An Update on the Pharmacological Management of Hyperthyroidism Due to Graves’ Disease

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Expert Opinion on Pharmacotherapy

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An update on the pharmacological management of hyperthyroidism due to Graves’ disease

Luigi Bartalena, Maria Laura Tanda, Fausto Bogazzi, Eliana Piantanida, Adriana Lai & Enio Martino

To cite this article: Luigi Bartalena, Maria Laura Tanda, Fausto Bogazzi, Eliana Piantanida, Adriana Lai & Enio Martino (2005) An update on the pharmacological management of hyperthyroidism due to Graves’ disease, Expert Opinion on Pharmacotherapy, 6:6, 851-861, DOI: 10.1517/14656566.6.6.851 To link to this article: http://dx.doi.org/10.1517/14656566.6.6.851

Published online: 14 Jun 2005.

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Download by: [84.123.137.110] Date: 21 February 2017, At: 10:47 Review An update on the pharmacological management of hyperthyroidism due to Graves’

1. Introduction disease 2. Antithyroid drug treatment Luigi Bartalena†, Maria Laura Tanda, Fausto Bogazzi, Eliana Piantanida, 3. Expert opinion Adriana Lai & Enio Martino †University of Insubria, Department of Clinical Medicine, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy

Pharmacological treatment, usually by thionamides (carbimazole, methimazole, propylthiouracil) is, in addition to radioiodine therapy and thyroidectomy, one of the available therapies for Graves’ hyperthyroidism. Thionamides represent the treatment of choice in pregnant women, during lactation, in children and adolescents and in preparation for radioiodine therapy or thyroidectomy. Side effects are relatively frequent but are in general mild and transient. Two main regimens are available: titration method (use of the lowest dose maintaining euthyroidism; duration: 12 – 18 months) and block-and-replace method. Neither one has clear advantages in terms of outcome but the latter method is associated with more frequent side effects. Hyperthyroidism relapses in ∼ 50% of patients, to whom ablative therapy should be offered.

Keywords: Graves’ disease, hyperthyroidism, methimazole, propylthiouracil, thionamides

Expert Opin. Pharmacother. (2005) 6(6):851-861

1. Introduction

Graves’ disease is an autoimmune thyroid disorder characterised, in its classical form, by goitre, hyperthyroidism, ophthalmopathy and, less frequently, dermopathy (pretibial myxedema) [1]. Hyperthyroidism is ultimately due to autoantibodies react- ing with the thyroid stimulating hormone receptor (TSH-receptor antibody; TRAb) and causing uncontrolled stimulation of thyroid function and growth [1]. TRAb is found in ∼ 80 – 90% of untreated Graves’ patients [1]. Graves’ disease is the most common form of hyperthyroidism in iodine-sufficient areas, with a prevalence of 2.7% in women and 0.3% in men [1]. The female/male ratio is ∼ 6 – 7:1, and the peak age of distribution is in the third to forth decades of life [1]. The ideal treatment of Graves’ hyperthyroidism would consist of the elimination of disease triggers, but this is not currently feasible. Therefore, treatments are aimed either at destroying the damaged thyroid (thyroidectomy, radioiodine therapy) or at controlling hyperthyroidism while waiting for a possible remission. Although the For reprint orders, please mechanisms of remission are not fully understood, it may result from a change in contact: the nature of TRAb; from a stimulating to a blocking antibody [2]. In addition, all [email protected] immunological features may fade away, including thyroid autoantibodies, TRAb and evidence of T lymphocyte sensitisation [3]. The latter phenomenon may occur in Graves’ patients with less severe immunoregulatory defects [2]. Pharmacological treatment of Graves’ hyperthyroidism is carried out by the use of thionamides; antithyroid drugs which inihibit thyroid hormone synthesis. Thus, Ashley Publications although thyroidectomy and radioiodine are thyroid ablative therapies leading to www.ashley-pub.com hypothyroidism, antithyroid drug treatment is a conservative therapy leaving the thyroid gland able to produce thyroid hormones.

Table 1. Selection of different treatment modalities for hyperthyroidism due to Graves’ disease.

Thionamides Radioiodine Thyroidectomy

First episode of hyperthyroidism Young age Yes No* Yes ‡ Adult Yes Yes Yes§ Relapse of hyperthyroidism Young age Yes¶ No* Yes ‡ Adults No Yes Yes§ Pregnancy Yes No Yes # Lactation Yes No Yes Suspected malignancy No No Yes Elderly No** Yes Yes ‡‡ Ophthalmopathy Yes Yes §§ Yes Side effects Yes ¶¶ Yes ## Yes *** *Radioiodine has been used in children and adolescents, apparently with no long-term complications; the authors prefer to use it after completion of linear growth and sexual development.‡If goitre is particularly large in the presence of complications from, or poor compliance with, thionamides. §If goitre is large and the patient refuses radioiodine, there is intolerance to thionamides or suspicion of associated malignancy. ¶As an alternative to thyroidectomy. #It is seldom necessary to be performed in the second trimester. **Usually in preparation for definitive therapy only. ‡‡Radioiodine is preferable if the patient’s general condition represents a high surgical risk. §§Radioiodine administration must be associated with concomitant glucocorticoid treatment. ¶¶Although relatively frequent, they are, in general, mild and transient. ## Progression of ophthalmopathy is the only risk (see above); hypothyroidism is a desired goal. ***Hypoparathyroidism and laryngeal nerve paralysis are rare if the surgeon is expert; hypothyroidism is a desired goal.

Selection from the different forms of treatment depends large (particularly if signs and/or symptoms of tracheal or on a series of factors, as illustrated in Table 1. Preconditions oesophageal compression are present), if the patient does not for antithyroid drug treatment include young age (children want to be treated by radioiodine therapy or if there is suspi- and adolescents), small goitre, first episode of hyperthy- cion of associated malignancy in a nodular lesion [1]. roidism, pregnancy, lactation, refusal of surgery or radioiod- Hypothyroidism is inevitable. The course of the ophthal- ine therapy [1]. Radioiodine therapy is required when mopathy is not affected by thyroid surgery. Complications, hyperthyroidism relapses following antithyroid drug treat- such as hypoparathyroidism and laryngeal nerve damage, are ment, in the presence of a small goitre (although larger goi- infrequent (1 – 2%) if the surgeon is expert. tres can be successfully treated by radioiodine), when the patient is > 18 years of age, in the elderly and when surgery is 2. Antithyroid drug treatment not accepted [1]. Whether or not radioiodine therapy represents the treatment of choice in patients with Graves’ oph- 2.1 Thionamides thalmopathy remains a matter of contension. Radioiodine The main drugs used in the management of Graves’ hyperthy- can cause the progression of pre-existing ophthalmopathy roidism are thionamides. These include carbimazole, its active (particularly in smokers) in ∼ 15% of cases but this untoward metabolite, methimazole (MMI), and propylthiouracil effect can easily be prevented by a concomitant short course (PTU). Carbimazole, mainly used in the UK, is rapidly con- of moderate doses of glucocorticoids [4]. Other factors, such verted to MMI and can be considered equivalent to it. MMI as smoking, late correction of postradioiodine hypothy- is the most commonly used thionamide in Europe and Japan, roidism and pre-existing active ophthalmopathy, are likely to whereas PTU is the most prescribed antithyroid drug in the contribute to this adverse effect of radioiodine [4]. This US and South America. modality of treatment is contraindicated in pregnancy and MMI and PTU are the antithyroid drugs of common use for during lactation. Radioiodine therapy is considered by many the management of hyperthyroidism due to Graves’ disease. physicians, particularly in US, to be the treatment of choice Both drugs are given orally and almost completely absorbed in the first episode of hyperthyroidism. Hypothyroidism fol- from the gastrointestinal tract. Although MMI binding to lowing both radioiodine administration or thyroidectomy serum proteins is negligible, PTU is largely (75 – 80%) bound, should not be considered an undue effect but a desired goal. mainly to albumin [5] (Table 2). The serum half-life of MMI is Surgery (total or near-total thyroidectomy) is required after longer than that of PTU (5 – 6 versus 1 – 2 h); the duration of the recurrence of hyperthyroidism following antithyroid drug MMI action is also longer (> 24 versus 12 – 24 h for PTU), treatment in patients < 18 years of age, when the goitre is likely owing to its slower intrathyroidal turnover [5] (Table 2).

852 Expert Opin. Pharmacother. (2005) 6(6) Bartalena, Tanda, Bogazzi, Piantanida, Lai & Martino

Table 2. Pharmacological characteristics of thionamides.

Methimazole Propylthiouracil Relative therapeutic potency 10 – 50 1 Absorption Almost complete Almost complete Binding to serum proteins Negligible 75 – 80% Half-life in serum (h) 5 – 6 1 – 2 Duration of action (h) > 24 12 – 24 Transplacental transfer Low Maybe lower Passage into milk Low Lower Route of administration Oral Oral Administration schedule Once daily 2 – 3 times daily Thyrotoxic storm Intravenous PTU available in some countries PTU: Propylthiouracil.

This has important implications because MMI can usually be with thionamides when Graves’ hyperthyroidism is compli- given as a single daily dose, whereas PTU, at least in the initial cated by iodine load, as with amiodarone-treated patients [12] phases of treatment, must be administered in 2 – 3 daily doses. (see Section 2.8.7). Because of its potential toxicity, it should be Both drugs cross the placenta and can be found in the milk but used neither for > 4 – 6 weeks nor at daily doses > 1 g [12]. Its this phenomenon is limited, particularly with PTU in view of main action is to deplete intrathyroidal iodine stores, thus ren- its very low lipid solubility [5]. The therapeutic potency of MMI dering thionamides more effective. β-Adrenergic antagonists is more than 10-fold greater than that of PTU [5] hence, doses are useful to control symptoms and signs of hyperthyroidism, of MMI required to control hyperthyroidism are lower than such as tachycardia and tremors in the first phases of treatment, those of PTU. This factor may show MMI to be superior; how- when the patients is thyrotoxic, and shortly after radioiodine ever, the choice between the two thionamides is largely related therapy, when hyperthyroidism is unlikely to be fully control- to personal preference and/or local availability. Cost may also be led. Glucocorticoids are not indicated in the management of an issue because in the US in 1999 the cost of 100 tablets was Graves’ hyperthyroidism, despite the autoimmune nature of ∼ $20 for PTU and $80 for MMI [6]; conversely, in the UK this disease but they do have a role in the management of PTU is more expensive than carbimazole. thyrotoxic storm [1] (see Section 2.8.8).

2.2 Non-thionamide drugs 2.3 Mechanism of action of thionamides Drugs other than thionamides have a limited role or are used Thionamide neither inhibits active thyroidal iodide trans- only under special circumstances [1,5]. Lithium carbonate is a port into the thyroid nor blocks the release of stored hor- weak antithyroid drug but can be used before and after radioio- mones from the thyroid. Accordingly, control of dine therapy to avoid radioiodine-associated (and MMI with- hyperthyroidism is not immediate and can require weeks, drawal-associated) rise in serum thyroid hormone levels [7] (see depending on the severity of hyperthyroidism and Section 2.8.5). Stable iodine is utilised in the preparation to intrathyroidal hormone stores. The effectiveness of thiona- thyroidectomy (see Section 2.8.6) because, besides its effect on mides is reduced if intrathyroidal iodine content is high (see thyroid hormone release from the thyroid, it decreases thyroid Section 2.8.7). The main action of intrathyroidal thiona- blood flow and may, therefore, reduce perioperative blood loss mide is to inhibit thyroid hormone synthesis [1]. This is [1,5]. Iodine is also employed in thyrotoxic storm (see Section accomplished because thionamides act as a preferential sub- 2.8.8). Oral iodinated contrastographic agents, such as iopanoic strate for thyroid peroxidase, the enzyme that catalyses acid and sodium ipodate, reduce thyroid hormone release and iodide oxidation, the iodination of tyrosine residues onto peripheral conversion of thyroxine (T4) to triiodothyronine thyroglobulin and the coupling of iodotyrosines (monoiodo- (T3), and can be used, in combination with thionamides, when tyrosine and diiodotyrosine) to form T4 and T3. In this severely thyrotoxic patients must urgently be submitted to thy- way, thionamides compete with thyroglobulin-linked tyro- roidectomy [8,9], in neonatal hyperthyroidism [10] (see sine residues and divert oxidised iodide from hormone Section 2.8.3) and in thyrotoxic storm (see Section 2.8.8). synthesis [13] (Table 3). PTU but not MMI, inhibits type I However, escape from inhibition occurs, as with stable iodine, 5′-deiodinase activity, thus leading to a decrease in periph- within a few weeks, therefore, these agents cannot be employed eral T4 deiodination and T3 formation [1] (Table 3). Evi- either as the sole therapy for hyperthyroidism or on a long-term dence derived from in vitro studies suggests that basis [11]. Potassium perchlorate is mainly used in association thionamides may have immunomodulatory actions, which

Expert Opin. Pharmacother. (2005) 6(6) 853 An update on the pharmacological management of hyperthyroidism due to Graves’ disease

Table 3. Mechanism of action of thionamides. Table 4. Side effects of thionamides.

Action Effect Adverse effect Frequency

Inhibition of iodide uptake No Blood Mild leukopenia Relatively frequent Inhibition of tyrosine residue iodination Yes* Agranulocytosis Rare (0.1 – 0.5%) Inhibition of iodotyrosine coupling Yes* Aplastic anaemia Very rare Inhibition of thyroid hormone release No Thrombocytopenia Very rare Inhibition of type I 5¢-deiodinase Yes‡ Skin Skin rash Relatively frequent *These actions are mediated by the inhibition of thyroid peroxidase. ‡Only for Urticaria Relatively frequent propylthiouracil. Itching Relatively frequent Aplasia cutis Very rare (MMI) may represent part of their therapeutic effect in autoim- Liver Hepatocellular Very rare (PTU) necrosis mune Graves’ disease [14]. However, it seems that these effects on immune reactions in vitro can only be observed Cholestasis Very rare (MMI) using doses higher than those achieved in vivo during Collagen Arthralgias Uncommon antithyroid drug treatment. Changes in autoimmune phe- SLE-like syndrome Very rare (PTU > MMI) nomena in vivo (e.g., decrease in serum TRAb levels or Vasculitis Very rare (PTU > MMI) changes in T-cell subsets) may simply reflect the correction of thyroid hyperfunction, which per se may theoretically Miscellaneous Loss of taste Rare (MMI) contribute to the maintainence of the thyroid autoimmune Hypothrombinaemia Rare (PTU) phenomena through persistent antigen exposure. Insulin autoantibodies Very rare MMI: Methimazole; PTU: Propylthiouracil; SLE: Systemic lupus erythematosus. 2.4 Side effects of thionamides Thionamide treatment can be considered a safe treatment. Overall, adverse effects of thionamides, although relatively rare but serious side effects (Table 4) include; aplastic anaemia, common (∼ 10% of patients), are usually mild and self-limit- hepatocellular necrosis (PTU), cholestasis (MMI), systemic ing, whereas serious side effects occur in < 5% of cases [15] lupus erythematosus-like syndrome, antineutrophil (Table 4). They are more common during the initial phases of cytoplasmic antibody-related vasculitis, hypothrombinaemia treatment, when drug dosage is higher. If an adverse effect is (PTU), hypoglycemia due to insulin autoantibodies and loss observed with one drug, the other thionamide can be substi- of taste (MMI) [15]. Aplasia cutis (i.e., the congenital absence tuted but crossreactivity is a frequent phenomemon ( ∼ 50%) of skin; localised or disseminated, most commonly limited to [15]. Minor effects include skin rash with urticaria and itching, the scalp) has been reported in a few infants born to arthralgia and mild gastrointestinal disturbances. Although hyperthyroid mothers given MMI during pregnancy, whereas relatively common, these phenomena are transient, tend to no such cases have been reported in those following PTU subside spontaneously or with antihistamines (in the case of treatment [18]. Very rare cases of embriopathy (choanal and of skin rash) and usually do not require drug withdrawal. oesophageal atresia, cardiac defects) have been reported in Transient and mild leukopenia can be observed in 10% of infants born to mothers given high doses of MMI early in adults and ≤ 25% of children. Agranulocytosis (neutrophil pregnancy [19] (see Section 2.8.1). count < 0.5 × 109/l) is one of the most serious complications of treatment [15]; it occurs in 0.1 – 0.5% of patients, develops 2.5 Different dose regimens abruptly and requires immediate thionamide withdrawal and Two different regimens of thionamide therapy are commonly prompt treatment with antibacterials. The administration of in use. The titration method is aimed at using the lowest granulocyte colony-stimulating factor (G-CSF) may reduce thionamide dose mainitaining euthyroidism; the second regi- the time required to restore normal granulocyte count and the men, the block-and-replace method, employs persistently time of hospitalisation [16], but a randomised and controlled high doses of thionamides in association with L-T4 trial failed to demonstrate any difference in the recovery time replacement to avoid hypothyroidism (Table 5). between untreated patients and patients given G-CSF [17]. In the titration method, the usual starting dose of thiona- Although there seems to be a dose-dependency of this serious mides is MMI 20 – 30mg/day, either in a single dose or in complication in the case of MMI, it is lacking in the case of divided doses, or PTU 300 – 400 mg, always in divided doses. PTU [15]. The abrupt and explosive onset of agranulocytosis The initial dose depends, at least in part, on the severity of makes routine leukocyte counts fruitless, however, patients hyperthyroidism; a lower dose of thionamide in patients with should be advised that in case of fever, sore throat or other severe hyperthyroidism may be inadequate to rapidly control signs of infections, a leukocyte count should be obtained thyroid hyperfunction, a higher dose in patients with mild

854 Expert Opin. Pharmacother. (2005) 6(6) Bartalena, Tanda, Bogazzi, Piantanida, Lai & Martino

Table 5. Features of titration method and block-and-replace method.

Method Features Titration method Initial moderate-to-high doses of thionamides. Dosage is then tapered down to the lowest daily dose maintaining euthyroidism. No l-T4 is added. Duration of treatment: 12 – 18 months. Block-and-replace method High doses of thionamides are given for the whole period. l-T4 is added in order to avoid hypothyroidism. Duration of treatment: 6 months.

hyperthyroidism may lead to hypothyroidism [20]. Further to study indeed showed that L-T4 administration after periodic assessment of thyroid function by serum-free thyroid antithyroid drug therapy was associated with increased hormone measurement (serum TSH remains suppressed for recurrence of hyperthyroidism [31]. The reason for this dis- several weeks to a few months after the restoration of euthy- crepancy remains unclear but the number of negative studies roidism), daily dosage of the drug is tapered down (unless the suggests that the addition of L-T4, as originally proposed by block-and-replace regimen is selected) to the lowest effective the Japanese group [23], is not useful. dose. It is not unusual that a daily dose of MMI 2.5 – 5 mg or PTU 50 – 100 mg is sufficient for good metabolic control. 2.6 Duration of treatment Euthyroidism is usually achieved within 4 – 12 weeks. Assess- Early studies suggested that short-term thionamide treatments ment of thyroid status should be made every 4 – 6 weeks for the (3 – 4 months) were as (poorly) effective as long-term treat- first 4 – 6 months, and then evey 3 – 4 months until the end of ments (12 – 18 months). However, using the titration treatment, usually after 18 – 24 months. method, more recent studies have documented that an 18- In the block-and-replace method, deliberately high doses of month treament with carbimazole was associated with a sig- thionamides are given together with L-T4 [21]. This regimen nificantly lower relapse rate than a 6-month treatment [32]. has advantages and disadvantages over the titration method. On the other hand, extension of thionamide therapy up to 24 Higher doses may theoretically exert an immunosuppressive or 42 months does not increase the rate of positive outcome effect useful to achieve permanent remission of the disease. of antithyroid drug treatment [33], although the use of high

However, this putative effect remains to be demonstrated. doses of thionamides may result in a longer relapse-free period With the block-and-replace regimen, avoidance of hypothy- following thionamide withdrawal [34]. Using the block-and- roidism seems to be simpler than with the titration method, replace regimen, prolongation of treatment from 6 months to and because the maximal effect is achieved after 6 months, 12 months does not increase the chance of achieving treatment is shorter and the number of visits lower. On the permanent remission of hyperthyroidism [35]. other hand, the prolonged use of higher doses of thionamides Thus, using the titration method, the best duration of (e.g., MMI 30 – 40 mg/day) exposes the patient to a higher treatment is 12 or, better yet, 18 months whereas, with the risk of side effects and complications. In addition, the high block-and-replace method, treatment should not be number of tablets that the patient must take every day may continued beyond 6 months. create problems of poor compliance. Finally, cost of this combined treatment is higher, at least in the 6-month period. 2.7 Results of treatment A recent systematic review of randomised or quasi-rand- The major drawback of thionamide antithyroid drug treat- omized studies showed that that the block-and-replace regi- ment is the high rate of treatment failure. Although, as previ- men does not offer any advantages in terms of permanent ously discussed, the latter can be influenced by the duration of remission of hyperthyroidism, although it bears a higher risk treatment (but not by the use of high doses of thionamides), of side effects [22]. Accordingly, the authors favour the use of at the end of the programme ∼ 30 – 70% of patients experi- the titration method as the therapeutic regimen of choice for ence a relapse of hyperthyroidism [36]. This may occur at any antithyroid drug therapy but others may equally prefer the time after thionamide withdrawal but most recurrences are block-and-replace method. observed within the first year after discontinuation of treat- A third therapeutic regimen of antithyroid drug therapy ment [36]. However, it should be noted that hyperthyroidism was proposed several years ago in Japan [23]. After restoring may recur even years after thionamide withdrawal [34]. This euthyroidism with MMI alone, patients were randomised to observation, in additon to the notion that in the long run continue for 12 months with either MMI alone or MMI and ∼ 15% of thionamide-treated patients become hypothyroid, L-T4; the latter group then continued treatment with L-T4 for underscores the need for a lifelong follow-up of Graves’ additional an 36 months. Relapses in the L-T4-treated group patients after the completion of antithyroid drug treatment. were significantly lower than in the group not receiving L-T4 There are no reliable predictors of the outcome of thionamide (2 versus 35%) [23]. Unfortunately, this study has not been treatment. However, as illustrated in Table 6, patients with large reproduced by several studies thereafter, in which either L-T4 goitres that do not shrink during treatment, those with severe or L-T3 were used after thionamide withdrawal [24-30]. One hyperthyroidism, which is difficult to control even with

Expert Opin. Pharmacother. (2005) 6(6) 855 An update on the pharmacological management of hyperthyroidism due to Graves’ disease

Table 6. Factors affecting the outcome of thionamide antithyroid therapy.

Variable Relapse rate is higher if: Goitre size Goitre is large Age Patient is young Gender Patient is a man Metabolic control during treatment Hyperthyroidism is difficult to control and requires high doses of thionamides Smoking Patient smokes TRAb TRAb is present at the end of thionamide treatment* *Relapses are also frequent in patients whose TRAb tests are negative at the end of thionamide treatment. TRAb: TSH-receptor antibody. relatively high doses of thionamides (MMI 20 – 30 mg/day or condition is naturally associated with partial immunosuppres- equivalent), and those showing TRAb levels that do not decrease sion [18]. Conversely, Graves’ hyperthyroidism, like chronic during treatment, are indeed very good candidates to have a autoimmune (Hashimoto’s) thyroiditis, may develop or be relapse of hyperthyroidism [36]. Patients having the above char- exacerbated in the postpartum period [18]. Thionamides repre- acteristics may be candidates for longer thionamide treatments, sent the treatment of choice for Graves’ pregnant women but whether the long-term outcome is improved in such a way is because radioiodine therapy is contraindicated in pregnancy uncertain. Failure of TRAb to become undetectable almost (as well as during lactation), and surgery is only exceptionally invariably leads to a relapse of hyperthyroidism following thion- required [18]. Both MMI and PTU have been used during amide withdrawal but, also, patients whose TRAb levels become pregnancy, although PTU has long been preferred in the US undetectable during treatment have a relatively high chance of because of its purported lower transplacental trasnfer due to experiencing a relapse of Graves’ hyperthyroidism [36]. The use its low lipid solubility and higher transport protein binding.

of newly developed TRAb assays, using recombinant human However, the concept that transplacental passage of PTU is TSH characterised by higher sensitivity and specificity [37], may lower than that of MMI has recently been challenged [40]. As help improve the diagnostic and predictive capacity of TRAb mentioned in Section 2.4, rare cases of aplasia cutis and assays in the management of Graves’ hyperthyroidism. embriopathy have been reported in the offspring of mothers Men have a lower remission than women [38], whereas given MMI but not PTU [18]. It should, however, be men- young age (< 40 years) seems to be associated with a higher tioned that embriopathy was associated with exposure to high relapse rate [38], possibly because hyperthyroidism tends to be doses of MMI during early pregnancy [19]. The above consid- less severe in the elderly. Smoking has been reported to erations seem to highlight PTU as the preferred choice, at reduce the likelihood of achieving a stable remission least during the first trimester of pregnancy when organogene- of hyperthyroidism [28,39]. sis takes place, particularly if high doses of thionamides are Although in children and adolescents a second course of needed to control hyperthyroidism. The goal of antithyroid antithyroid drug treatment is required if hyperthyroidism drug treatment during pregnancy is to use the lowest dose of relapses, in adults, recurrence of hyperthyroidism after thiona- thionamides that is sufficient to maintain free thyroid hor- mide therapy is an indication to switch to ablative therapy by mones in the high-to-normal range, avoiding the risk of fetal either radioiodine or thyroidectomy, because the chance of hypothyroidism and goiter on one hand, and the risk that attaining stable remission of hyperthyroidism with a second even mild maternal hypothyroidism may affect subsequent course of thionamides is low. A possible exception to this rule neuropsychological development in the offspring on may be represented by the rare event of a second episode of the other [18]. Graves’ hyperthyroidism occurring many years after the The use of thionamides during lactation appears to be completion of a course of thionamide treatment. safe, and doses of MMI 20 mg/day do not affect the new- born’s thyroid function [18]. PTU is also safe for breastfeed- 2.8 Special situations ing. In view of thionamide pharmacokinetics, it seems wise 2.8.1 Pregnancy and lactation to suggest that the thionamide pill be taken shortly Untreated hyperthyroidism in pregnancy bears the risk of low after breastfeeding. birth weight, prematurity, stillbirth, a small increase in congenital malformations and pre-eclampsia [18]. Thus, control of 2.8.2 Children and adolescents thyroid hyperfunction is mandatory, although autoimmune Thionamide treatment represents the first-line treatment hyperthyroidism due to Graves’ disease generally tends to for the majority of children and adolescents affected with spontaneously improve during pregnancy, mainly because this Graves’ disease [41]. Radioiodine therapy or thyroidectomy

856 Expert Opin. Pharmacother. (2005) 6(6) Bartalena, Tanda, Bogazzi, Piantanida, Lai & Martino

Table 7. Thionamide treatment and outcome of radioiodine therapy.

Thionamide treatment Efficacy of radioiodine therapy Prior to radioiodine administration Reduced with propylthiouracil, not with methimazole Concomitantly to radioiodine Reduced Shortly after radioiodine Reduced are valid alternatives if thionamides do not effectively con- ablative therapy rather than thionamide therapy in patients trol hyperthyroidism (especially if goitre is large) or with substantial ocular involvement. compliance with therapy is poor. Sometimes it is necessary to switch to ablative treatments because of drug side 2.8.5 Thionamide treatment before, during and after effects, which are more common in young patients. Treat- radioiodine therapy ment is usually longer than in adults and may last for sev- Whether the pretreatment of Graves’ hyperthyroidism with eral years. Longer duration of treatment has been thionamides affects, namely reduces, the effectiveness of associated with higher cure rates [41]. One study showed subsequent radioiodine therapy is a matter of long debate, that > 75% of children and adolescents treated with thion- based mainly on retrospective studies. Two recent prospec- amides for > 11 years remained in remission [42]. Every tive, randomised studies demonstrated that pretreatment effort is usually made to continue thionamide therapy until with MMI does not reduce the cure rate of hyperthy- completion of physical growth and sexual development; roidism after radioiodine therapy [49,50]. On the other treatment is then interrupted and, in the case of relapse, hand, a recent randomised clinical trial showed that pre- switched to ablative therapy by either radioiodine treatment with PTU was associated with associated with a or thyroidectomy. reduced cure rate [51]. Thus, it would seem that, in agree- ment with previous reports, only PTU pretreatment may 2.8.3 Neonatal hyperthyroidism lower the efficacy of radioiodine, probaly owing to the fact This is due to transplacental passage of TRAb from the that its radioprotective effect lasts longer than that of MMI maternal side [43]. Because of this pathogenic mechanism, (Table 7). This problem can, however, be overcome by it is a transient condition; nevertheless, a vigorous treat- increasing the administered dose of radioiodine by 25% ment with thionamides, in association with propranolol or [52]. Pretreatment with thionamides has the clear beneficial other β-adrenergic antagonists and iodine (or oral effect of controlling hyperthyroidism; this is mandatory in iodinated contrastographic agents [44]) is warranted. the elderly and in patients with relevant comorbidity [53]. Leaving the patient untreated prior to radioiodine admin- 2.8.4 Ophthalmopathy istration exposes him/her to a prolonged period of uncon- Radioiodine therapy can cause the progression of Graves’ trolled hyperthyroidism, as radioiodine takes several weeks ophthalmopathy in ∼ 15% of cases [2], particularly in to be fully effective. Another positive aspect of preradio- patients who have pre-existing ophthalmopathy and are iodine thionamide treatment is that it depletes intrathyroi- smokers [2], or whose postradioiodine hypothyroidism is dal iodine stores, thus limiting a possible rise in serum not promptly corrected by L-T4 replacement therapy; on thyroid hormone levels after radioiodine-induced thyroid the contrary, neither thyroidectomy nor antithyroid drug damage [54]. In this regard, it is worth mentioning that treatment substantially influence the course of eye disease after thionamide withdrawal, 4 – 5 days prior to radio- [45]. However, the correction of hyperthyroidism using iodine therapy, a short course of lithium carbonate, to be thionamide therapy may be accompanied by an improve- continued for 2 weeks after radioiodine administration, ment of ocular involvement [46]. An open issue is whether effectively prevents any increase in serum thyroid hormone hyperthyroidism of patients who have associated Graves’ levels either due to thionamide withdrawal to radioiodine ophthalmopathy should be treated by conservative therapy cytotoxicity [7], and is associated with a more prompt con- (thionamides) or ablative therapy (radioiodine therapy or trol of hyperthyroidism and goiter shrinkage after radio- thyroidectomy) [47]. Because Graves’ ophthalmopathy is iodine [55]. If thionamide pretreatment (at least using probably initiated by autoimmune reactions directed MMI) does not seem to reduce radioiodine effectiveness, against antigen(s) shared by the thyroid and the eye, many available data convincingly indicates that the continuation experts believe that complete removal of thyroid antigens of antithyroid drug treatment during radioiodine therapy (and intrathyroidal autoreactive T lymphocytes) may be [56], or its resumption shortly after [57], is associated with a associated with an amelioration of the ophthalmopathy higher rate of treatment failure (Table 7). Thus, thionamide [48]. Others suggest that this approach would not affect the treatment should be reinstituted only in at-risk patients course of eye disease once it has been triggered. No final (old patients with associated comorbidity) and ≥ 7 – 10 answer is available to this problem but the authors favour days after radioiodine administration.

Expert Opin. Pharmacother. (2005) 6(6) 857 An update on the pharmacological management of hyperthyroidism due to Graves’ disease

2.8.6 Treatment with thionamides in the preparation administration of propranolol or other β-adrenergic to surgery antagonists is important to counterbalance peripheral actions Hyperthyroidism must be controlled pharmacologically of thyroid hormones through the inhibition of type I before thyroidectomy. Thionamides should be given until 5′-deiodinase activity [58]. Plasmapheresis, aimed at removing euthyroidism is restored, and iodide (Lugol’s solution or satu- thyroid hormone from the circulation, should be used only rated solution of potassium iodide) for 1 – 2 weeks prior to in exceptional cases. General support measures, including surgery. If surgery is urgent, a combination of oral iodinated volume repletion, external cooling, cardioactive drugs and contrastographic agents, particularly iopanoic acid, β-adrener- antibiotics, as appropriate, should also be taken. gic antagonists and glucocorticoids, should be used because of the delayed effect of thionamides [9]. 3. Expert opinion

2.8.7 Graves’ disease occurring in amiodarone-treated Pharmacological treatment for hyperthyroidism due to patients Graves’ disease has been used for > 60 years. There is no Amiodarone, an iodine-rich antiarrhythmic drug, causes thy- doubt that thionamides represent a valid, safe and non-inva- roid dysfunction (either thyrotoxicosis or hypothyroidism) in sive tool to control thyroid hyperfunction. Likewise, it is ∼ 15% of treated patients [12]. Amiodarone-induced thyrotox- equally clear that this treatment leads to permanent remission icosis (AIT) can be distinguished into two main forms: type II (cure) of Graves’ hyperthyroidism only in ∼ 50% of treated AIT, a destructive thyroiditis, which must be treated by ster- patients. Search for effective predictors of treatment failure oids [12]; and type I AIT. The latter develops in an abnormal has so far not identified patients who are inevitably destined thyroid gland, with nodular goitre or latent Graves’ to relapse and, therefore, may avoid a useless treatment and disease [12]. Under these conditions, the huge iodine load due should be switched to definitive (although destructive) treat- to amiodarone administration makes thionamide therapy less ments, such as radioiodine or thyroidectomy. Available data effective, owing to high intrathyroidal iodine content [12]. indicates that the use of high doses of thionamides does not Thus, in type I AIT occurring in a thyroid gland affected with add any clear advantage compared with the use of the lowest Graves’ disease, the addition of potassium perchlorate (see dose of the drug capable to maintain euthyroidism. The addi- Section 2.2) is useful because this drug depletes intrathyroidal tion of L-T4 after thionamide withdrawal does not seem to iodine stores and favours the antithyroid effect of thiona- reduce failure rate. Likewise, although the titration method mides. Potassium perchlorate is usually used for 3 – 6 weeks at duration of treatment of 12 – 18 months is associated with a doses ≤ than 1 g/day because of its possible toxicity on bone better outcome compared with short-term regimens, the marrow and the kidney [12]. After the correction of Graves’ extension of treatment beyond 18 – 24 months does not offer hyperthyroidism complicated by iodine contamination (fol- any further advantage in terms of long-term successful out- lowing amiodarone withdrawal), a definitive therapy by either come. Antithyroid drug therapy is the first-line treatment thyroidectomy or radioiodine (if thyroidal radioactive iodine during pregnancy and breastfeeding, and does not show any uptake is high enough) is usually offered, particularly if amio- link to associated ophthalmopathy. Side effects are limited, darone therapy needs to be reinstated for the underlying especially if low doses are used (but dose-dependency does not cardiac problems [12]. seem to exist for PTU). According to this discussion, our opinion concerning 2.8.8 Thyrotoxic storm antithyroid drug therapy with thionamides is as follows: Thyrotoxic storm is a rare form of life-threatening severe hyperthyroidism [58]. It is an endocrine emergency and treat- • Thionamides are the first-line treatment in pregnant ment must be aggressive. It is far less common than in the women, children and adolescents, adults experiencing the past, owing to earlier diagnosis and better management of first episode of hyperthyroidism and patients who are being Graves’ hyperthyroidism. Thionamides play a major role in submitted to radioiodine therapy or thyroidectomy. This its management by reducing thyroid hormone synthesis. treatment is also indicated in patients with Graves’ ophthal- Higher than usual doses are employed, such as MMI 20 mg mopathy, independently of whether they will be treated every 4 – 6 h. PTU is preferred by some thyroidologists due with radioiodine or thyrodectomy because control of hyper- to its inhibitory effect on peripheral conversion of T4 to the thyroidism may have some beneficial effects on eye disease. metabolic active hormone, T3. Inorganic iodide (Lugol’s • We prefer MMI to PTU in view of the lower risk of side solution, saturated solution of potassium iodide) is an impor- effects and the possibility of giving the drug as a single daily tant adjuvant because it inhibits thyroid hormone release dose, thus increasing the patient’s compliance. Local availa- from the thyroid; however, it must be initiated after antithy- bility is also an issue because, for example, PTU is not on roid drugs because it is necessary that iodide organification the market in Italy. In pregnant women, the risk of MMI- be inhibited by thionamides [58]. As an alternative to inor- associated aplasia cutis and embriopathy is very low, but the ganic iodide, oral iodinated contrastographic agents (iopa- use of PTU, which has never been associated with untoward noic acid, sodium ipodate) can be utilised [58]. The fetal effects, should be endorsed, at least in the first trimester

858 Expert Opin. Pharmacother. (2005) 6(6) Bartalena, Tanda, Bogazzi, Piantanida, Lai & Martino

of pregnancy. In any case, treatment of pregnant women during the first 3 – 12 months because this is the period should employ the lowest dose of thionamides maintaining when most recurrences occur. In case of relapse of free thyroid hormone levels in the high-normal range. hyperthyroidism, we usually do not offer a second course of • We favour the titration regimen over the block-and-replace antithyroid drug treatment but switch to ablative therapy. regimen because the former is simpler, is likely to be Because relapse of hyperthyroidism, as well as the onset of associated with better patient compliance and has a lower hypothyroidism, may occur even later, patients treated with incidence of side effects. We do not advise the use of thionamides are bound to lifelong periodical assessment of TSH-suppressive L-T4 therapy after MMI withdrawal. thyroid status. • Duration of treatment should be neither < 12 months nor > 18 months if the titration method is used (or > 6 months Acknowledgements with the block-and-replace regimen). An exception to this rule is represented by hyperthyroidism in children and ado- This work was supported in part by grants from the lescents, who may continue antithyroid drug treatment University of Insubria (to Bartalena) and the University of until somatic growth and sexual development are complete, Pisa (to Martino), and from the Ministry for Education, Uni- (i.e., around the age of 18). versity and Research (to Bartalena), for ‘Novel pathogenic, • After thionamide withdrawal, follow up should be strict clinical and therapeutic aspects of Graves’ ophthalmopathy’.

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