Surface water mitigates the anti-metamorphic effects of elevated perchlorate concentrations in New Mexico spadefoot toad larvae (Spea multiplicata).

Perchlorate (ClO4-) has potential to negatively impact amphibian populations by inhibiting thyroid hormone production, and thus metamorphosis in developing larvae. However, variability exists in species sensitivity, and there is evidence suggesting that natural surface waters can mitigate the anti-metamorphic potential of perchlorate. New Mexico spadefoot toad tadpoles, Spea multiplicata, were exposed to natural surface waters spiked with nominal concentrations of 0, 1000, 1350, 1710, 3000, 5110, and 8000 µg/L perchlorate ion for up to 42 days. No consistent dose-response trends were observed in mortality, rate of metamorphosis, Gosner stage, mass, or length. This study suggests that perchlorate exposure to concentrations as high as 8000 µg/L in natural surface waters does not result in adverse effects on New Mexico spadefoot tadpoles and emphasizes the importance of using site-specific conditions and species when evaluating ecological risks in perchlorate-impacted areas.

Underlying Mechanisms of Pituitary-Thyroid Axis Function Disruption by Chronic Iodine Excess in Rats.

BACKGROUND: Iodine is essential for thyroid hormone synthesis and is an important regulator of thyroid function. Chronic iodine deficiency leads to hypothyroidism, but iodine excess also impairs thyroid function causing hyperthyroidism, hypothyroidism, and/or thyroiditis. This study aimed to investigate the underlying mechanisms by which exposure to chronic iodine excess impairs pituitary-thyroid axis function. METHODS: Male Wistar rats were treated for two months with NaI (0.05% and 0.005%) or NaI+NaClO4 (0.05%) dissolved in drinking water. Hormone levels, gene expression, and thyroid morphology were analyzed later. RESULTS: NaI-treated rats presented high levels of iodine in urine, increased serum thyrotropin levels, slightly decreased serum thyroxine/triiodothyronine levels, and a decreased expression of the sodium-iodide symporter, thyrotropin receptor, and thyroperoxidase mRNA and protein, suggesting a primary thyroid dysfunction. In contrast, thyroglobulin and pendrin mRNA and protein content were increased. Kidney and liver deiodinase type 1 mRNA expression was decreased in iodine-treated rats. Morphological studies showed larger thyroid follicles with higher amounts of colloid and increased amounts of connective tissue in the thyroid of iodine-treated animals. All these effects were prevented when perchlorate treatment was combined with iodine excess. CONCLUSIONS: The present data reinforce and add novel findings about the disruption of thyroid gland function and the compensatory action of increased thyrotropin levels in iodine-exposed animals. Moreover, they draw attention to the fact that iodine intake should be carefully monitored, since both deficient and excessive ingestion of this trace element may induce pituitary-thyroid axis dysfunction.

Radioactive iodide (131 I-) excretion profiles in response to potassium iodide (KI) and ammonium perchlorate (NH4ClO4) prophylaxis.

Radioactive iodide ((131)I-) protection studies have focused primarily on the thyroid gland and disturbances in the hypothalamic-pituitary-thyroid axis. The objective of the current study was to establish (131)I- urinary excretion profiles for saline, and the thyroid protectants, potassium iodide (KI) and ammonium perchlorate over a 75 hour time-course. Rats were administered (131)I- and 3 hours later dosed with either saline, 30 mg/kg of NH(4)ClO(4) or 30 mg/kg of KI. Urinalysis of the first 36 hours of the time-course revealed that NH(4)ClO(4) treated animals excreted significantly more (131)I- compared with KI and saline treatments. A second study followed the same protocol, but thyroxine (T(4)) was administered daily over a 3 day period. During the first 6-12 hour after (131)I- dosing, rats administered NH(4)ClO(4) excreted significantly more (131)I- than the other treatment groups. T(4) treatment resulted in increased retention of radioiodide in the thyroid gland 75 hour after (131)I- administration. We speculate that the T(4) treatment related reduction in serum TSH caused a decrease synthesis and secretion of thyroid hormones resulting in greater residual radioiodide in the thyroid gland. Our findings suggest that ammonium perchlorate treatment accelerates the elimination rate of radioiodide within the first 24 to 36 hours and thus may be more effective at reducing harmful exposure to (131)I- compared to KI treatment for repeated dosing situations. Repeated dosing studies are needed to compare the effectiveness of these treatments to reduce the radioactive iodide burden of the thyroid gland.

Total thyroidectomy for amiodarone-associated thyrotoxicosis: should surgery always be delayed for pre-operative medical preparation?

OBJECTIVE: Amiodarone can induce severe hyperthyroidism that justifies its withdrawal and the introduction of antithyroid drugs. Continuing amiodarone use, failure to control hyperthyroidism and poor clinical progress may require thyroidectomy. This study aimed to evaluate patients' post-operative development and mid-term outcome after thyroidectomy for amiodarone-associated thyrotoxicosis. STUDY DESIGN: Prospective case series. SETTING: Tertiary care centre. SUBJECTS AND METHODS: We prospectively collected cases of amiodarone-associated thyrotoxicosis requiring thyroidectomy due to failure of antithyroid treatment, despite amiodarone discontinuation. Post-thyroidectomy complications were compared immediately, 30 days and one year post-operatively, and also for scheduled versus emergency surgery cases. RESULTS: Of 11 total cases, nine scheduled thyroidectomy cases had no morbidity after elective surgery. Two cases required emergency surgery for multiple organ failure and cardiac problems. Immediate post-operative complications (mostly haemodynamic) occurred in both cases (emergency vs routine surgery, p = 0.018). CONCLUSION: In such cases, pre-operative medical treatment is vital to limit peri- and post-operative complications, but surgery should not be delayed if the haemodynamic status deteriorates. Surgery, with careful anaesthesia, is the cornerstone of the treatment.

Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial.

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in nature, but most physicians are reluctant to continue amiodarone. When prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT type 1 and 2, perchlorate (ClO(4)) might be useful because ClO(4) reduces the cytotoxic effect of amiodarone on thyrocytes. OBJECTIVES: Our objectives were to demonstrate the feasibility of continuation of amiodarone in AIT type 2 and to evaluate the usefulness of ClO(4) (given alone or in combination with prednisone) in AIT type 2. DESIGN AND SETTING: A randomized multicenter study was conducted in 10 Dutch hospitals. METHODS: Patients with AIT type 2 were randomized to receive prednisone 30 mg/d (group A, n = 12), sodium perchlorate 500 mg twice daily (group B, n = 14), or prednisone plus perchlorate (group C, n = 10); all patients continued amiodarone and were also treated with methimazole 30 mg/d. Follow-up was 2 yr. MAIN OUTCOME MEASURES: Treatment efficacy (defined as TSH values ≥ 0.4 mU/liter under continuation of amiodarone) and recurrent thyrotoxicosis were evaluated. RESULTS: Initial therapy was efficacious in 100, 71, and 100% of groups A, B, and C, respectively (P = 0.03). The 29% failures in group B became euthyroid after addition of prednisone. Neither the time to reach TSH of 0.4 mU/liter or higher [8 wk (4-20), 14 wk (4-32), and 12 wk (4-28) in groups A, B, and C respectively] nor the time to reach free T(4) of 25 pmol/liter or below [4 wk (4-20), 12 wk (4-20), and 8 wk (4-20) in groups A, B, and C) were significantly different between groups (values as median with range). Recurrent thyrotoxicosis occurred in 8.3%. CONCLUSION: Euthyroidism was reached despite continuation of amiodarone in all patients. Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes.

Facing the nuclear threat: thyroid blocking revisited.

CONTEXT: People being exposed to potentially harmful amounts of radioactive iodine need prophylaxis to prevent high radiation-absorbed doses to the thyroid. OBJECTIVE: Parameters determining the individual protective effect of a pharmacological intervention were investigated. DESIGN AND PARTICIPANTS: Biokinetics of (123)I was evaluated in 27 healthy volunteers (aged 22-46 yr, median 25 yr, in total 48 assessments) twice in a baseline measurement of the undisturbed kinetics and in an intervention assessment 48 h later. INTERVENTIONS: Seven regimens using single doses of potassium iodide (KI) or sodium perchlorate (SP) at different times relative to exposure were compared: 100 mg KI (-24, 2, 8, 24 h), 100 mg SP (2 h), or 1 g SP (2, 8 h). MAIN OUTCOME MEASURES: Different drugs and dosages and the influence of individual parameters of iodine kinetics should be tested. RESULTS: Mean dose reductions for interventions at -24, 2, 8, and 24 h relative to the activity incorporation were 88.7, 59.7, 25.4, and 2.8%, respectively. One gram SP was equally effective as 100 mg KI; residual uptake was observed after 100 mg SP. The individual dose reduction decreased exponentially with the effective half-life of the activity in the blood. Kinetics in subjects older than 40 yr was as assumed in official guidelines for the prophylaxis after nuclear accidents but was faster in younger participants. CONCLUSIONS: Data on the efficacy of thyroid blocking used in the guidelines are adequate for older people but not for young individuals with their typically faster kinetics. SP may be used for thyroid blocking as alternative for individuals with iodine hypersensitivity.

[Response to adjuvant therapy with potassium perchlorate in amiodarone-induced thyrotoxicosis: observations on three cases]. / A propósito de tres casos. Respuesta a la terapia adyuvante con perclorato potásico en la tirotoxicosis inducida por amiodarona.

INTRODUCTION: Amiodarone-induced thyrotoxicosis (AIT) is a common clinical disorder that may be life threatening and whose clinical manifestations and response to treatment may vary among patients. METHODS: We present three patients treated with amiodarone for atrial fibrillation who developed AIT at least 36 months after beginning the treatment. Thyrotoxicosis worsened the underlying cardiac disorders and was resistant to treatment based on the combination of dexamethasone 8-12 mg/day i.v., thioamides 45 mg/day p.o., beta blockers and potassium perchlorate at doses of 800 to 1000 mg per day p.o. Two of the patients attained sustained euthyroidism after 12 and 32 days of combined treatment, while the third required total thyroidectomy. CONCLUSION: The combination of thioamides with potassium perchlorate is an appropriate form of therapy for AIT in patients resistant to thioamides. The use of this combination should be evaluated in patients with mixed AIT or AIT of unclear etiology.

Evaluation of potassium iodide (KI) and ammonium perchlorate (NH4ClO4) to ameliorate 131I- exposure in the rat.

Nuclear reactor accidents and the threat of nuclear terrorism have heightened the concern for adverse health risks associated with radiation poisoning. Potassium iodide (KI) is the only pharmaceutical intervention that is currently approved by the Food and Drug Administration for treating (131)I(-) exposure, a common radioactive fission product. Though effective, KI administration needs to occur prior to or as soon as possible (within a few hours) after radioactive exposure to maximize the radioprotective benefits of KI. During the Chernobyl nuclear reactor accident, KI was not administered soon enough after radiation poisoning occurred to thousands of people. The delay in administration of KI resulted in an increased incidence of childhood thyroid cancer. Perchlorate (ClO(4)(-)) was suggested as another pharmaceutical radioprotectant for 131I- poisoning because of its ability to block thyroidal uptake of iodide and discharge free iodide from the thyroid gland. The objective of this study was to compare the ability of KI and ammonium perchlorate to reduce thyroid gland exposure to radioactive iodide (131I-). Rats were dosed with 131I- tracer and 0.5 and 3 h later dosed orally with 30 mg/kg of either ammonium perchlorate or KI. Compared to controls, both anion treatments reduced thyroid gland exposure to 131I- equally, with a reduction ranging from 65 to 77%. Ammonium perchlorate was more effective than stable iodide for whole-body radioprotectant effectiveness. KI-treated animals excreted only 30% of the (131)I(-) in urine after 15 h, compared to 47% in ammonium perchlorate-treated rats. Taken together, data suggest that KI and ammonium perchlorate are both able to reduce thyroid gland exposure to 131I- up to 3 h after exposure to 131I-. Ammonium perchlorate may offer an advantage over KI because of its ability to clear 131I- from the body.

Amiodarone-induced thyrotoxicosis. A review.

Amiodarone (AM), a potent class III anti-arrhythmic drug, is an iodine-rich compound with a structural resemblance to thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the commonly employed doses, AM causes iodine overload up to 50-100 times the optimal daily intake, which may be responsible of a spectrum of effects on thyroid function often counterbalancing its heart benefits. Although most patients on chronic AM treatment remain euthyroid, a consistent proportion may develop thyrotoxicosis (AM-induced thyrotoxicosis, AIT) or hypothyroidism. AIT is more prevalent in iodine-deficient areas and is currently subdivided in two different clinico-pathological forms (AIT I and AIT II). AIT I develops in subjects with underlying thyroid disease, and is caused by an exacerbation by iodine load of thyroid autonomous function; AIT II occurs in patients with no underlying thyroid disease and is probably consequent to a drug-induced destructive thyroiditis. Mixed or indeterminate forms of AIT encompassing several features of both AIT I and AIT II may be also observed. The differential diagnosis between AIT I and AIT II (which is important for the choice of the appropriate therapy) is currently made on radioiodine uptake (RAIU), which may be high, normal or low but detectable in AIT I, while is consistently very low or undetectable in AIT II and on colour-flow Doppler sonography (CFDS) showing normal or increased vascularity in AIT I and absent vascularity in AIT II. Quite recently, studies carried out in our Units at the University of Cagliari (Italy) showed that sestaMIBI thyroid scintigraphy may represent the best single test to differentiate AIT I (showing increased MIBI retention) from AIT II (displaying no significant uptake). Treatment of AIT is dependent from its etiology. AIT usually responds to combined thionamides and potassium perchlorate (KClO4) therapy, AIT II generally responds to glucocorticoids, while indeterminate forms may require both therapeutic approaches. In patients with AIT I definitive treatment of hyperthyroidism by administration of (131)I, initially not feasible for the low RAIU and/or the risk of thyrotoxicosis exacerbation, is advised after normalization of iodine overload. To control severe AIT additional treatment with lithium carbonate, the use of short course of iopanoic acid and plasmapheresis have been also proposed. In cases resistant to medical treatment and/or in patients with severe cardiac diseases who cannot interrupt AM or require quick AM reintroduction, total thyroidectomy (possibly carried out by minimally invasive video-assisted technique) may be proposed after rapid correction of thyrotoxicosis with combination of thionamides, KClO4, corticosteroids and a short course of iopanoic acid.

Potassium perchlorate only temporarily restores euthyroidism in patients with amiodarone-induced hypothyroidism who continue amiodarone therapy.

CONTEXT: Amiodarone-induced hypothyroidism (AIH) may occur in patients with or without underlying thyroid disorders. In the latter, restoration of euthyroidism, after amiodarone discontinuation, can be facilitated and accelerated by a short course of potassium perchlorate (KClO4). However, it is unknown whether KClO4 may exert similar effects on thyroid function of AIH patients if amiodarone treatment is continued. OBJECTIVE: To evaluate the effects of KClO4 on thyroid function in AIH patients (without underlying thyroid disease) while continuing amiodarone treatment. DESIGN AND PATIENTS: An open, prospective study of 10 consecutive AIH patients without underlying thyroid abnormalities referred to a tertiary referral center, and treated with KClO4 (600 mg/day) for a period of 26+/-13 days (range, 15-45 days). An additional, historical group of 12 consecutive patients with subclinical AIH left untreated while continuing or after withdrawing amiodarone was retrospectively evaluated as to the outcome of thyroid function. MEASUREMENT: Serum free T4, free T3, and TSH concentrations were measured at booking, during KClO4 treatment and after withdrawing the drug. RESULTS: In the prospective study, KClO4 treatment restored euthyroidism in all patients within 28+/-11 days (range, 15-45 days). After KClO4 withdrawal, however, all patients became hypothyroid again after 45+/-15 days (range, 30-60 days). Two patients developed mild leukopenia (1 case) or a slight increase in serum creatinine levels (1 case), which promptly normalized after KClO4 withdrawal. In the historical group, followed for at least 12 months, euthyroidism was spontaneously and stably achieved after an average of 6 months in 5 patients in whom amiodarone could be discontinued, while subclinical hypothyroidism persisted in 7 patients in whom amiodarone had to be continued. CONCLUSIONS: KClO4 very effectively restores normal thyroid function in AIH patients without underlying thyroid abnormalities, despite the fact that amiodarone therapy is continued. However, euthyroidism does not persist after KClO4 is withdrawn; in addition, spontaneous recovery of euthyroidism does not seem to occur in this subset of AIH patients, unless amiodarone is discontinued. Therefore, also in view of its potential side-effects, KClO4 cannot be recommended as a first-line treatment for AIH if amiodarone needs to be continued, while LT4 replacement is recommended under these circumstances, with periodical reassessment of thyroid function.

[Therapy and prevention of hyperthyroidism]. / Therapie und Prävention der Hyperthyreose.

A decreased serum TSH level can be observed in more than 10% of the German population. Although treatment is not mandatory in each of these cases patients with an unrecognized autonomous thyroid dysfunction have a substantial risk of developing thyrotoxicosis when exposed to large amounts of iodine. Thionamid drugs in combination with potassium perchlorate are given for preventive and therapeutic reasons until definitive thyroidectomy or radioiodine therapy is performed. In younger patients Graves' disease is the main cause of hyperthyroidism. Medical treatment with antithyroid drugs is established to render patients euthyroid. Having decreased the dose as far as possible, drug therapy is continued for 12-18 months to achieve a maximum rate of permanent remission. Ongoing clinical research aims to characterize clinical or laboratory predictors associated with a high risk of relapse after medication is stopped. Selenium supplementation is proposed to be a new therapeutic approach for autoimmune thyroid disease. It is already used quite liberally although data of powerful randomized trials are not available.

Scintigraphy for risk stratification of iodine-induced thyrotoxicosis in patients receiving contrast agent for coronary angiography: a prospective study of patients with low thyrotropin.

The risk of iodine-induced thyrotoxicosis in euthyroid patients receiving iodine-containing contrast agents is known to be low, but data on this risk in patients with latent hyperthyroidism are scarce. We investigated the role of thyroid scintigraphy using Tc-99m preceding the application of iodine-containing contrast material to estimate the risk of iodine-induced thyrotoxicosis in patients with low levels of TSH. In a prospective study on 91 patients, thyroid scintigraphy was performed before coronary angiography (CA). In patients with technetium thyroid uptake (TCTU) less than 1%, CA was done without prophylactic drugs (n = 56). Patients with TCTU greater than 1% were treated either with 900 mg of perchlorate or, depending on the autonomous volume, combined with 20 to 60 mg thiamazole. In the 56 patients with TCTU less than 1%, no case of iodine-induced hyperthyroidism occurred within 4 wk after CA. In the patients who received prophylactic drugs, two cases of mild thyrotoxicosis were observed. Our data suggest that in patients with low levels of TSH, the risk of hyperthyroidism after application of iodine-containing contrast media is negligible if TCTU is less than 1%. In these patients, CA can be performed without administration of prophylactic drugs.

[Amiodarone and the thyroid gland]. / Amiodaron a tarczyca.

Amiodarone is an iodine-rich drug. Its chronic administration may lead to disturbances in thyroid hormone metabolism and/or overt gland dysfunction. It causes an increased in serum fT4, rT3, and TSH concentrations and a decreased serum level of fT3 without thyroid dysfunction. Amiodarone may induce thyrotoxicosis (AIT--Amiodarone-induced thyrotoxicosis) or hypothyroidism (AIH--Amiodarone-induced hypothyroidism) in some persons. AIT occurs more frequently in areas with low iodine intake. The excess iodine contributes to excessive thyroid hormone synthesis-type I AIT or may lead to thyroiditis and a destructive process of thyroid follicular cells, resulting in excess thyroid hormone release-type II AIT. The mixed form of AIT also occurs. Type I AIT should be treated with antithyroid drugs alone or in association with potassium perchlorate, type II AIT benefits from treatment with glucocorticoids, whereas the mixed form of AIT is most effectively treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. AIT often requires thyroidectomy after restoration of euthyroidism or radioiodine therapy, provided that 24-h thyroid radioactive iodine uptake values permit. AIH prevails in areas with high dietary iodine intake. It requires a discontinuation of amiodarone therapy and thyroid hormone (levothyroxine) replacement. It can remit spontaneously. Amiodarone and L-thyroxine therapy is also possible. Baseline thyroid function tests, thyroid antibodies, and imaging examinations such as thyroid ultrasound on initial evaluation and follow-ups every 6 months must be carefully monitored before starting amiodarone therapy.

A stepwise approach to the treatment of amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) is a complex therapeutic challenge. Two major forms have been described: type I and type II. Methimazole (MMI) and potassium perchlorate (KCLO(4)) is the treatment of choice for the former, whereas corticosteroids are used for the latter. However, mixed forms appear frequently and it is not easy to prescribe corticosteroids because of side effects. The present study investigated the validity of a stepwise therapeutic approach to AIT. Twenty patients with AIT were given 30-50 mg/d of MMI and 1000 mg/d of KCLO(4) initially for a month. Euthyroidism or a significant decrease in serum thyroid hormone levels could be achieved in 12 of the patients (7 with type I, 5 type II). Prednisolone, 40-48 mg/d was added for the 8 nonresponding patients (7 type I, 1 type II) and euthyroidism was achieved in all. The prednisolone dose was decreased when free thyroxine (T(4)) levels normalized, and MMI was titrated, maintaining euthyroidism until urinary iodine excretion normalized. Mixed forms of AIT may prevail in iodine-deficient areas. Initial classification of the patients may cause unnecessary corticosteroid use in a substantial number of patients with AIT. A stepwise approach is feasible; however, when the patient is gravely ill, MMI, KCLO(4), and prednisolone could be prescribed simultaneously.

[Hyperthyroidism due to excess iodine]. / Hyperthyroïdies par surcharge iodée.

TWO TYPES: Hyperthyroidism may develop in around 10% of patients in excess iodine. It may reveal an undetected pretoxic thyroid disease (type I) or have been induced by excess iodine in previously normal thyroid gland or in an euthyroid goiter (type II). IODINE EXCESSE REVEALING THYROTOXICOSIS: In the former situation, symptoms appear shortly after the iodine load, thyroid scintigraphy shows significant uptake and therapy includes discontinuation of iodine excess, antithyroid drugs, potassium perchlorate and, if necessary, thyroidectomy or a therapeutic dose of iodide 131. IODINE-INDUCED THYROTOXICOSIS: In the latter situation (type II) hyperthyroidism may occur several years after the initiation of iodine excess, scintigraphy shows very low or no uptake, spontaneous remission is observed within six months, despite the persistence of iodine excess, and treatment is based on corticosteroids.

Tc-99m pertechnetate scintigraphy before and after potassium perchlorate administration for the diagnosis of retrosternal goiter.

A 52-year-old woman was hospitalized because of dyspnea and dysphagia. Thoracic computed tomography revealed a retrotracheal mass. Tc-99m pertechnetate scintigraphy showed intense accumulation of radioactivity corresponding to the mediastinal mass detected by computed tomography. Repeated Tc-99m pertechnetate scintigraphy performed after oral administration of potassium perchlorate (KCLO4) revealed complete disappearance of the radioactive accumulation in the mediastinum, suggesting that the retrotracheal mass was a retrosternal goiter. Subsequent surgical removal and analysis of the mass showed it was indeed a retrosternal goiter. This case highlights the importance of Tc-99m pertechnetate thyroid scintigraphy with and without KCLO4 administration as a simple, accurate, and cost-effective imaging method to diagnose retrosternal goiter.