Abstract
In this issue of Thyroid, Chung and colleagues (5) retrospectively compared remission rates in 40 Graves' disease patients whose serum TSH concentrations rose above 10 μIU/L during methimazole treatment with 37 age- and sex-matched controls who did not have elevated serum TSH during methimazole therapy. All patients were treated for a minimum of 24 months, after which treatment was discontinued either because thyroid stimulating antibodies were undetectable or biochemical euthyroidism was restored. Methimazole-associated hypothyroidism typically occurred after 7–8 months when average doses of methimazole therapy were 10–15 mg daily. None of the patients had severe symptoms necessitating discontinuation of methimazole, and the hypothyroidism was easily controlled with dose reduction in nine subjects or temporary combination therapy with levothyroxine in the remaining 31 patients. Remission rates of Graves' disease at 6, 12, and 24 months following methimazole discontinuation were significantly higher in those who developed hypothyroidism when compared with controls. Effects were independent of other factors including thyroid stimulating antibody status, duration of antithyroid drug treatment, and gross parameters for goiter size. The authors conclude that methimazole-associated hypothyroidism during maintenance treatment is an expression of favorable responsiveness to antithyroid drugs or is a sign of a milder underlying disease process and advocate that elevated serum TSH concentrations during methimazole treatment is a favorable indicator of long-term remission (5).
This paper raises a number of important issues. The first one relates to the current role of antithyroid drugs in the treatment of Graves' disease. In general, these drugs are used in two ways: as the primary treatment for hyperthyroidism or as preparative therapy before administration of radioactive iodine or surgery (1). Since the three main therapeutic options for Graves' disease are all similarly effective as initial treatment (6), the selection process depends on many factors, including the preferences of clinicians and patients, availability of a skilled surgeon, and local restrictions on the therapeutic use of isotopes. Radioiodine is generally preferred by U.S. clinicians, whereas antithyroid drug therapy is the first-line treatment nearly everywhere else (7,8). Further refinements in the identification of those subjects who are likely to remain in long-term remission following a prolonged course of thionamides will aid clinicians and patients in this decision-making process. Validation of findings presented by Chung et al. (5) in prospective studies is required in order to verify the prognostic significance of raised serum TSH concentrations during methimazole treatment.
When antithyroid drugs are chosen as the first-line treatment, further controversies surround the choice of thionamide to be used and its dose. Both methimazole and propylthiouracil effectively control hyperthyroidism, although methimazole is better in controlling more severe hyperthyroidism, has better compliance rates, and causes less toxicity (1). Minor side effects including cutaneous reactions, arthralgia, and gastrointestinal occur in approximately 5% of patients and tend to be mild or transient. Agranulocytosis is the most feared adverse effect and one large series reported similar rates in patients receiving propylthiouracil and those treated with methimazole (9). In contrast, a large study of antithyroid drugs reporting 5.23 million prescriptions of thionamide drugs in England and Wales indicated a higher frequency of neutrophil dyscrasias (agranulocytosis and neutropenia) in patients prescribed propylthiouracil (10). In addition, recent evidence has indicated a markedly higher incidence of agranulocytosis in a comparison of a large patient group receiving 30 mg methimazole daily with a similarly sized group treated with a daily dose of 15 mg, indicating that development of this significant adverse effect may be dose dependent (11).
Hepatic complications represent a further group of adverse effects associated with the use of antithyroid drugs, and this has recently received considerable attention. Serious hepatic adverse effects including acute liver failure occur more frequently with propylthiouracil than with methimazole (12), especially in children in whom the prevalence of propylthiouracil-related acute hepatic failure is estimated to be as high as 1 in 2000 patients (13). In a joint initiative, the American Thyroid Association and the American Association of Clinical Endocrinologists (14) have examined the evidence and recommended that proylthiouracil not be prescribed as a first-line agent in adults or children. Current guidance indicates that methimazole is the first-line drug to be used in treating patients with hyperthyroidism and that the use of propylthiouracil should be reserved for individuals in the first trimester of pregnancy, patients with life-threatening thyrotoxicosis or thyroid storm, and patients who have experienced adverse effects of methimazole (except agranulocytosis) and for whom radioiodine or surgery are not an option (13,14). Furthermore, in view of the evidence presented by Takata et al. (11), it seems reasonable to recommend that the prescribed dose should enable control of hyperthyroidism within a reasonable timeframe and lower doses than often used in the past should generally be prescribed. The recommendation by Chung et al. (5) not to discontinue antithyroid drugs or to markedly reduce the dose in those patients developing hypothyroidism whilst on thionamide drugs, seems difficult to reconcile with the guidance provided by the studies of Takata et al. (11) and others. It is notable however that in practice Chung et al. (5) employed relatively low doses of methimazole (MMI) and avoided a block replacement strategy that generally requires higher doses of thionamide drugs.
Graves' hyperthyroidism is caused by thyroid stimulating antibodies that bind to and activate the TSH receptor on thyroid cells as part of an autoimmune process (15). Treatment of Graves' disease is directed at the thyroid gland itself rather than at the dysregulated immune system, although there are several lines of evidence to support the notion that thionamide drugs have clinically important immunosuppressive actions (1). In patients taking these drugs, the serum concentrations of thyroid stimulating antibodies (16) as well as other immunologically important molecules including adhesion molecules (17), interleukins, and interleukin receptors (18,19) decrease with time (1). Furthermore, thionamide drugs may induce apoptosis of intrathyroidal lymphocytes (20) and decrease the expression of major histocompatibility complex class II molecules on thyroid cells (21). In addition, most studies show increased numbers of circulating suppressor T cells (22) and a decreased number of helper T cells, natural killer cells, and activated intrathyroidal T cells during antithyroid drug therapy (1).
Despite evidence for an immune-modulatory effect of antithyroid drugs, there are a number of arguments to be made against this immunosuppressive hypothesis (23). Firstly, remission of Graves' disease during antithyroid drug therapy is independent of the type of drug and dose, with perchlorate being equally effective in inducing remission as thionamide drugs (24). Secondly, a prospective randomized study demonstrated similar remission rates in patients rendered euthyroid by thionamide drugs and those undergoing subtotal thyroidectomy followed by levothyroxine replacement (6). Thirdly, remission follows euthyroidism independent of drug dose, whereas one would expect a more rapid and probably more sustained remission of the disease with higher doses if this effect was due to immunosuppression (25). Finally, the induction of remission is independent of the additional use of levothyroxine, as employed by centers using a block-replace regimen, when this strategy would be expected to reduce the immunosuppressive effects of antithyroid drugs (26). Taking all these lines of evidence into account it seems plausible that remission of Graves' disease may be associated with restoration of the euthyroid state, rather than being a specific effect of thionamide drugs (23).
Despite the high risk of relapse following thionamide treatment and the recent concerns regarding adverse drug reactions, there are certain subsets of patients with Graves' disease in whom treatment with antithyroid drugs alone may be preferred. Pregnancy and breastfeeding are absolute contraindications to administration of radioactive iodine and treatment with thionamide drugs is usually preferred. In view of rare reports of birth defects associated with methimazole (27) as well evidence that propylthiouracil crosses the placenta less than methimazole (28), pregnancy is one of the few situations in which treatment with propylthiouracil is recommended as a first-line drug (13).
The optimal treatment of Graves' disease in childhood remains a matter of debate. Most children are initially treated with antithyroid drugs, although lasting remission after about 24 months of treatment occurs in less than 30%. For the remaining patients, total thyroidectomy or radioiodine therapy represent definitive therapeutic options, both of which carry a high risk of development of permanent hypothyroidism (29). Furthermore, concerns about potential thyroid malignancy, hyperparathyroidism, and increased risk of mortality associated with administration of radioiodine (30,31) have resulted in this being a less preferred therapeutic approach amongst pediatric endocrinologists. There is a distinct lack of evidence-based strategies for the management of Graves' disease in children, highlighting the need for prospective randomized trials with long-term follow-up, evaluating the efficacy and safety of short- and long-term treatment with antithyroid drugs, radioactive iodine, or surgery (29). In addition, stratification of patients according to the risk of relapse will lead to significant improvements in the management of pediatric Graves' disease and confirmation of the findings presented by Chung and colleagues (5) in children may prove to be useful in this respect.
Patients with Graves' ophthalmopathy represent a further subset in whom antithyroid drug therapy is preferred by many clinicians. Radioiodine therapy may cause progression of eye disease in about 15% of cases and this is more likely in smokers and in those who have pre-existing ophthalmopathy and if post-radioiodine hypothyroidism is not corrected promptly (32). Concomitant administration of glucocorticoids is highly effective in preventing radioiodine-associated progression of Graves' ophthalmopathy. Neither antithyroid drug therapy nor thyroidectomy affect the natural course of Graves' eye disease (32) and a recent systematic review showed no statistically increased risk of ophthalmopathy when comparing radioiodine therapy with surgery, whereas this risk was significantly higher when comparing radioiodine and antithyroid drugs (33). At present, it remains a matter of debate whether thionamide drugs are the preferred treatment modality for patients with Graves' ophthalmopathy.
In summary, antithyroid drugs continue to be important in the management of Graves' disease and most patients with hyperthyroidism will receive these drugs at least in the short to medium term. Efforts to predict the likelihood of lasting remission following a prolonged course of thionamide drugs have failed to identify parameters that are sufficiently sensitive and specific to predict response in individual patients. A carefully performed study presented by Chung et al. (5) and published in this issue of Thyroid indicates that the development of raised serum TSH concentrations during treatment with methimazole may be a useful prognostic indicator in this respect.