T3 Production Rate Research Articles

99mTc-MDP uptake in thyroid nodule: Contribution of SPECT-CT and ultrasonography

Iodine kinetic studies were performed in seven patients with hot thyroid nodules, three diffuse toxic goiters and one normal control, using a double label technique (131I and 125I-thyroxine). The investigation was complemented by partial kinetic studies in 29 further subjects, including normal control subjects and euthyroid or hyperthyroid patients with diffuse or nodular goiter. Thyroid iodide uptake and hormonal secretion parameters were significantly increased, up to twice control values, in hot nodules without clinical signs of thyrotoxicosis. Values similar to those of Graves' disease were found in toxic nodular goiter. The exchangeable iodine pool was markedly reduced in those glands where the nodule was adenomatous and radioiodide uptake of normal parenchyma was completely suppressed. In two cases of nontoxic hot nodule with histologic diagnosis of multinodular goiter, and incomplete suppression of the “extranodular” thyroid, the exchangeable iodine pool was comparable to that of normals. The T4 disposal rate was increased, mainly due to a significantly higher metabolic deiodination which seemed to keep pace with the increased T4 production rate in nontoxic nodules. This could be the reason why the mean peripheral T4 pool of clinically nontoxic patients with hot nodules is comparable to that of normal persons, and there are no evident signs of hypermetabolism in spite of the greater thyroid hormone production. A significant “non-T4-iodine” release, probably mainly iodide, was found in every subject. The amount of iodine lost by the thyroid through this “iodide leak” did not relate to the T4 secretion rate but seems to be directly related to the thyroid exchangeable iodine pool size.

Thyroid hormone production rates in rat liver and intestine in vivo: a novel graph theory and experimental solution.

We develop a novel method for finding sufficient experimental conditions for discriminating and quantifying individual biomolecule production sources in distributed, inhomogeneous multisource systems in vivo, and we apply it experimentally to a complex, unsolved problem in endocrinology. The majority of hormonal triiodothyronine (T3) is produced from prohormone thyroxine (T4) in numerous nonthyroidal organs and, with one exception, the T3 production rate has not been fully resolved in any single extrathyroidal organ of any species. Using a readily generalized graphic method called cut-set analysis, we show here that measured steady-state responses in several organs to three independent tracer infusions, two into blood and one directly into the organ(s) of interest, are sufficient to resolve this problem for organs fully accessible to direct infusion in vivo. We evaluated local T3 production in rat liver and intestine, which also required T3 bile flux measurements, and we found that liver produces approximately 31% and whole intestine approximately 6% of whole body T3 from T4. With thyroidal production included, liver contributes approximately 15% and intestine approximately 3% of whole rat T3 production. This new methodology is broadly applicable, especially to biosystems that include molecular interconversions at multiple sites.

Effect of exogenous thyroid-stimulating hormone on thyroid papillary carcinoma cells in tissue culture.

To determine the prognostic value of thyroid suppression therapy in patients with thyroid carcinoma, we studied the effect of thyroid-stimulating hormone (TSH) on the morphology, proliferation rate, and the T3, T4 production rate of primary thyroid carcinoma cells in culture. From August 1997 to February 1998 tissues were collected for immediate culture from 13 patients undergoing surgery for thyroid cancer. Cells were incubated for 48 h with TSH in different concentrations. T3 and T4 production was measured by radioimmunoassay; cell proliferation was measured in a radioactive counter. Morphology was determined by cytologic examination. Ten samples were eligible for analysis. Changes in TSH affected T3 and T4 levels. The proliferation rate was not influenced by TSH levels. Thyroid papillary carcinoma cells grown in culture maintain their T3 and T4 synthesis ability. This ability is TSH-dependent and correlates with TSH concentration. The morphology of the cells is also maintained. However, their proliferation is not TSH-dependent, placing the current postthyroidectomy treatment policy in question.

Role of cytokines in the pathogenesis of the euthyroid sick syndrome.

Nonthyroidal illness (NTI) is associated with complex changes in thyroid function tests and thyroid regulation known as the euthyroid sick syndrome (ESS) (1). The most common abnormality is a reduction in serum total triiodothyronine (TT3) and, to a lesser extent, free T3 (FT3) concentrations (2). Kinetic studies showed that the daily production rate (PR) of T3 is decreased, while its clearance is unchanged in NTI (3). The reduction in serum TT3 concentration is usually accompanied by an increase in serum reverse T3 (rT3) concentration (1), although the latter is normal in patients with chronic renal failure (4), AIDS (5), or traumatic brain injury (6). PR of rT3 is unchanged, but its clearance is reduced (3). These changes in serum TT3 and rT3 concentrations are related to inhibition of the activity of type I 5-deiodinase (5-DI), the enzyme catalyzing deiodination of thyroxine (T4) to T3 and of rT3 to 3,3 -diiodothyronine (7). Serum thyrotropin (TSH) concentration is usually normal, although suppressed values may be found in a minority of patients (1). In addition, a decrease in the nocturnal surge of TSH has been consistently reported in patients with NTI (8–12). Abnormalities of TSH glycosylation causing its decreased biological activity were also described (13). The decrease in serum TSH secretion is in some instances related to the use of dopamine and glucocorticoids in critically ill patients (14). The pathogenesis of changes in serum thyroid hormone and TSH concentrations leading to ESS is not completely understood. Reduced T3 generation in peripheral tissue may be related not only to a decreased 5-DI activity, but also to decreased T4 transport into tissues (15). Substances, such as 3-carboxy-4-methyl-5propyl-2-furanpropanoic acid (CMPF) and indoxylsulfate, which are increased in chronic renal failure, and bilirubin and free fatty acids (FFA), which are increased in other NTI, were reported to decrease T4 uptake in rat liver tissue (16, 17). Interestingly, CMPF and indoxyl-sulfate did not affect TSH secretion in cultured rat anterior pituitary cells (18). Recently, particular attention was focused on the role of cytokines in the pathogenesis of ESS. Cytokines are multifunctional molecules with different biological effects and target cells, which can exert autocrine (on the same cells that secrete them) and paracrine (on adjacent cells), but also endocrine (on distant cells) actions (19). They are usually produced in response to inflammation, infections and cellular injury, and their physiological role remains to be clarified (19). In general, cytokines act through binding to specific cellsurface receptors that were demonstrated also in thyrocytes (20, 21). In addition, thyrocytes synthesize and release cytokines, which might be involved in autocrine or paracrine regulation of thyroid function (22–32). The importance of cytokines in thyroid pathophysiology was recently underscored (Fig. 1). They participate in the pathogenesis of thyroid autoimmune disease by contributing to the growth and differentiation of B and T cells, by inducing expression of HLA class II antigens and adhesion molecules, by recruiting and activating immune cells and by modulating the course of the disease (33). Interleukin-6 (IL-6) and possibly other cytokines are useful markers of thyroid-destructive processes (34). Cytokines have a role in the pathogenesis of Graves’ ophthalmopathy, since they induce orbital fibroblast proliferation and glycosaminoglycan production, and expression of HLA class II antigens, adhesion molecules and heat shock proteins in orbital fibroblasts (35). Numerous studies in vitro and in vivo (both in animals and humans) were carried out in recent years on the effects of cytokines on thyroid function. Since the number of published papers on this issue is very large, in this review we analyzed the most crucial studies to discuss the role of cytokines in the pathogenesis of ESS.

Effects of marginal iodine deficiency on thyroid hormone production, distribution and transport in nonpregnant and near-term pregnant rats.

During pregnancy maternal thyroid hormones are of great importance for normal development of the central nervous system of the fetus. Iodine deficiency of the mother carl result in an impaired development of the fetal brain. In large areas of the world iodine intake is moderately low. To study the effects of marginal iodine deficiency (MID) on the production, distribution, and transport of thyroxine (T4) and 3,5,3'-tri-iodothyronine (T3) in nonpregnant and near-term pregnant rats we performed kinetic experiments (three-compartment analysis). Despite unchanged plasma T4 and T3 during MID, the production and plasma clearance rates of T4 decreased 30% (P = 0.01) in MID nonpregnant (MID-C) rats. For T3, the plasma clearance rate was increased 70% (P = 0.046), while the T3 production was more than doubled (P = 0.042) in MID-C rats. In MID near-term pregnant rats T3 production was decreased 20% (P = 0.04). Hepatic deiodinase type I activity increased during MID in both nonpregnant and pregnant rats. It appears that during MID, rats are able to maintain their euthyroid status. The pronounced increase in transport of T4 from plasma to the fast pool observed in pregnant rats on a normal iodine diet did not occur during MID. In conclusion, in rats MID affects maternal thyroid hormone metabolism, thus influencing the availability of maternal T4 for the fetus.

Steady-state regulation of whole-body thyroid hormone pool sizes and interconversion rates in hypothyroid and moderately T3-stimulated rats.

Steady-state regulation of whole-body T3 and T4 distribution and metabolism were directly evaluated and compared in hypothyroid, euthyroid, and in euthyroid rats moderately T3-stimulated by continuous infusion of 0.15 microg/day L-T3 per 100 g BW, thereby supplementing euthyroid T3 sources by two thirds. Our goal was to develop deeper insights into the hierarchy, quantitative adequacy, and sensitivity of this regulatory system, in response to these hormone production challenges in constant steady state. We used a novel whole-body steady-state experiment design model and data analysis approach, which entails nonexclusive whole-body homogenate extracts and blood collected after 7-day infusions of tracer T3 (T3*) or T4*, quantitatively analyzed chromatographically for T3*, T4* and metabolite* concentrations. Hormone regulation implications across the 3 groups were assessed by comparing (per 100g BW) total body T4 to T3 and T3 from T4 conversion rates (CR(4-3) and CR(3-4)), total body pool sizes (Qtot) and distribution volumes (V(D)), total body production (PR), or plasma appearance rates (PAR), plasma clearance rates (PCR), and elimination rates (k). In the hypothyroid rats, absolute production of T3 from T4 was only a fourth of that in euthyroids: CR(3-4) = 1.55 vs. 6.77 ng/h, but the percent (efficiency) of whole-body T4 converted to T3 was more than double that in euthyroids: %CR(4-3) = 45.4% vs. 21.0%, reflecting an effective doubling of type I and/or type II 5'-deiodinase activity on a whole-body basis in response to severe curtailment of thyroidal production. Whole-body T3 pools and T3 production and clearance rates were all about 2 to 3 times lower in hypo- than in euthyroids: minimum Qtot = 36.8 vs. 100 ng, V(D3) = 148 vs. 236 ml, PAR3 = 3.44 vs. 9.09 ng/h, PCR3 = 13.8 vs. 21.3 ml/h; and nearly all T4 pool size, production, clearance and elimination rates also were very substantially reduced: PCR4 = 0.540 vs. 0.941 ml/h, PR4 = 4.11 vs. 38.3 ng/h, Qtot4 = 128 vs. 702 ng, k4 = 0.0322 vs. 0.0530 h(-1). In moderately T3-stimulated rats, presumed central feedback effects of the added T3 on T4 production and total body pool size also were quite pronounced: PR4 = 21.4 ng/h and Qtot4 = 346 ng were reduced to about half that in euthyroids, but T4 elimination indices were virtually unchanged, and T3 production and elimination were minimally affected. Thus, overall, stabilizing negative feedback regulation of TH functioning at different hierarchical levels is quite bidirectionally sensitive. We found very tight (inhibitory) control over thyroidal T4 secretion, possibly also T3 secretion, and probably also absolute T3 production from T4, in response to moderate (+68%) supplements in T3 production; and the efficiency of total body T3 production from available T4 was amplified substantially in the severe primary hypothyroid state, although not nearly enough to compensate for the malady. Finally, the blood to total body pool fractions (Qb/Qtot) of both T3 and T4, but not the plasma or blood hormone levels, remained remarkably constant in response to these oppositely directed hormone production challenges, suggesting this ratio as an actively regulated, homeostatically-maintained entity.

Metabolism of sulfoconjugated thyroid hormone derivatives in developing sheep

Although the production of thyroxine (T4) in the developing ovine fetus ranges from 20 to 50 micrograms.kg-1.day-1, production rates for 3,5,3'-triiodothyronine (T3) average only 1-2 micrograms.kg-1.day-1, whereas reverse T3 (rT3) production rates approach 5-6 micrograms.kg-1.day-1. Thus the fate of the majority of fetal T4 production is uncertain. Recently we have reported significant concentrations of various thyroid hormone sulfoconjugates in serum and other fetal compartments. In the present study, we used steady-state kinetic techniques in developing sheep to establish the clearance and production rates for T4, T3, and rT3 sulfates. These studies confirm that T4, T3, and rT3 sulfate are predominant metabolites of thyroid hormone in the developing ovine fetus. Plasma clearance rates for T3, T4, and rT3 sulfates are low in the fetus, averaging 0.67 +/- 0.07, 1.46 +/- 0.11, and 4.1 +/- 1 ml.kg-1.min-1, respectively. Clearance rates for these thyrosulfoconjugates increase two to fourfold postnatally, probably reflecting increased activity of 5'-monodeiodinase after birth. Moreover, fetal production rates for these sulfated thyroid hormone metabolites exceed those of 2-wk-old sheep 4- to 10-fold. The data suggest that a significant route of fetal T4 metabolism is sulfation followed by deiodination to rT3 sulfate.

Decreased peripheral 3,5,3'-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues.

T4, rT3, and T3 kinetic studies have been performed in a T4-substituted female who showed an increased serum T4/T3 ratio and substantially increased rT3 serum levels in the presence of normal serum thyroid hormone binding properties. The kinetic studies were performed to discriminate between T4 transport inhibition into plasma T3-producing tissues and inhibition of extrathyroidal T4 to T3 conversion. The principal findings were that both T4 and rT3 transport were inhibited into the rapid equilibrating pool (REP), which mainly consists of the liver. The plasma T3 production rate was decreased. Despite an elevated serum free T4 level, serum TSH was elevated, pointing to T4 transport inhibition at the level of the thyrotroph as well. Transport of T4 and rT3 was normal to the slowly equilibrating pool, whereas no transport inhibition of T3 was found to either pool. Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.

Thyroxine and triiodothyronine distribution and metabolism in thyroxine-replaced athyreotic dogs and normal humans.

Reported parenteral L-thyroxine (T4) replacement doses (10-20 micrograms.kg-1 x day-1) are larger than T4 production rates (2.5 micrograms.kg-1 x day-1) in athyreotic dogs but not humans. Furthermore, initial volumes of 3,5,3'-triiodothyronine (T3) tracer distribution exceed those for T4 in both species. To evaluate these discrepancies, serum T4 and T3 tracer kinetic studies from T4-replaced athyreotic dogs (5 micrograms.kg-1 x day-1 sc) and euthyroid humans were analyzed in a three-pool model (rapidly and slowly equilibrating pools with serum). Dogs had lower total T4 (41%) and T3 (31%) and higher free fractions of T4 (432%) and T3 (456%) than humans. Initial T3 distribution volumes were 454% those for T4 in dogs and 149% in humans, 498% of predicted plasma volumes in dogs and 121-138% in humans. Thus plasma volumes were used as time 0 estimates for T3 data analysis. Dogs had higher fractional T4 and T3 transfer rates from serum to the rapid pools (440-451%), total T4 clearance (353%) and production rates (147%), similar total T3 clearance, but lower free T3 clearance (32%) and production rates (45%) than humans. These findings suggest: 1) higher fractional transfer rates of T4 and T3 from serum to tissues and total serum T4 clearance rates in dogs than humans relate to lower canine serum T4 and T3 binding, and 2) parenteral L-T4 replacement doses required to achieve upper-normal serum total T4 concentrations in athyreotic dogs (5 micrograms.kg-1 x day-1) correspond to T4 production rates (6.8 micrograms.kg-1 x day-1).

Thyroxine sulfate is a major thyroid hormone metabolite and a potential intermediate in the monodeiodination pathways in fetal sheep.

T3 and rT3 production rates in the fetus account for roughly only a third of the total T4 production rate; thus, the fate of the majority of T4 produced in the fetus is unknown (the "T4 disposal gap"). We developed sensitive and specific T4 sulfate (T4S) and T3 sulfate (T3S) RIAs to investigate the roles of these compounds in fetal T4 metabolism. T3, T4, T3S, and T4S were determined in a variety of tissue fluid and/or serum samples obtained from fetal, newborn (n = 6), and adult (n = 6) sheep. Four groups of fetal animals, with gestational ages of 94 days (n = 5), 110-111 days (n = 6), 130-131 days (n = 6), and 145 days (n = 6; term = 150 days), were studied. In addition, type I 5'-monodeiodinase (5'-MDI) activity was quantified in liver and kidney tissues. 5'-MDI activities were lower in 94- to 131-day-old fetuses than in fetuses near term or in newborn animals. Mean serum T3 concentrations increased progressively from 94 days (19 ng/dl) to term (371 ng/dl), while mean T3S and T4S serum concentrations were highest at 130 days gestation (237 and 989 ng/dl), decreasing to term. Serum T3S and T4S concentrations decreased further in newborns and adult sheep. T4S and T3S levels in allantoic fluid were significantly higher than those in urine and amniotic fluid in all fetal age groups studied. T4S levels in bile were high from 94-130 days gestation (873-1006 ng/dl), decreasing by 50% at term (529 ng/dl). T4S concentrations in meconium were 46- to 83-fold higher than those in bile from 94 days gestation to term. In contrast, bile T3S levels increased progressively from 94-145 days gestation (191-605 ng/dl), while meconium T3S levels decreased during the same period (33-14 micrograms/100 g). These data demonstrate that 1) sulfated iodothyronines, particularly T4S, are major thyroid hormone metabolites in the fetus; 2) both T4S and T3S are excreted into bile and urine and concentrated in meconium and allantoic fluid; and 3) the high levels of T4S and T3S in serum and other fluids may reflect lower tissue type I 5'-MDI activities. We speculate that T4S and T3S may be further metabolized to other sulfated metabolites and may account in part for the T4 disposal gap in fetal sheep.

Effect of selenium deficiency on hepatic type I 5-iodothyronine deiodinase activity and hepatic thyroid hormone levels in the rat.

Selenium deficiency in rats for a period of up to 6 weeks inhibited both the production of 3,3',5-tri-iodothyronine (T3) from thyroxine (T4) (5'-deiodination) and also the catabolism of T3 to 3,3'-di-iodothyronine (5-deiodination) in liver homogenates. The hepatic stores of T3 were decreased by only 8% in selenium deficiency, despite the T3 production rate from T4 being only 7% of the rate found in selenium-supplemented rats. Hepatic glutathione S-transferase (GST) activity was increased in both hypothyroidism and selenium deficiency, but apparently by different mechanisms, since mRNA expression for this family of enzymes was lowered by hypothyroidism and increased in selenium deficiency. It is concluded that, since both T3 production and catabolism are inhibited by selenium deficiency, there is little change in hepatic T3 stores, and therefore the changes in the activity of certain hepatic enzymes, such as GST, that are found in selenium deficiency are not the result of tissue hypothyroidism.

Propranolol and Thyroid Hormone Metabolism

Propranolol decreases plasma T3 and increases plasma rT3 in a dose-dependent manner due to a decreased production rate of T3 and a decreased metabolic clearance rate of rT3, respectively, caused by inhibition of the conversion of T4 into T3 and of rT3 into 3,3'-T2. This inhibition of 5'-deiodination is not secondary to inhibition of thyroid hormone transport across the plasma membrane. Propranolol and its major metabolite, 4-hydroxypropranolol, are not directly responsible for these effects, but an unidentified metabolite of propranolol might be involved. beta-blockers ameliorate clinical symptoms and signs of thyrotoxicosis independent of the decrease of plasma 13, that is confined to beta-blockers with membrane-stabilizing activity, such as propranolol and alprenolol. The decrease of plasma T3, however, appears responsible for some of the metabolic responses to beta-blockers.

Medium 3,5,3′-Triiodo-L-thyronine (T3) and T3Generated from L-Thyroxine Are Exchangeable in Cultured GC cells*

Previous studies in rats have shown that the ratio anterior pituitary nuclear L-triiodothyronine (T3) derived from intracellular deiodination of L-thyroxine [T3(T4)]/plasma T3(T4) is much greater than for exchangeable T3 [T3(T3)]. We have addressed the hypothesis that T3(T4) is either selectively accumulated or selectively retained by nuclei in comparison to exchangeable T3 [T3(T3)] in cultured GC cells. GC cells readily generated T3 from T4. When mean medium T3(T4) was experimentally maintained at a low percentage (less than 16%) of total medium T3, to mimic in vivo conditions, nuclear T3(T4) was 2-fold greater than nuclear T3(T3) and the nuclear: medium ratio for T3(T4) was 11-13-fold greater than for T3(T3). The t1/2 of release of nuclear T3(T4) and T3(T3) were indistinguishable from one another and both sources of T3 distributed similarly between the nuclear and cytosol compartments. Thus, in agreement with previous in vivo studies, T3(T4) is derived from cellular T4 and is a significant source of nuclear T3 in GC cells. No evidence for a separate nonexchangeable T3(T4) pool was found as the almost identical cellular distribution and release rates of T3(T4) and T3(T3) from nuclei suggest that T3(T4) generated in these pituitary tumor cells is fully exchangeable. Our findings suggest that the high concentration of T3(T4) in the nuclear fraction is the result of a high intracellular production rate of T3 from T4 relative to the rate of release of T3 from the cell.

Increasing Age Impairs the Thyroid Hormone Response to Overfeeding

Aging in both man and rodent is associated with increases in body weight and body fat. In young adult rats, mixed calorie overfeeding increases triiodothyronine production and decreases weight gain efficiency compared with chow diets. This study was undertaken to determine whether 4- and 14-month-old adult rats have similar responses in thyroxine (T4) and triiodothyronine (T3) metabolism during mixed calorie overfeeding. Four- and 14-month-old male Sprague-Dawley rats were each separated into two groups (n = 14): control (CHOW) versus chow + mixed calorie (CAFE) overfeeding for 28 days. The 4-month-old CAFE-fed rats ingested 662 +/- 54 extra kcal over 28 days and gained 147 +/- 7 vs 113 +/- 5 g (P less than 0.01) for their age-matched CHOW group. The 14-month-old CAFE group ingested 309 +/- 45 extra kcal and gained 58 +/- 6 g weight vs -12 +/- 5 g for their age-matched CHOW group (P less than 0.01). Serum T4 concentrations were unchanged during overfeeding or aging. The serum T3 concentration was increased 24% in the 4-month-old CAFE group compared with the age-matched CHOW group (P less than 0.05), but there was no difference in the serum T3 concentration between the 14-month-old CAFE and CHOW groups. The metabolic clearance and production rates of T3 and T4 were decreased in the 14-month-old vs 4-month-old groups (P less than 0.01). The T3 metabolic clearance rate was increased in the CAFE versus CHOW group in the 4-month-old groups (137.3 +/- 11.2 vs 103.0 +/- 10.1 ml/kg/hr, P less than 0.01) but unchanged in the 14-month-old CAFE and CHOW groups (47.6 +/- 6.6 vs 53.4 +/- 5.3 ml/kg/hr, not significant). Liver type I iodothyronine 5'-deiodinase activity increased during overfeeding in the young (63.6%, P less than 0.02) but not in the older rat group. T4 and T3 production rates were decreased in the older rats and did not increase during overfeeding as observed in the young adult rat.

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg.kg-1.day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylamiodarone levels under the above experimental conditions were 0.20 +/- 0.067 and 0.17 +/- 0.058 mg/l, respectively, which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]-tetraiodothyroacetic acid (10 muCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 +/- 0.008 in controls to 0.074 +/- 0.009 l/day in amiodarone-treated rabbits (p less than 0.05). However, when expressed per unit body weight (1.day-1.kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 +/- 6.7 h in controls vs 49.2 +/- 12.4 h in amiodarone-treated).(ABSTRACT TRUNCATED AT 250 WORDS)

The hidden, nonexchangeable pool of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in man: does it exist?

The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (+/- SD) production rate of T4, T3 and rT3 were: 119 +/- 43, 40.0 +/- 22.0 and 54.9 +/- 20.0 nmol.day-1.(70 kg)-1, respectively. Thus 79.5 +/- 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.

Thyroid hormone metabolism in hypermetabolic patients with haematological disorders.

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.

Exercise regulation of triiodothyronine metabolism.

Negative caloric balance reduces triiodothyronine (T3) production in both humans and rodents. The effects of chronic voluntary exercise and various levels of caloric intake and balance on T3 metabolism were studied in adult male C57/BL6 mice to determine if exercise had any direct effects on T3 production in vivo and in vitro. Chronic voluntary exercise was induced by the addition of running wheels to cages for 28 days. Ad libitum-fed exercising mice ingested 20% greater calories (P less than 0.02), maintained body weight, and increased T3 production (53.1 +/- 5.3 vs. 42.3 +/- 3.4 ng.h-1.100 mg body wt-1; P less than 0.01). Exercising animals pair fed to sedentary ad libitum-fed controls decreased their body mass to an equivalent degree as underfed sedentary animals (caloric intake 75% of ad libitum-fed controls) but had increased T3 clearance compared with weight-matched underfed sedentary control (P less than 0.05). Animals that were underfed and exercised decreased their body weight to a greater extent (P less than 0.01) compared with the sedentary underfed group, but T3 production rates were equal. Activity of liver 5'-deiodinase activity was decreased almost 50% (P less than 0.01) during both exercise plus pair feeding and exercise plus caloric restriction but decreased only 28% during caloric restriction alone (P less than 0.01). T3 metabolic clearance and production rates in vivo were correlated to caloric intake (r = 0.73, P less than 0.01), but an interaction between exercise and caloric balance was observed. Chronic voluntary exercise modulates T3 metabolism via several mechanisms. Exercise has an apparent stimulatory effect independent of caloric intake, but also there are regulatory effects dependent on the absolute level of caloric intake and relative caloric balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid hormone turnover in patients with small cell carcinoma of the lung.

Patients with small cell carcinoma of the lung often present with symptoms suggestive of hyperthyroidism i.e. weight loss without anorexia. Consequently [125I]T4 and [131I]T3 turnover was studied using simultaneously iv bolus injection and noncompartmental analysis in 6 patients with untreated small cell carcinoma of the lung and 14 normal subjects of comparable ages. Both T4 and T3 production rates were enhanced, T4 production being in median 135 nmol.day-1.70 kg-1 (range 111-200) in patients with small cell carcinoma of the lung vs 98 nmol.day-1.70 kg-1 (range 69-134) in controls (P less than 0.01), and T3 production being 46 nmol.day-1.70 kg-1 (range 33-65) vs 31 nmol.day-1.70 kg-1 (range 24-45) (P less than 0.01). The mean transit time was shortened for both T4 and T3, T4 mean transit time being 5.9 days (3.9-8.0 days) vs 8.3 days (6.1-11.2 days) in controls (P less than 0.01), and T3 mean transit time being 0.74 days (0.36-0.98 days) vs 1.03 days (0.81-1.45 days) in controls (P less than 0.01). Serum total and free T4 and T3 levels were unchanged. Basal serum TSH levels and the TSH response to iv TRH were also normal. Thyroid-stimulating immunoglobulins were only present in the serum in 1 of 6 patients. Thus, thyroid hormone production seemed under pituitary regulation. The peripheral effect of thyroid hormones was evaluated measuring serum sex hormone binding globulin levels, which were increased to in median 270% (77-310%) (P less than 0.01) of that in controls, suggesting some degree of hyperthyroidism in liver tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutathione deficiency and peripheral metabolism of thyroid hormones during dietary cysteine deprivation in rats.

1. For a period of 24 d, young rats received a diet containing 120 g casein/kg or the same basic diet supplemented with 1.93 g cysteine/kg. 2. The thyroxine (T4) turnover was decreased in rats receiving the cysteine-deficient diet compared with that of rats on the supplemented diet. Moreover, the extrathyroidal T4 pool and T4 disposal rate decreased. 3. Cysteine deprivation also decreased the peripheral metabolism of 3,5,3'-triiodothyronine (T3). The T3 distribution space, extrathyroidal pool of T3 and T3 disposal rate were diminished. 4. In vitro, deiodination of T4 in liver homogenate assayed with endogenous glutathione (GSH) demonstrated decreased T3 production rates in the case of cysteine deficiency. This difference was minimized by the addition of GSH in amounts sufficient to saturate the reaction kinetics. In the light of this finding, GSH is probably involved in the promotion of certain thyroidal problems induced by a cysteine-deficient diet.