Intrathyroidal Iodine Metabolism Research Articles

Clinical prognosis in BRAF-mutated PTC

BRAF mutation has recently emerged as a potential prognostic marker for papillary thyroid carcinoma (PTC) due to several studies suggesting that it may condition the development of tumors with aggressive behavior. A study of the phenotypes of thyroid follicular cell lines and transgenic mice characterized by targeted expression of BRAF mutation indicates that, at variance with RET/PTC rearrangement, it induces or facilitates genomic instability and higher invasiveness and eventually deeper tumor de-differentiation and more significant suppression of apoptosis. An analysis of differential gene expression of PTCs harboring BRAF mutation versus PTCs characterized by other genetic alterations shows an important impairment of the expression of genes related to intra-thyroidal iodine metabolism machinery, up-regulation of Glut-1 mRNA, methylation-induced gene silencing of tumor suppressor genes and up-regulation of pro-angiogenetic proteins such as VEGF. Correlation of BRAF mutation with PTC clinico-pathological features yields controversial results, with several studies showing the association with unfavourable clinico-pathological qualities, while others do not confirm the findings. This review will summarize the studies in favor of or in contrast with a role of BRAF mutation as a prognostic marker in PTC. We will also indicate what information we still need in order to routinely introduce this indicator in clinical practice.

Evaluation of DEHAL1 expression in functional and non-functional thyroid tumors

The iodotyrosine dehalogenase 1 (DEHAL1) has recently been identified as a novel enzyme in the thyroid hormone production and generation system. It catalyses the deiodination of free mono- and diiodotyrosines liberated during thyroglobulin proteolysis, which allows efficient recycling of iodine and tyrosine within the thyroid gland. In this paper we investigated whether changes in intrathyroidal iodine metabolism e.g. with altered thyroid function or in differentially functioning thyroid nodules affect DEHAL1 expression, and furthermore whether DEHAL1 is a marker of thyroid differentiation. Real-time PCR was performed to determine quantitative DEHAL1 mRNA expression in a series of 10 toxic adenoma, 15 cold thyroid nodules, 25 corresponding normal thyroid tissues, 8 Graves' disease samples, 12 follicular carcinoma and 11 papillary thyroid cancers. In addition, immunohistochemical analysis was performed to assess DEHAL1 protein expression and subcellular localisation in a set of 5 toxic adenoma and 11 cold thyroid nodules and their surrounding normal thyroid tissues, 11 papillary thyroid cancers, 5 follicular carcinomas, 2 anaplastic and 5 medullary thyroid carcinomas. The main findings were a marked upregulation of DEHAL 1 protein expression in toxic thyroid adenomas and Graves'disease with strong apical staining, and papillary cancers. In contrast we found a significant downregulation of DEHAL1 mRNA expression in all thyroid cancers samples and equivocal expression levels in benign thyroid pathologies and normal thyroids. In summary, upregulation of DEHAL1 protein expression is consistent with DEHAL activation during thyrotoxicosis, and mRNA DEHAL1 downregulation is in agreement with DEHAL1 downregulation in dedifferentiated thyroid lesions. The discrepancy between mRNA and protein expression in our series raises the possibility for further splice variants and/or altered DEHAL1 translation as well as alterations in DEHAL1 functionality in functionally and morphologically distinct thyroid pathologies.

Evidence for abnormal iodination of thyroglobulin in cold thyroid nodules

Using a proteomics approach we previously observed upregulation of proteins involved in the reduction of peroxide in cold thyroid nodules. Further we gained first evidence for an abnormal processing of thyroglobulin (Tg) in CTN since several differential isoforms of Tg combined with a drastically increased induction of the cysteine protease cathepsin B as well as upregulation of molecular chaperones were detected by proteome analysis in CTN compared to the surrounding normal thyroid tissue (ST). These results point to either (I) a defect in the integrity of Tg which might prevent the organification and coupling of iodide (I-) to from thyroid hormones or (II) to a principal defect in the uptake and transport of I- in CTN. To investigate the functional protein expression characteristics in CTNs in more detail, immunohistochemical analysis was performed in a series of 12 CTNs and corresponding normal thyroid tissues. The following proteins were studied: (1) proteins involved in intrathyroidal iodine metabolism (Pendrin, ThOX 1/2 and TPO, Tg, T4-Tg); (2) proteins involved in the antioxidative system (PDRX 5, GST-π,) and (3) proteins involved in Tg-processing (cathepsin B). We found (I) complete absence of T4-rich iodinated Tg in CTNs while overall Tg expression was not altered, (II) higher expression of ThOXs and TPO in CTNs compared to ST, (III) upregulation of the antioxidant enzyme PDRX 5 in CTNs and (VI) expression of pendrin depending on follicular size (upregulation only in small follicles in normal thyroid tissues). Taken together, this study confirms the data obtained by proteomics and further reinforce the hypothesis of an altered Tg function with most likely compensatory yet ineffective upregulation of the thyroid hormone synthesis apparatus in CTNs. Moreover, it is tempting to speculate that increased proliferation in combination with deranged abundant peroxide generation may contribute to somatic mutations leading to clonal CTNs.

Update on intrathyroidal iodine metabolism.

The thyroid concentrates iodide from the serum and oxidizes it at the apical membrane, attaching it to tyrosyl residues within thyroglobulin (Tg) to make diiodotyrosine and monoiodotyrosine. Major players in this process are Tg, thyroperoxidase (TPO), hydrogen peroxide, pendrin, and nicotinamide adenine dinucleotide phosphate (NADPH). Further action of TPO, hydrogen peroxide (H2O2), and iodinated Tg produce thyroxine (T4) and triiodothyronine (T3). Hormone-containing Tg is stored in the follicular lumen, then processed, most commonly by micropinocytosis. The lysosomal enzymes cathepsins B, L, and D are active in Tg proteolysis. Tg digestion leaves T4 and T3 intact, to be released from the cell, while the 3,5'-diiodotyrosine (DIT) and 3-iodotyrosine (MIT) are retained and deiodinated for recycling within the thyroid. Some areas of especially active recent research include: (1) the role of molecular chaperones in directing properly folded TPO and Tg to the apical membrane; (2) details of proteolytic pathways; (3) modulation of iodine metabolism, not only by thyrotropin (TSH) but by iodine supply and by feedback effects of Tg, glutathione, and inhibitory elements in the N-terminal region of Tg; and (4) details of Tg structure and iodotyrosyl coupling. Despite general agreement on the major steps in intrathyroidal iodine metabolism, new details of mechanisms are constantly being uncovered and are greatly improving understanding of the overall process.

Effect of excess iodide on thyroid function of rainbow trout,Salmo gairdneri

The acute and chronic effects of excess iodide (KI or NaI) were studied on thyroid function of rainbow trout at 11±1°C. No Wolff-Chaikoff effect, characteristic of mammals, was observed and instead plasma L-thyroxine (T4) levels increased 6 hr after a single iodide injection. Plasma 3,5,3'-triiodo-L-thyronine (T3) did not change and by 24 hr plasma T4 returned to normal. This iodide-induced elevation in plasma T4 was probably not due to toxic effects demonstrated at higher NaI or KI doses. A single iodide injection also decreased the plasma iodide distribution space, decreased the fractional rate of plasma iodide loss and completely blocked thyroidal uptake of radioiodide. Injections of iodide over a 22-day period elevated plasma iodide 200X with no mortality and no influence on plasma T4 or T3. It is concluded that: (i) apart from the transient 6h increase in plasma T4, trout thyroid function, as judged by plasma hormone levels, is insensitive to considerable iodide excess, (ii) non-invasive iodide suppression of thyroidal radioiodide recycling may be useful in kinetic studies of(125)I-labeled thyroid hormones, and (iii) fundamental differences in intrathyroidal iodine metabolism appear to exist between mammals and fish.

Intrathyroidal iodine metabolism in preterm infants and risk of hypothyroidism

Top of pageAbstract In order to elucidate the mechanisms responsible for the high frequency of transient hypothyroidism observed in premature infants in Belgium, we conducted morphological and biochemical studies of thyroid glands collected immediately after death in 14 premature infants (gestational ages 25–35 weeks) who died less than 12 days after birth and compared the results with those obtained in normal adults and in adults with iodine poor non-toxic colloid goiter. The thyroid glands of the prematures exhibited morphological characteristics of hyperstimulation and their serum levels of TSH at the time of death were markedly elevated (27.1±4.5(SEM) μU/ml). In the prematures and in the adults with colloid goiter as compared to normal adults, the concentrations of intrathyroidal iodine, MIT, DIT, and T4 were markedly reduced. In the glands of prematures, the MIT/DIT and T3/T4 ratios were normal but, as compared to adults with colloid goiter, the concentrations of thyroglobulin and the fraction of organified iodine were markedly reduced. These two factors result in an unsufficient utilization of the available iodine, which partly accounts for the very low iodine content of the thyroids observed in the Belgian prematures (20 to 100 μg v. 10,000 to 20,000 in normal adults). In our country this reduction of the thyroidal pool of iodine could be aggravated by the low dietary supply of iodine and play a decisive role in the development of transient hypothyroidism in prematures.

Clinical pharmacokinetics of antithyroid drugs.

Organic antithyroid drugs used today include propylthiouracil and the mercaptoimidazolines, carbimazole and methimazole. They can be measured with accuracy and in small quantities in serum by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay. Bioavailability of these drugs varies from 80 to 95%. During absorption carbimazole, which itself is inactive, is completely converted to methimazole. The total volume of distribution is about 40L for methimazole and around 30L for propylthiouracil, which is about 80% protein-bound, while methimazole is virtually non-protein-bound. Drug transfer across the placenta and into breast milk is also higher for the more lipid-soluble methimazole than for propylthiouracil, which is excreted into breast milk only in small quantities so that no harmful effect to the suckling infant is to be expected. Both drugs are concentrated in the thyroid gland, exerting an effect on intrathyroidal iodine metabolism for periods exceeding those in which serum concentrations can be measured. Less than 10% of both drugs is excreted unchanged in the urine, but detailed metabolic pathways are unknown. The half-life of methimazole is 3 to 5 hours with a total clearance of about 200ml/minute. Propylthiouracil has a half-life of 1 to 2 hours with a clearance of around 120ml/min/m2. Some studies have shown an increased rate of metabolism of anti-thyroid drugs in hyperthyroidism, in particular for methimazole. No reliable information exists regarding pharmacokinetics of these agents in renal and hepatic failure or in children. The clearance of propylthiouracil is unchanged in the elderly. Several mechanisms for the inhibiting effect of these agents on intrathyroidal hormone metabolism have been suggested. In contrast to methimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to triiodothyronine. Preliminary dose-response studies with propylthiouracil suggest a peak therapeutic serum concentration of above 4 micrograms/ml in the treatment of thyrotoxicosis. The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.

Effects of phenylbutazone on thyroid iodine metabolism in vitro.

Abstract. Several alterations of thyroid function parameters have been reported in patients treated with phenylbutazone and we have studied the effect of this drug on the intrathyroidal iodine metabolism. An inhibition of the iodide transport expressed in terms of T/M ratios was observed in bovine thyroid slices incubated with high phenylbutazone concentrations. 10−3m produced 72% inhibition whereas lower concentrations showed no significant difference as compared with controls. Iodotyrosine synthesis was affected by 10−4m and 10−5m phenylbutazone. Formation of iodothyronine synthesis was markedly affected between 10−4m and 10−7m phenylbutazone concentrations. Thyroid peroxidase activity was measured by tyrosine-iodinase, triiodide and guaiacol assays. Soluble, pseudosolubilized and crude peroxidase preparations from bovine glands, as well as the soluble enzyme from human thyroids, have shown inhibition of tyrosine-iodinase activity when incubated with phenylbutazone in concentrations ranging from 10−3m to 10−8m, with a Ki of 4 × 10−6m for bovine thyroid peroxidase and of 6 × 10−6m for human soluble peroxidase. Formation of triiodide was affected between 10−3m and 10−8m phenylbutazone concentrations. Guaiacol peroxidation was scarcely affected by the action of the drug. We have concluded that phenylbutazone affects the intrathyroidal iodine metabolism through the inhibition of thyroid peroxidase in concentrations which are usually present in the sera of patients treated with this drug.

Chemical determination of iodinated compounds in human thyroid.

As a tool with which to detect iodinated compounds in human thyroid specimens, we have reevaluated a nonincineration technique which has so far been employed in the determination of thyroxine-iodine in peripheral blood. The catalytic action of iodoamino acids in the Ce-As reaction was enhanced by a small amount of Cl2. On the contrary, a large amount of Cl2 inhibited the reaction unexpectedly. Among iodide, iodotyrosine and iodothyronine, iodide was the most effective catalyst in the Ce-As reaction and iodothyronine was the least effective one. Protein seemed to inhibit this reaction of thyroglobulin. But the result of iodine content in thyroglobulin by this technique agreed well with that by incineration when measured 127I was corrected by percent activity of dializable part of the total activity of 131I-thyroglobulin with the same protein concentration, after the NaClO treatment. The results of human thyroid specimens were as follows: the thyroglobulin content of five normal subjects was 8.0 +/- 1.5% of wet thyroid weight. That of Hashimoto's disease was significantly decreased which seemed compatible with the decrease in iodine content of thyroglobulin, whereas thyroglobulin content of Graves disease treated with 1-methyl, 2-mercaptoimidazole followed by a large dose of iodide was well preserved in spite of a lower degree of iodination of thyroglobulin. As for the distribution of iodoamino acids-iodine in normal thyroid, T4 was 20.5 +/- 0.7%. This technique ultimately looks promising as a tool with which to study intrathyroidal iodine metabolism in human.

EFFECTS OF AMIODARONE ON THYROID IODINE METABOLISM IN VITRO1)

Since alterations of thyroid function have been reported in patients treated with amiodarone, 2-butyl,3-(4-diethylaminoethoxy-3,4-diiodo, benzoyl) benzufuran, the effects of this drug on the active iodide transport, organic iodine formation, thyroid peroxidase and the enzymatic iodotyrosine deiodination, were studied. In pig thyroid slices the iodide transport was affected by amiodarone at concentrations of 10(-4) M and 10(-5) M, showing a decrease of T/M (tissue/medium) ratios of 20% and 23%, respectively. Lower concentrations produced no significant differences from the controls. Iodotyrosine synthesis was only, but poorly, affected by 10(-4) M and 10(-5) M amiodarone. Inhibition of the DIT formation was greater than that produced for MIT. Thyroid peroxidase activity, as measured by the tyrosine-iodinase assay, showed a 20% decrease at 10(-3) M amiodarone. None of the other concentrations have affected the activity of the enzyme, except for 7% at a concentrations of 10(-4) M. The iodotyrosine deiodination was affected by amiodarone only at a concentration of 10(-3) M and 10(-4) M. The inhibitions were of 22.5% and 16.8%, respectively. We have concluded that, under the conditions of our study, amiodarone per se does not affect the intrathyroidal iodine metabolism in concentrations which are usually present in the sera of patients treated with this drug. However, it is not possible to rule out an in vivo direct action, if amiodarone is substantially concentrated in the human thyroid gland.

A comparative study of avian and rat patterns in thyroid function—I. intrathyroidal iodine metabolism

1. Ducks, pigeons or quail, fed an iodine adequate diet (IAD) show a very small T 3/T 4 ratio compared to the rat (0·03 vs 0·14). 2. The stable iodine content of the duck thyroid is four to five times greater than in the rat (4·70 ± 0·30 μg/mg thyroid vs 0·86 ± 0·08 μg/mg) corresping to an elevated 131I retention after a tracer dose injection. 3. Equilibration between pre-existing 127I and newly injected 131I, occurs after 48 hr in the rat and 96 hr in the duck. 4. Iodine deficiency leads to equilibrium between % of iodine in MIT and DIT in the rat thyroid, while % in MIT remains smaller than in DIT in the duck thyroid.

Alterations in intrathyroidal iodine metabolism in response to chronic iodide administration.

In order to observe the alterationsin intrathyroidal iodine metabolism which occur in response to chronic iodide administration, iodine metabolism in rats given 500 µg of iodide/ day (iodide group) was compared to that in rats given 10 μg of iodide/day (control group). Ratswere given 126I with 127I in their drinking water for 4 weeks until the time of sacrifice. Rats were also injected with 131I and killed at various time intervals up to 48 hr after 131I. In the 2 groups, thyroidal 127I content and serum iodothyronine- 127I concentrations did not differ significantly from each other, while absolute iodine uptake calculated from thyroidal clearance of 131I multiplied by the serum 127I concentration was 2.5 times greater in the iodide group than in the control. With respect to both m I and 131I, the. proportion of iodothyronines as a per cent of total thyroidal organic iodine did not differ greatly in the 2 groups. This indicated the apparently contradictory results that the iodide group took up 2.5 times a...

Defective intrathyroidal iodine metabolism in nontoxic goiter: inadequate iodination of thyroglobulin.

Different parameters of intrathyroidal iodine metabolism have been investigated in 27 sporadic nontoxic goiters, and compared with similar observations carried out in normal thyroid glands. In nontoxic goiters, the marked drop in 127I concentration is found to be linked with a similar fall in the iodination level of the thyroglobulin, the average value being .06% compared with .23% in normal glands. The percentage distribution of the iodoaminoacids in the glands shows a significant decrease in the amount of iodine present as DIT and T4. In each sample, the ratio DIT*/MIT*+DIT* decreases as a function of the drop in the iodine concentration of the tissue; the 2 parameters also show marked modifications in different samples taken from the same glands. The T4-127I percentage is about normal in some goiters, but appears noticeably lower when the iodination level of the thyroglobulin falls under .1%. An almost parallel modification occurs in the T4/DIT ratio. The relative specific activities of the different iodoaminoacids were studied after the successive administration of 125I and 131I. No compound showed delayed incorporation of radioiodine. It is concluded that the abnormal distribution of the iodoaminoacids in goitrous glands is not caused by any specific defect of the hormone synthesis, but that it merely reflects a critical reduction in thyroglobulin iodination.

Intrathyroidal iodine metabolism in the rat. The iodotyrosines.

Intrathyroidal iodine metabolism in the rat. The iodotyrosines.

Sex differences in the pattern of radioiodine excretion in the urine of intact stilboestrol-treated guinea pigs.

THE effects of oestrogen on intra-thyroidal iodine metabolism have been widely investigated1–3, but very little is known about its influence on the excretion of iodine in urine. In thyroidectomized castrated male rats on a daily maintenance dose of dl-thyroxine there is some indication that 50 µg of œstradiol benzoate daily for one week causes a slight retention of radioiodine1. Feldman3 has observed a decreased renal clearance of iodine-131 in both castrated and hypophysectomized rats receiving 500 I.U. of œstrone daily, but the decrease was not significant when compared with controls. It is most likely1,4 that oastrogen influences thyroidal activity by depression of renal excretion of iodine-131. It has also been reported that œstrogen influences the distribution of radioiodine in castrated male rats5.

A Probable Abnormality in Intrathyroidal Iodine Metabolism in Hyperthyroidism1

ABSTRACT Euthyroid and hyperthyroid patients were given radioiodine. Measurements were made of thyroid uptake, urinary radioiodine excretion, serum protein-bound radioiodine concentration and body radioactivity for from 5 to 15 days before and for from 7 to 15 days after Tapazole was started. Stable serum protein-bound iodine concentration and urinary iodine excretion were determined. After Tapazole administration the urinary excretion of radioiodine increased above the amount predicted from a block of the uptake of recycling extrathyroidal hormonal radioiodine in euthyroid patients but equaled the predicted increase in hyperthyroid patients. An effect of Tapazole on the peripheral metabolism of thyroxine was not demonstrated clearly, nor would it probably have accounted for the difference noted. Iodide therapy resulted in a striking diminution in urinary radioiodine excretion in one patient receiving Tapazole, with a concomitant slowing in the decrease of thyroidal radioiodine without a reciprocal effect...