3.3.6 Antithyroid drug treatment for thyrotoxicosis

The most effective and commonly used antithyroid drugs are the thionamides, including carbimazole and its active metabolite methimazole (not available in the UK). These act by inhibiting the synthesis of thyroid hormones, principally by interfering with the iodination of tyrosine by serving as preferential substrates for the iodinating intermediate of thyroid peroxidase. Oxidized iodine is thus diverted from potential iodination sites in thyroglobulin. The iodinated antithyroid drugs are desulfurated and further oxidized to inactive metabolites. There is also some evidence for an immunosuppressive action which is of doubtful clinical significance as most patients relapse after drug withdrawal. Another thionamide, propylthiouracil, is, in addition, a potent inhibitor of type 1 outer ring deiodinase and acutely inhibits thyroxine (T₄) to triiodothyronine (T₃₎ conversion, but there is no good evidence to suggest that this effect is of any clinical relevance. Propylthiouracil tends to be reserved for those patients who have developed an adverse reaction to carbimazole or methimazole.

The natural history of the hyperthyroidism of Graves’ disease is shown in Fig. 3.3.6.1. A course of antithyroid drugs is appropriate for the minority (30–50%) of patients in whom a single episode of hyperthyroidism is followed by prolonged remission. The majority of patients have a relapsing and remitting course over many years and despite efforts to predict the natural history of the hyperthyroidism, using markers such as HLA status, the presence of thyrotropin (TSH)-receptor antibody (TRAb), goitre size, serum thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone, and thyroid suppressibility (alone or in combination), it has not proved possible to categorize individual patients with Graves’ disease in respect of outcome with any degree of accuracy (1). On a group basis, small goitre, low serum concentration of TRAb, and increasing age favour remission after a course of antithyroid drugs, whereas the risk of relapse in a young male with severe hyperthyroidism and a large vascular goitre is so great that most would advocate surgery as the primary treatment. Standard practice in Europe has been that the initial treatment in most patients under 40–45 years of age is with an antithyroid drug, with a recommendation for surgery should relapse occur. In the USA, however, ¹³¹I therapy is not restricted to older patients and the use of antithyroid drugs is relatively uncommon. Antithyroid drugs are not normally indicated in the treatment of toxic nodular goitre, unless to render the patient euthyroid before surgery, as recurrence of hyperthyroidism is invariable after drug withdrawal. There is no role for antithyroid drugs in subacute or postpartum thyroiditis in which the thyrotoxicosis is caused by the release of preformed thyroid hormones.

The most consistent observation in patients with Graves’ hyperthyroidism has been that the longer the duration of therapy, the better the remission rate. In a study in children with Graves’ disease, and there is no reason to believe that the results in adults would be different, when antithyroid drug withdrawal was attempted regularly, the mean duration of hyperthyroidism was 4.5 years; this is probably an underestimate as remission was defined as euthyroidism for 12 months (2). The conventional period of antithyroid drug therapy of 12–24 months is best viewed as a compromise by which those destined to have a single short-lived episode of hyperthyroidism are identified and primary destructive therapy by surgery or with ¹³¹I avoided. Most patients (50–70%), however, usually relapse within the first 2 years.

Although radio-iodine is increasingly the treatment of choice in patients with hyperthyroidism due to Graves’ disease, there perhaps needs to be more caution about a therapy that almost always results in hypothyroidism. This is especially so when there is no consensus on what constitutes correct thyroid hormone replacement (3) and when there is anxiety about the bioequivalence of branded versus generic l-thyroxine and between the various generic preparations (4). Some patients abhor the idea of irradiation of any kind and patients worry that they will gain excessive weight if rendered hypothyroid and this may be true if serum concentrations of TSH are simply restored to the reference range with thyroxine (5). Of some concern are the recent reports that ¹³¹I treatment itself may cause increased morbidity and mortality from cardiovascular disease in the long term (6, 7). There is no reason why patients with relapsing and remitting hyperthyroidism cannot be treated with successive doses of antithyroid drugs. Indeed, continuing methimazole uninterruptedly for 10 years after the first relapse has been shown to be safe and cheaper than ¹³¹I (8).

Carbimazole is available as 5 and 20 mg tablets. The initial dosage is 40–45 mg daily for 3–4 weeks, reducing to 30 mg daily for a further 3–4 weeks, with further adjustments on the basis of measurement of serum concentrations of T₃, T₄, and TSH, until a maintenance dose of 5–15 mg daily is achieved, usually within 3–4 months. Patients begin to feel an improvement at 10–14 days. Once-daily dosage is appropriate for all but the most severely thyrotoxic, who benefit from being given carbimazole as 20 mg twice daily or 15 mg three times daily. Initial changes in drug dosage should be based on thyroid hormone concentrations, as delayed recovery of thyrotrophs, previously exposed to high levels of T₃ and T₄, may result in inappropriately low serum TSH concentrations. After 10–12 weeks of treatment, serum TSH is the best guide as to whether the dosage of carbimazole is appropriate, high and low concentrations indicating excessive and inadequate therapy, respectively. A daily dose of 20 mg carbimazole is almost as effective in restoring euthyroidism by the 10th week as 40 mg daily in mild to moderate hyperthyroidism (9). However, in the absence of overwhelming evidence that the major adverse reaction, agranulocytosis, is dose-related, there would seem little point in delaying the restoration of thyroid function to normal from 4 to 10 weeks, particularly in patients with troublesome symptoms or serious complications such as atrial fibrillation. The appropriate dose of propylthiouracil is 10 times that of carbimazole, and 30 mg methimazole is approximately equivalent to 40 mg carbimazole.

The rate of reduction in the serum concentrations of TRAb, T₃, and T₄ is slower and the dose of carbimazole required to achieve euthyroidism greater in patients with Graves’ disease who smoke. Smoking is also associated with a greater chance of relapse after a standard course of antithyroid drugs (Fig. 3.3.6.2) (10).

In this regime, carbimazole is continued at the high dosage of 30–45 mg daily after the patient is euthyroid, and hypothyroidism avoided in the long term by adding thyroxine at a dosage of 100–150 µg daily. The dose of thyroxine, but not carbimazole, is adjusted to maintain serum TSH within the lower part of the reference range. This combination therapy has long been thought to be beneficial in patients with significant ophthalmopathy, presumably as a result of avoiding hypothyroidism, and in those with brittle ‘hyperthyroidism’, fluctuating between over- and undertreatment with antithyroid drugs despite good compliance and supervision, and now known to be due to changing concentrations and activities of TRAb (Table 3.3.6.1). Remission rates are not improved by standard block and replace therapy. Claims for a regime in which, after 18 months of combined therapy, thyroxine alone was continued for a further 3 years, during which time the relapse rate was less than 2% have not been substantiated (11).

The adverse effects of antithyroid drugs can occur at any time but almost always within 3–6 weeks of starting treatment. There is some cross-sensitivity between carbimazole (methimazole) and propylthiouracil. Although it is common practice to change to the alternative antithyroid drug in the event of a minor adverse reaction, such as a skin rash, opinion is divided over whether the development of agranulocytosis is an absolute contraindication to further drug therapy.

The most serious adverse reaction is agranulocytosis, which develops in 0.2–0.5% of patients. Agranulocytosis is characterized by fever, systemic upset, oropharyngeal bacterial infection, and a granulocyte count of less than 0.25 × 10⁹/l. The onset is sudden and the consensus is that there is no purpose in routine monitoring of the white blood cell count (12). Patients should simply be instructed to contact their medical practitioner immediately in the event of developing a sore throat or mouth ulceration. After stopping antithyroid drug therapy, the white blood cell count returns to normal within 1–3 weeks, during which time the affected patient should be isolated and treated with broad-spectrum antibiotics. Recovery of the white blood cell count may be hastened by the use of granulocyte colony stimulating factor, but its value in those with the most profound reduction in granulocyte count (less than 0.1 × 10⁹/l) is unclear (13). Mild leucopenia with a relative lymphocytosis is common in Graves’ disease and is not a contraindication to the use of antithyroid drugs.

The most common reactions are nausea, loss of taste, headache, and hair loss, which may be self-limiting and do not necessarily require drug withdrawal. The most troublesome in this category is a skin rash, which is usually urticarial and affects between 1% and 2% of patients. A migratory polyarthritis may occur alone or in association with the rash and resolves within 4 weeks of stopping treatment. Much rarer adverse effects include cholestatic jaundice (14), vasculitis which may be associated with antineutrophil cytoplasmic antibody (15), a lupus-like syndrome, and the nephrotic syndrome.

Iodine-131 takes some 6–8 weeks to be effective, and during this latent period hyperthyroidism may be exacerbated, with an increase in morbidity and even mortality in those with severe thyrotoxicosis and associated cardiovascular disease. For this reason it is not uncommon to render the patient euthyroid before radio-iodine treatment and to continue the antithyroid drug for 6 weeks thereafter. In order not to interfere with the efficacy of the ¹³¹I, carbimazole should not be given for 48 h before and after treatment. If this course of action is not taken, the thyroid gland is more resistant to the effects of ¹³¹I and larger doses should be used (16). An added advantage of pretreatment with an antithyroid drug is that the patient is more likely to comprehend the various aspects of treatment when not in the agitated and unreceptive state of hyperthyroidism.

Maternal hyperthyroidism in pregnancy is usually due to Graves’ disease. TRAb crosses the placenta and, if the mother is thyrotoxic, it must be assumed that the fetus is similarly affected. Before effective treatment was available the fetal death rate could be as high as 50%. Fortunately, antithyroid drugs also cross the placenta and, by careful monitoring of maternal thyroid function, normal fetal development can be achieved, even though cord blood may show evidence of overtreatment. Like other organ-specific autoimmune diseases, Graves’ hyperthyroidism tends to improve or even remit during pregnancy. A small daily dose of antithyroid drug, such as 5–10 mg carbimazole, will maintain free T₄ and TSH concentrations in the reference ranges (Fig. 3.3.6.3). It is good clinical practice to review the mother every 4 weeks during pregnancy and to stop the antithyroid drug 4 weeks before the expected date of delivery to avoid any possibility of fetal hypothyroidism when brain development is at a maximum. Measurement of TRAb concentration in maternal serum at the last review before delivery may be helpful, as a high level is a predictor of neonatal thyrotoxicosis. Since thyroid hormones cross the placenta relatively poorly, the ‘block and replace’ regime is not recommended in pregnancy.

Aplasia cutis congenita is a rare disorder of the skin, usually affecting the scalp and less than 3 cm in diameter, which has been reported in a small number of neonates whose mothers received methimazole during pregnancy. Aplasia cutis congenita has not been reported in association with propylthiouracil, which is widely used in North America, and there are those who take the view that propylthiouracil is the drug of choice in pregnancy or in those planning pregnancy. The consensus, however, is that there is insufficient evidence to establish a direct causal relationship between aplasia cutis congenita and methimazole. Since both carbimazole (methimazole) and propylthiouracil are equally effective in controlling Graves’ hyperthyroidism during pregnancy, it makes sense to use the preparation with which one has most experience.

If hyperthyroidism recurs after delivery, is due to Graves’ disease and not post-partum thyroiditis, and the mother wishes to breastfeed, propylthiouracil is the drug of choice as it is transferred to the milk one-tenth as well as carbimazole (methimazole). Carbimazole will not affect thyroid function in the infant if a dosage of less than 15 mg daily is employed (17), and daily doses of 5–10 mg methimazole given for 1 year to breastfeeding mothers had no deleterious effect on infant thyroid function or subsequent intellectual development (18).

Many of the clinical features of hyperthyroidism, such as palpitations, tremor, and heat intolerance, are ameliorated, but not abolished, by the use of nonselective β-blockers. For example, the resting heart rate may fall from 120 to 90 beats/min. Although β-blockers also inhibit the extrathyroidal conversion of T₄ to T₃, the fall in serum T₃ concentrations is small and is not thought to contribute to their efficacy. The principle use of β-blockers is in relieving troublesome symptoms before investigation and treatment, during the latent period of 10–14 days or 6–8 weeks before antithyroid drugs or ¹³¹I begin to be effective, and during the transient hyperthyroid phase of subacute or postpartum thyroiditis.

The most commonly used β-blocker is propranolol. The usual dosage is 80–160 mg daily as a long-acting preparation. Clearance of propranolol may be variably accelerated in patients with thyrotoxicosis and dosages as high as 480 mg daily may be necessary to control heart rate. Nadolol in a single daily dose of 80–160 mg is an alternative nonselective β-blocker.

These drugs are contraindicated in patients with thyrotoxicosis and obstructive airways disease, as they may precipitate worsening bronchospasm; insulin-dependent diabetes mellitus, as they may slow the recovery from and mask the symptoms of hypoglycaemia; and cardiac failure, unless this is associated with atrial fibrillation and is primarily due to the hyperthyroidism.

Iodide, as potassium iodide, is normally used only in the preparation of patients with hyperthyroidism for surgery. When euthyroid, the antithyroid drug is stopped 10–14 days before surgery and potassium iodide (60 mg 3 times daily) is substituted. This maintains thyroid status principally by inhibiting thyroid hormone release and reduces the vascularity of the gland, making surgery technically easier. Potassium iodide has also been used successfully in combination with propranolol in preparing patients for surgery over a period of 10 days (19). Although this regime cannot be universally recommended, it is valuable in patients with mild to moderate hyperthyroidism in whom domestic or business pressures make urgent surgical treatment necessary.

The oral cholecystographic agents sodium ipodate (Oragraphin) and sodium iopanoate (Telepaque) as well as having an iodide effect, also reduce T₄ to T₃ conversion by inhibiting outer ring deiodinase. Serum T₃ concentrations fall dramatically within 24 h compared with the 5–7 days for potassium iodide. The dosage of these agents is 0.5–1.0 g daily. As cholecystography has been superseded by ultrasound examination of the gallbladder these agents are, unfortunately, no longer widely available.

Perchlorate competitively inhibits iodine transport and was used successfully in the treatment of hyperthyroidism. Unfortunately it was associated with the development of aplastic anaemia and gastric ulceration and should only be considered in the management of severe hyperthyroidism induced by amiodarone therapy, which is difficult to control with thionamides alone in areas of iodine deficiency.

Lithium has an iodide-like action and has been used in the management of hyperthyroidism. Patients may escape, however, from the effects of lithium, and, indeed, long-term therapy in patients with manic depressive illness is associated with an increased risk of thyrotoxicosis. In addition, the therapeutic window for lithium is narrow and the current consensus is that the drug has no place in the treatment of hyperthyroidism (20).