normal after T3 infusion.
Significance:
This study suggests that repression of the disappearance of serum T4 in rats after Tx is a homeostatic response to decreased serum T3 concentrations. Additionally, T4 glucuronide is a storage form of T4, but may also have biological significance. These results suggest strongly that repression of deiodination of T4 by D1 in the liver and kidneys plays a major role in thyroid hormone homeostasis in Tx rats, and that hepatic UGT also plays a key role in this mechanism.
Thyroid hormone profiles and 5′-monodeiodinase activity were determined in tilapia at different stages of early development. The results showed that both T4 and T3 were present in significant amounts in fertilized eggs. There was a steady decrease in both T4 and T3 levels during embryonic development. The levels continued to decline after hatching until around 7 days later when most of the yolk had been absorbed. The T4 level started to rise then, suggesting that the larval thyroid had begun to produce T4 at this time, which coincided with the period of faster growth of the larvae. The T3 level remained fairly constant until around 20 days after which it rose significantly.
In vitro determination of 5′-monodeiodinase activity (5′-D activity) in the whole-body homogenates of larvae showed that the enzymatic conversion of T4 to T3 was not detectable in eggs and 3-day-old larvae but detected in 5-day-old and older larvae. There was a gradual increase in the Vmax as development proceeded indicating increasing 5′-D activity during larval development. The Km values did not differ significantly in the different stages of development. These results are discussed in relation to the growth and development of the larvae.
The monodeiodination of thyroxine (T4) to triiodothyronine (T3) was studied in vitro using liver, kidney, and muscle obtained from two-year old Angus and Hereford steers. Tissues were homogenized in .1 M phosphate buffer-.25 M sucrose - 5 mM EDTA, pH 7.5, and centrifuged at 2000 × g for 30 min. Supernatants were incubated with T4 (1.3 μM) at 37 C and T3 generated was measured by radioimmunoassay of an ethanol extract of the incubation mixture. The T4 to T3 conversion in Angus liver homogenate was dependent upon pH, temperature, duration of incubation (5–120 min), homogenate (.025–.20 g-eq tissue/ml), and substrate concentration (.32–6.43 μM T4). The apparent Km and Vmax of the conversion were .64 μM T4 and 1.87 ng T3 generated/hr/mg protein, respectively. Mean T4 to T3 conversion in Angus liver and kidney was 1.37 and .22 ng T3/hr/mg protein. The presence of 2 mM dithiothreitol (DTT), a sulfhydryl protective agent, significantly increased T3 generation in liver and kidney (5.12 and 4.58 ng/hr/mg protein) and also revealed activity in muscle (05 ng/hr/mg protein). In liver and kidney from Hereford steers conversion activity was 2.89 and .48 in absence and 10.91 and 5.38 ng T3/hr/mg protein in presence of DTT, respectively. These results demonstrate the presence of a very active enzymatic system responsible for the peripheral 5′-monodeiodination of T4 to T3 in cattle.
The goitrogenic potential of a low glucosinolate rapeseed meal (RSM) (Brassica napus L. ’Tower’) in dairy cows was evaluated by a thyrotropin-releasing hormone (TRH) test. The TRH test consisted of measuring the plasma concentrations of thyroid-stimulating hormone (TSH) and thyroid hormones after an intravenous injection of 300 μg TRH. A high glucosinolate RSM (B. napus L. ’Midas’) and soybean meal (SBM) served as positive and negative controls, respectively. Tower and Midas RSM were fed at 0, 5.7, 13.2 and 18.9% of the total diet (air-dry basis) and SBM was added to bring the protein level in the supplement for all diets to 18.9%. Tower and Midas RSM were evaluated in two separate 4 × 4 Latin squares. When Midas RSM was fed at levels of 13.2 and 18.9% in the diet, plasma TSH concentrations were increased (P < 0.05) in response to TRH. Similarly, plasma thyroxine (T4) concentrations were decreased (P < 0.05). This indicates that diets with 13.2 and 18.9% Midas RSM contain sufficient quantities of goitrogens to affect thyroid function. Similar trends were observed when the 5.7% Midas RSM diet was fed. Triiodothyronine (T3) concentrations and T3:T4 ratios were not affected by Midas RSM in the diet. The plasma TSH, T4 and T3 concentrations in response to TRH were similar for cows fed the Tower RSM and SBM diets. The use of Tower RSM up to 18.9% of the total diet is without goitrogenic effect as measured by the TRH test.
A basic premise in any intensive culture system is to maximize
growth at minimum cost, with an end product that is of high nutritive value and aesthetically acceptable to the consumer. This review is directed towards evaluating the role for thyroid hormones and steroids in fish culture. Particular attention has been given to the following topics: growth, appetite, food conversion, carcass composition, salt water tolerance, species specificity, deleterious responses and economic implications.
Hypothyroidism and hyperthyroidism are both associated with clinically significant cardiovascular derangements. In hypothyroidism, these include pericardial effusion, heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. Although these usually occur in individuals with intrinsic heart disease, thyroid dysfunction alone rarely causes serious but reversible cardiovascular dysfunction. Patients with commonly encountered cardiac disorders, e.g., idiopathic cardiomyopathy and atrial fibrillation, should be screened for potentially contributing subclinical thyroid diseases. In patients with heart failure and hypothyroidism, initial management should focus on diagnosis and optimal management of any primary cardiac disease, whereas in hyperthyroidism, aggressive measures to control excess thyroid hormone action should generally have the highest priority.
Thirty-six patients with chronic hepatic diseases and ten normal control subjects with matching ages were studied by various clinical, laboratory and histopathologic means. Estimation of serum levels of thyroid hormones and thyroid stimulating hormones (TSH) showed that the average values of rT3, T4 and TSH were higher in the group of chronic liver disease as compared to the controls. In the meantime, the average value of T3 for those presenting with liver affection was lower than the controls. The severity of changes was most marked in the group of established cirrhosis followed by that of hepato-splenic schistosomiasic and chronic active hepatitis in that order of frequency.
Humic substances are implicated as a kind of environmental goitrogen, and increased prevalence of goiter has been recently noticed in the blackfoot disease endemic area in the southwest of Taiwan, where well water is rich in humic substances. In this study we have investigated the effects of humic substances on hepatic 5′-monodeiodinase (5′-MD) in rats to gain knowledge of such effects on thyroid hormone metabolism. Aliquots of rat liver microsome (about 5 μg of protein) were preincubated in 0.1 M Tris buffer (pH 7.4) for 30 min with or without various concentrations (12.5-800 μg/ml) of humic acids, then incubated with thyroxine (T4, 2.5 μM; final volume 1 ml) and dithiothreitol (DTT, 5 or 25 mM) in the same buffer for 30 min. The 3,5,3′-triiodothyronine (T3) generated during incubation was quantified by radioimmunoassay (RIA) of ethanol extracts of the incubation mixture. Humic acids caused a dose-dependent inhibition of hepatic T4 5′-monodeiodi-nation. The mean dose (± sd) that caused a 50% inhibition of 5′-MD activity was 58 ± 6 μg/ml (n = 8). The inhibition was not a result of the depletion of T4 during incubation of T4 with humic acids. Free radical scavengers — catalase (300 U/ml) and superoxide dismutase (100 U/ml) — had no effect on the inhibition of hepatic T4 5′-monodeiodination induced by humic acids. Our data suggest that humic acids influence thyroid hormone metabolism by inhibiting hepatic 5′-MD activity.
Basal thyroid hormone levels were measured in 68 women with liver cirrhosis (LC) of different etiology (alcoholicn=34, posthepatitic Bn=9, PBCn=5, cryptogeneticn=18, M. Wilsonn=2). In addition the rise of TSH after 400 g TRH was measured in 23 women with LC and compared with the data obtained from 17 women of a control group. There was no difference of the median T4-concentrations (LC 8.0 g/dl versus 7.2 g/dl) but a significant correlation of T4 to the grade of decompensation of LC. In contrast of T4 there was a marked decrease of T3 in LC-patients (109 ng/dl versus 143 ng/dl) and a rise of reverse T3 (0.21 ng/ml versus 0.13 ng/ml). The decrease of T3 and rise of reverse T3 equally correlated to the severeness of LC. TBG concentrations fell according to the grade of decompensation of LC and T4/TBG-quotient exhibited no difference to the control data (0.51 both). Though basal thyroid hormones and TSH show euthyroidism the significant augmented TSH release after TRH (-TSH 7.0 versus 3.2 U/ml) indicate a status of latent hypothyroidism. In alcoholic cirrhosis the degree of TSH release was much higher than in non alcoholic cirrhosis. Estradiol and estrone levels correlated significantly negatively to T4, T3, estrone negatively to TBG and positively to reverse T3 but not to TSH and TSH release. Otherwise TSH release correlated positively to estradiol. The thyroid status in women with liver cirrhosis does not differ from the thyroid hormone profile found in men with cirrhosis.
To evaluate thyroid function in 19 patients with fulminant hepatitis (FH), we have measured total and free 3,5,3′-triiodothyronine
(T3) and thyroxine (T4), 3,3′,5′-triiodothyronine (reverse T3, rT3), thyroidstimulating hormone (TSH) and thyroxin-binding
globulin (TBG) in patients with FH, compared with those of 80 patients with other various liver diseases and of 10 healthy
controls. Patients with FH showed the lowest values of serum T3 and the highest levels of rT3 among all patients with liver
diseases studied. Furthermore, patients with FH showed a significant increase of rT3 in comparison with subacute hepatitis
(SAH), “acute-on-chronic” (AOC) type of hepatic failure, ordinary and severe forms of acute hepatitis (AHo and AHs) and decompensated
liver cirrhosis (LC-D). In addition, serum T3 and rT3 and the rT3/T3 ratio significantly correlated with prothrombin time
(PT) and plasma methionine level. We also found that serum T3 and rT3 concentrations and the rT3/T3 ratio showed early and
rapid normalization in cases of FH that survived, but they did not improve in patients with fatal outcome. These results suggest
that serum T3, particularly rT3 concentrations and the rT3/T3 ratio may be useful indicators for assessing the severity and
prognosis of patients with FH and can be considered to the sensitive indices for functioning hepatic microsomal reserve as
well.
The effect of increasing age on the ability to metabolize thyroxine by rat liver homogenate was studied. Rats aged 6 weeks
(young), 6 months (mature), and 20 months (senescent) showed no difference in the ability to deiodinate thyroxine at the 51-position to form T3. There was, however, an age related decrease in the ability to generate excess iodide, implying less degradation through
the 5-monodeiodinase pathway.
Paired arterial and venous cord blood samples were obtained from 42 normal newborns (24 males and 18 females). T4 was determined in all paired samples. In addition, other indices were determined: T3 in 40, RT3 in 29, TBG in 29, thyroglobulin (Tg) in 14, and TSH in 11. Gender difference in any of the thyroid indices was not found. Arterial and venous cord serum thyroid indices correlated positively (T4, r = 0.743; T3, r = .907, rT3, r = .920; TBG, r = .752; Tg, r = .934, and TSH, r = .989; P < 0.005). The difference between the means ± SD of arterial and venous levels was significant (P < 0.01) only for rT3 (191 ± 43.2 v 224 ± 55.8 ng/dL). Arterial (T4v T3, r = .453, P < .005; T4v RT3, r = .660, P < 0.005) and venous (T4v T3, r = .620, P < 0.005; T4v rT3, r = .612, P < 0.005); T3 and rT3 levels correlated positively with T4 levels. In contrast, T3 and rT3 levels for arterial (r = .216, P > 0.1) and venous (r = .216, P > 0.1) samples did not show a significant correlation. These data are in keeping with earlier reports for animal placental models studied in vitro, suggesting that placental inner ring deiodination of maternal thyroxine is a source of fetal RT3.
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