Prophylaxis and treatment of iodinated contrast media-induced hyperthyroidism

Intervention trials assessing the efficacy/effectiveness and safety of perchlorates in this clinical setting were mainly conducted in Central Europe. One randomized clinical trial, published in 1996, was completed on 51 patients with euthyroid autonomously functioning nodules (pre-toxic phase) who underwent coronary angiography. These patients represented a population subgroup of particular interest. They were at high risk of iodine media contrast-induced hyperthyroidism following non-deferable procedures in a clinical contest of high cardiovascular risk with the need for limiting the chance of occurring hyperthyroidism in the short and long term. Patients were randomized to receive methimazole 20 mg/day (n = 17), sodium perchlorate (n = 17), and control (no treatment, n = 17). The intervention lasted 16 days (from one day before coronary angiography to 14 days after the procedure) [20]. Both active treatment groups showed similar thyrotropin (TSH) values, thyroid iodine uptake (scintigraphy), and 24-h urinary iodine excretion by comparing time zero with 30 days after. Controls exhibited a relevant reduction of TSH values with a relevant reduction of thyroid iodine uptake and 24-h urinary iodine excretion. Four cases of hyperthyroidism were described (2 controls and one case for each arm of treatment). Although the study results elucidated several physiological mechanisms related to the potential benefit of antithyroid treatment to prevent iodinated contrast media-induced hyperthyroidism, the clinical soundness of the findings was far from being acceptable for supporting extensive use of antithyroid treatment in this cluster of patients.

One non-randomized observational study was conducted on 32 patients with euthyroid multinodular goiter exposed to iodinate media contrast following computerized tomography, coronary or peripheral angiography, or transcatheter aortic valvuloplasty. Among them, 12 were allocated to receive prophylactic intervention with methimazole alone or in combination with ionic inhibitors (including perchlorates); the remaining did not undergo prophylaxis [21]. Methimazole (20 to 40 mg per day) was administered for 16 days (from one day before to 14 days after the procedures). Potassium perchlorate was administered at 900 mg daily up to 10 days after the procedures. The follow-up visits were carried out 4 to 405 days after administering iodinated contrast media. Seventeen patients underwent at least two administrations of iodinated contrast media during the follow-up. Twenty-one patients (58%) were diagnosed with hyperthyroidism, with a remarkable difference in the frequency of diagnosis between the two groups (15% prophylaxis vs. 65% non-prophylaxis, p < 0.01). The evolution of media contrast-induced hyperthyroidism averaged 52 days. No cases of overt hyperthyroidism were diagnosed in the group of patients treated with antithyroid medications. Overall, the results of this study demonstrated the therapeutic effectiveness of prophylactic treatment with antithyroid medication in attenuating the risk of long-term incident iodine media contrast-induced hyperthyroidism. Nevertheless, the lack of randomization and specific cardiovascular endpoints significantly reduced the evidence level for recommendation.

A third study has recently been published to reassess the relevance of the prophylaxis of iodine media contrast-induced in high-risk patients: people aged more than 65 years; admission to the coronary unit because of coronary revascularization or valvuloplasty; thyroid diseases predisposing to iodine media contrast-induced hyperthyroidism (GD, multinodular goiter, autonomously functioning adenoma; overt or subclinical hyperthyroidism). Patients (n = 61, mean age 72 years) were allocated in two groups: prophylaxis with methimazole alone or in combination with sodium perchlorate (n = 23) and no treatment (n = 38). The mean daily methimazole dose was 10 mg when it was administered alone (5 patients) and in combination with sodium perchlorate (n = 17) as well. Only one patient received sodium perchlorate alone. The mean daily perchlorate dose was 600 mg, administered from 7 to 14 days. The combined prophylaxis with methimazole and perchlorate was administered for ten days in the mean. It is unclear the duration of prophylaxis with methimazole alone. Methimazole was administered in 3 naïve patients before the study entry; the starting dose of methimazole was based on background levels of free thyroxine (fT4) and free triiodothyronine (fT3), also considering individual comorbidities. The clinicians involved in the study discretionally selected the candidate patients for prophylaxis, what kind of therapeutic regimen would have been appropriate for each patient (perchlorate alone, methimazole alone, or combination) and total daily dose, and the duration of prophylaxis. Thyroid function was checked at baseline, 4–10 days, 11–30 days, and 30–90 days after the procedures. Patients who received prophylaxis compared to controls had lower baseline body mass index and TSH and higher fT4 values. Thyroid function 11 to 30 days after the procedures was unchanged in 58%, improved in 28%, and worsened in 15% of patients. Risk factors associated with occurring hyperthyroidism were baseline impaired renal function (creatinine 1.14 mg/mL in mean), higher TSH values (1.13 mUI/L), and no prophylaxis (8 cases, 21% vs. 1 case, 4%). One fatality was also registered. The patient had multinodular goiter and background overt hyperthyroidism, and was admitted to the coronary unit for revascularization while on methimazole and sodium perchlorate two days before the angiography. Death was attributable to the deterioration of background cardiovascular disease. Lastly, the authors presented a cost estimation of prophylaxis. Prophylaxis with methimazole costs around 3.48 euros, while prophylaxis with methimazole and sodium perchlorate costs 7.91 euros per person [22]. Although this study was well-designed and conducted, it did not resolve criticisms highlighted by previous studies. More precisely, the lack of randomization, the low number of participants and outcomes, the lack of cardiovascular endpoints, and the relatively low follow-up limited the level of evidence of the results. Moreover, there were considerable selection and allocation biases due to patients’ selection, medications to use, titration, and different evolution of prophylaxis.

Treatment of amiodarone-induced hyperthyroidisms

A pilot study published in 2003 showed that a stepwise approach based on the administration of methimazole and potassium perchlorate for 30 days, followed by glucocorticoids in patients not achieving euthyroidism due to persisting or relapsing hyperthyroidism after an initial response, was associated with better outcomes in AIT. The stepwise approach overcomes the therapeutic uncertainty of the management of AIT. On the one hand, it could be challenging to establish the leading mechanism of hyperthyroidism to differentiate type 1 from type 2 AIT, considering that the overlapping form of AIT is frequently observed. On the other hand, the stepwise approach restricts the use of glucocorticoids in terms of number of treated patients and cumulative dose-exposure. More precisely, the study found that starting with methimazole (30–50 mg/day) and potassium perchlorate 1,000 mg/die up to 30 days resulted in the restoration of euthyroidism in 12 of 20 patients (7 initially diagnosed with type 1 and 5 with type 2 AIT). Therefore, only eight patients received oral glucocorticoids (prednisone 40–80 mg/day) as they did not respond to methimazole and perchlorates. All patients achieved euthyroidism at the end of the trial [23].

No additional randomized controlled trials were conducted to confirm or deny the efficacy of this approach in AIT, so the lack of solid evidence in the field has generated relevant discrepancies in the clinical management of AIT worldwide. An international survey published in 2008 highlighted differences and analogies between American and European Endocrinologists. According to the survey’s responders, AIT was the most prevalent thyroid dysfunction among amiodarone users in Europe but not in the United States (hypothyroidism was more prevalent compared to hyperthyroidism). European, compared to American Endocrinologists, performed a comprehensive diagnostic workup while diagnosing AIT, including concomitant measurement of TSH, fT4, fT3 values, thyroid autoimmunity, neck ultrasound with color Doppler examination, and thyroid scintigraphy. More than European, American Endocrinologists declared that amiodarone discontinuation was usually unnecessary in type 1 and, more frequently, in type 2 AIT. Thionamides were the treatment of choice for type 1 AIT. Combining methimazole with perchlorates was more commonly observed in Europe than in the United States (31% vs. 15%), and the same was true for the combination of methimazole plus glucocorticoids in type 2 AIT [24].

One Dutch randomized, unblinded, controlled trial (2012) explored the efficacy and safety of sodium perchlorate in type 2 AIT [25]. The pharmacologic rationale was in the potential of sodium perchlorate to mitigate the cytotoxic effect of amiodarone on thyrocytes. All the participants were diagnosed with type 2 AIT and were advised not to discontinue amiodarone. All patients received methimazole 30 mg per day over the entire study duration. Besides background methimazole treatment, they were randomized to receive prednisone 30 mg/day (n = 12, group 1), sodium perchlorate 1,000 mg/day (n = 14, group 2), or both perchlorate and glucocorticoids (n = 10, group 3). The study endpoint was the achievement of euthyroidism, defined as a TSH value of more than 0.4 mUI/L while on amiodarone. Follow-up visits were scheduled every four weeks within the first six months, bimonthly from 6 to 12 months, and every six months during the second year. TSH was checked before each follow-up visit to manage medical treatment as follows: 1) if TSH was equal to or more than 0.4 mUI/L, the treatment was tapered until discontinuation in two weeks; 2) if TSH was lower than 0.4 mUI/L after three months from the randomization, the treatment was intensified by adding sodium perchlorate 1,000 mg/day (if group 1) or prednisone 60 mg/day (if group 2); 3) if TSH was <0.4 mUI/L after six months from the randomization, the treatment was furtherly potentiate at discretion of clinicians. Patients were mostly men, with a mean age lower than 60 years, and a mean TSH of 0.01 mUI/L. Group 1 and group 3 patients achieved euthyroidism, while prednisone 30 mg/day was added to background treatment in four (29%) patients of group 2 (who were on sodium perchlorate only). Time to normalization of TSH was shorter in group 1 (4 to 20 weeks, 8 on average) than in group 2 (4 to 32 weeks, 14 on average) and group 3 (4 to 28 weeks, 12 on average). A similar trend was also observed for fT4: group 1 (4 weeks in mean), group 2 (12 weeks in mean), group 3 (8 weeks in mean). None discontinued amiodarone. One relapsing hyperthyroidism was documented in group 1 (after 24 weeks). It was managed easily with the achievement of euthyroidism in 8 weeks. Two cases of relapsing hyperthyroidism were detected in group 3 after 12 and 72 weeks, respectively (remission in 4 weeks for both). Most participants reached normal TSH values at the end of the follow-up. Two participants from group 1, one from group 2, and three from group 3 were diagnosed with hypothyroidism (TSH > 5 mUI/L) and were consequently replaced with levothyroxine. One patient of group 1 with an established diagnosis of type 2 diabetes on a background insulin regimen experienced relevant deterioration of glucose control, which was managed by increasing the mean daily insulin dose. One patient of group 2 had myalgias accompanied by serological elevation of creatine phosphokinase and dermal exanthema after two weeks of treatment. The other two patients in the group 2 had nausea. One patient of the group 3 had serological elevation of transaminase after 12 weeks of treatment. Two patients of group 2 did not complete the study: one died after around 18 months of follow-up, and the second underwent cardiac transplantation after 21 weeks from the randomization. Moreover, one patient of the group 3 did not complete the follow-up due to methimazole-induced agranulocytosis while treating relapsing thyrotoxicosis. Overall, the study results indicate that sodium perchlorate alone is less effective than prednisolone when added to methimazole in treating type 2 AIT. This study has the same limitations mentioned above.

Treatment of Graves’ disease

Evidence suggests that thionamides, compared to potassium perchlorates, are similarly effective in GD [26], thus confirming the remission of GD increases along with the decline of anti-TSH receptor antibody title over the follow-up but controverting an immunomodulatory adjuvant effect of thionamides [26, 27]. Nevertheless, thionamides are the treatment of choice of GD [28]. Thionamides are potent antithyroid medications to restore euthyroidism upon the treatment has started, despite their unpredictable effect on the risk of relapsing/recurring hyperthyroidism. The daily dose of thionamides depends on the severity of hyperthyroidism, as the antithyroid effect of thionamides is dose-dependent. It is unclear whether adverse events related to chronic exposure to thionamides are entirely dose-dependent since severe adverse events have also been described in patients who had assumed a low-moderate daily dose regimen.

Ionic inhibitors, including saturated iodide solutions, were more frequently prescribed in the “pre-thioamides era” [29]. They could be considered as a second-choice treatment of GD. One Japanese observational study assessed the effectiveness of potassium iodide in patients with GD who had developed intolerance or contradictions to thionamides (n = 204) [30]. Among these 204 patients, 44 received potassium iodide, and 29 (66%) achieved adequate control of thyroid hormone levels with a mean daily dose ranging from 10 to 400 mg. Seventeen individuals (40%) achieved the euthyroidism through the entire 7-year follow-up. Fifteen individuals did not achieve the euthyroidism, although a high-dose potassium iodide (up to 750 mg/day) was prescribed. Seven of them controlled the disease after the reintroduction of low-dose methimazole. Around 70% of participants who were assuming potassium iodide (<200 mg/die) obtained adequate control of GD over the 7-year follow-up. Only 35% of patients who had taken high-dose iodine (>200 mg/die) achieved euthyroidism. Overall, the result of this study indicates that ionic inhibitors can be an effective pharmacological alternative in patients with hyperthyroidism for whom thionamides are contraindicated or not tolerated. However, it should be considered that the chance of remission of GD was significantly lower in patients requiring a high-dose potassium iodide regimen (i.e., >200 mg/day). The low number of participants, the observational design of the study, the lack of randomization, and the management of patients during the follow-up lead to considerable selection and allocation biases and reduce the level of evidence of results.

Two observational studies conducted in patients with GD who underwent thyroidectomy showed that the administration of iodate solution (Lugol solution, potassium iodide 100 mg/mL) 10 days before surgery, compared to no treatment, significantly reduced thyroid vascularization, intrathyroidal inflammation and suppressed effectively thyroid hormone synthesis [31, 32]. The approach is also associated with faster recovery from hyperthyroidism ahead of thyroid surgery and lower risk of intraoperative bleeding, thus increasing the level of safety of the entire surgical procedure. The ETA guidelines have implemented this indication, although the level of evidence is still low.

Treatment of hyperthyroidisms and thyrotoxicosis in pregnancy

Evidence is even more limited in pregnant women. According to the European Food Safety Authority, chronic exposure to perchlorates is not associated with teratogenic effects or other mechanisms of embryo and fetal toxicity, as similarly observed in adults as long as chronic consumption by food is lower than 0.3 μg/kg of body weight.

Chronic exposure to perchlorates by food, even contaminated food, is a rare event. However, consumers of exclusively plant-based diets may be exposed to this rare event, especially in the case of inadequate iodine supplementation. The risk of acute intoxication by perchlorate is negligible (https://www.efsa.europa.eu/en/efsajournal/pub/3869).

Nevertheless, the long-term effects of chronic exposure to perchlorate for therapeutical purposes are still unclear in human pathology. It is a partially positive result, especially in pregnant women, as lithium carbonate (another medication of the ionic inhibitor class) has been demonstrated to provide teratogenic effects, and its use in pregnancy is hence outlawed [33].

Sodium perchlorate is known to cross the haemato-placental barrier. However, a daily dose not exceeding 1000 mg per day of sodium perchlorate is not associated with adverse events as long as it does not lead to maternal hypothyroidism, thus putting off the potential adverse effects on fetal outcomes to iatrogenic hypothyroidism in the early stages of pregnancy rather than the exposure to perchlorate per se [3].

Treatment of thyroid storm

The thyroid storm is a rare but potentially fatal condition. Only a few studies have been conducted to test the efficacy and safety of specific pharmacological treatments in thyroid storm with confusing results [34]. The literature review shows anecdotal cases and sporadic experiences [35,36,37] or case series [38] managed in emergency circumstances during intensive care with severe cases of thyrotoxicosis accompanied by hemodynamic decompensation and marked alteration of the level of consciousness (coma). High-dose thionamides are the treatment of choice. Ionic inhibitors, including perchlorates, may be considered an additional therapeutic option in patients requiring intensification of therapy as an add-on to methimazole, glucocorticoids, and beta-blockers.