Controversies in the management of Graves' disease

The large published literature on the management of Graves' Hyperthyroidism reflects the persisting controversies regarding optimum management of this common condition. This was highlighted in surveys of the European and American Thyroid Associations in 1986 and 1990 in which members were asked questions regarding the investigation and treatment of a 43-year-old female with moderate hyperthyroidism, a diffuse goitre and minimal eye signs ( 13; 38). Some of the areas where expert opinion differed are shown in Table 1. We aim in this review to highlight areas in which the literature does, we believe, provide guidance in the management of Graves' disease, and summarize the state of knowledge in those areas in which the data remain inconclusive. Direct comparison of methimazole (MMI) and propylthiouracil (PTU) given in divided daily doses, found that doses of 30 or 40 mg of methimazole or 300 or 400 mg of propylthiouracil reduced thyroxine levels to normal or subnormal levels in three months in all but one patient ( 20). MMI appeared more effective since 56% of patients treated with 400 mg of PTU but all patients who received 40 mg of MMI became hypothyroid in this period of time. However, a higher dose of PTU may have had comparable effects. Unfortunately, a comparison of drug efficacy with pretreatment thyroid hormone levels, a strong determinant of time to euthyroidism, was not made. Carbimazole, the thionamide most commonly used in the UK, is converted to MMI in vivo but gram for gram is less potent. No direct comparisons of PTU and carbimazole, are available and there are no data directly comparing long-term remission rates of one drug vs another. Carbimazole and methimazole have the advantage of single daily dosing, increasing the chances of patient compliance, and a larger body of literature on their use. On the other hand, PTU is more protein bound, justifying its use in pregnancy and breast feeding and it is additionally able to inhibit T4 to T3 conversion. Reduced passage of PTU into placental tissue and breast milk has been shown in comparison to carbimazole ( 27; 14). However, the value of these effects on clinical outcome have not been compared and at present individual variation in the choice of drug used remains justified. Thionamide dosing regimens in Graves' disease need to be considered in two parts: initial therapy to achieve euthyroidism and subsequent treatment to effect a long-term remission. The European Multicentre trial reported a higher percentage of patients (93% v 78%) becoming euthyroid at 6 weeks with a starting dose of Methimazole of 40 mg than with 10 mg ( 4). In addition, fewer patients (0.5% v 4%) were persistently hyperthyroid 3 months following the initiation of the higher dose. Hypothyroidism was avoided in this study by the introduction of thyroxine. Within the low dose treatment group (methimazole 10 mg), it was those individuals with large goitre and high pretreatment serum T3 who were still hyperthyroid at 6 weeks. These findings have been recently confirmed in a study comparing 20 mg and 40 mg of carbimazole for the initiation of treatment of Graves' disease ( 33). The percentage of patients no longer hyperthyroid at 4 weeks was greater with 40 mg of carbimazole (86% vs 52% for total T4). In addition, 75% of patients in the highest quartile for pretreatment thyroid function (Total T4 > 260 nmol/l) were still hyperthyroid at 4 weeks if treated with 20 mg carbimazole, in contrast to only 14% of those on 40 mg carbimazole ( 33). Unacceptably high failure rates have also been reported with PTU at doses of 200 mg/day or less ( 20). Since the initial aim is to render patients euthyroid as quickly as possible, we would recommend that thionamide treatment is started at a high dose, for example, carbimazole 40 mg, methimazole 30–40 mg or PTU 400–600 mg. Higher doses should not be used routinely as they may be associated with an increased incidence of serious side-effects (see below). Around 90% of patients will be euthyroid or hypothyroid by 6 weeks on these doses, with only those severely toxic initially, or with poor compliance, remaining hyperthyroid. Thyroid function should be checked at this stage with a view to adjustment of the dose and/or the initiation of thyroxine. After normalizing thyroid function with a high dose of thionamides, it would seem logical to taper the dose to the lowest level required to maintain euthyroidism. Two studies have suggested improved long-term remission rates from the use of continuous high dose ‘block and replace’ methimazole (i.e. with the addition of thyroxine to allow maintenance of high thionamide doses) compared to a dose titrated regimen ( 37; 19). However, the doses used in both studies were very high (60 mg of methimazole or more), and in the study of Jorde et al. treatment duration was short (6 months) and the relapse rate in both groups high (58 vs 77% − see Table 2). Four other prospective trials including the large European Multicentre have shown no improved outcome from high dose therapy ( Table 2) ( 30; 35; 9; 26). In both the European and American surveys, 80–90% of endocrinologists who used medical therapy initially, opted to continue treatment for more than 12 months ( 13; 38). Two early studies appeared to suggest comparable results with short course (around 4 months) as prolonged ( 16; 5), but relapse rates were high in both these studies (more than 70%) and neither had an appropriate control group. In contrast, the only prospective randomized controlled trials using titrated doses of thionamide found extending treatment beyond 6 months to 18 months to be beneficial ( Table 3) ( 1). An additional 5 series, in one of which 8 year follow-up data were available, have shown benefit in treatment for at least 12 months ( 40; 44; 18; 30; 47), two of these claiming benefit in treatment for at least 2 years ( 40; 18), but none of these were randomized studies. There has been one prospective randomized study of dose duration using continuous ‘block and replace’ and here the outcomes after 6 and 12 months of treatment were indistinguishable ( Table 3) ( 49). The reason for this discrepancy is unclear, particularly in view of the data suggesting little difference between low and high dose treatment presented above. The evidence therefore remains incomplete but at present, treatment for 18 months can be recommended for titration therapy in adults. With this approach, 2 year post treatment remission rates of around 60% should be achievable in adults in iodine sufficient areas. The risk of side-effects needs to be taken into account when choosing dose and duration of drug therapy. The incidence of serious haematological events (agranulocytosis, aplastic anaemia) ranges from 0.17% to 2.8% in most studies ( 37; 45; 51; 41; 35; 31; 19). An early study using 120 mg methimazole, a dose much higher than that used in routine practice, reported an 8% agranulocytosis rate and a further review of 10 cases of agranulocytosis found that all occurred at doses of 20 mg or more and 55% occurred at doses of 40 mg or more ( 31). The vast majority of cases are also reported to occur within 3 months of starting therapy ( 45; 51; 41; 31), when doses are at their highest in many regimens. Hepatoxicity also occurs with thionamides and may be more common at higher drug doses ( 51; 2). Minor adverse events such as rash, pruritus, arthralgia, and gastritis occur in 10–25% of patients ( 37; 51; 35; 49; 31; 19). Several studies comparing high and low dosage regimes report no adverse events at all with either dose ( 4; 33; 20; 26), presumably due to underreporting of minor side-effects. However, where minor adverse events are reported, these appear to show a clearer relationship than agranulocytosis to dose within the commonly prescribed range ( 37; 51; 35; 19). Overall, the toxicity data suggests that doses in excess of 60 mg of methimazole should not be used because of the high risk of agranulocytosis. However, it should be emphasized that agranulocytosis has been reported with doses of methimazole as low as 10 mg methimazole ( 35), and as late as 12 months or more after starting therapy ( 45). Minor side-effects may be more clearly dose-related in the usual therapeutic range providing some, albeit weak, support for regimes titrating the dose of thionamide to the lowest possible level. 17) suggested that the addition of thyroxine to thionamide therapy and its continuation up to 3 years after stopping methimazole, could reduce the relapse rate in Graves' disease from 35% to less than 2%. The improved outcome was associated with a dramatic decrease in levels of anti TSH receptor antibodies. However, 5 additional studies including one designed to repeat this finding ( 29) and another also performed in a Japanese population ( 43) have failed to confirm these results ( 36; 34; 26). As a result, there now appears to be little evidence for an independent beneficial effect of thyroxine on relapse rates after medical therapy. Goitre size ( 24; 52), young age ( 15; 52), ophthalmopathy, high pretreatment thyroid hormone levels and high titres of anti-TSH receptor antibodies (TRAb) have all been associated with poor remission rates ( 24; 50; 15; 52; 47). A recent meta-analysis of 18 studies between 1975 and 1991 confirmed an association between the absence of TRAb at the end treatment and increased chance of long-term remission (P < 0.00001) ( 10). However, the positive predictive value of TRAb measurement for relapse was still unacceptably low, with up to 25% of patients remaining in remission despite persisting TRAb levels. Vitti et al. recently correlated multiple pretreatment parameters with outcome in a large cohort of 306 patients ( 47).The remission rate in patients with a large goitre (> 40 mls) and high pretreatment titre of TRAb was as low as 9% in contrast to a rate of 80% with a small goitre and a low titre of antibodies. Nonetheless, reliable prediction of outcome was still not possible for the majority of patients indicating that the measurement of these parameters has a limited role in guiding the choice of therapy. Many patients receive thionamides prior to radioiodine (RAI), either to control thyrotoxicosis before primary therapy with radioiodine or because they have relapsed following a trial of drug therapy. Retrospective studies suggest that the failure rate of RAI therapy is increased 2.5–3 fold if thionamide therapy is not withdrawn 7 days before treatment ( 21; 25). 25) also noted a trend towards an increased failure rate even if thionamides were withdrawn a week or more before RAI dosing (9% failure rate − no thionamide; 17% − withdrawn > 7 days before; 29% − withdrawn 4–7 days before). However, if thionamides have only been given in a brief course to achieve euthyroidism, thyroid function may already be returning to thyrotoxic levels 7 days after stopping therapy ( 6). Interestingly, a prospective study of thionamide therapy begun 4 days after RAI indicates little effect on radioidine efficacy at this time ( 23), and some authors recommend routine block-replace therapy for 6 months post RAI to avoid sudden onset hypothyroidism. Note that the analysis of pre and post-treatment with thionamides in retrospective studies is complicated by the fact that the biggest factor determining success of radioiodine is the pretreatment thyroid function and those patients pretreated with thionamides tend to be those with the highest initial T3/T4 levels. This may explain why not all studies have shown an inhibitory effect of RAI pretreatment and in some cases have shown a deleterious effect of postradioiodine treatment with thionamides ( 39; 28). Pending prospective studies of this question, it seems reasonable to use RAI as primary therapy without thionamides for mild thyrotoxicosis or to withdraw thionamides a minimum of 7 days before therapy and consider increasing the dose of RAI given if local protocols use relatively low doses (e.g. 7 mCi (259 MBq) or less). Controversy remains surrounding the effects of radioiodine on Graves' eye disease and this issue has been extensively debated elsewhere ( 8). Studies in which worsening of ophthalmopathy have been reported have potentially been confounded by more frequent occurrence of periods of hypothyroidism after radioiodine as compared to other treatment modalities and, in one case an uneven distribution of smokers between treatment groups ( 42). Both hypothyroidism and smoking are known to be independent risk factors for ophthalmopathy. Most recently, a randomized controlled study of 450 patients has confirmed that glucocorticoids (0.4–0.5 mg/kg of prednisone) begun 2–3 days postradioiodine treatment, continued for one month and then tailed off over 2 months, improves existing ophthalmopathy in the majority of patients and appears to completely prevent the development of new eye disease ( 3). These remarkable results were achieved with no reported side-effects from steroid therapy. Within this study, radioiodine alone did appear to worsen ophthalmopathy as compared to treatment with methimazole (15% vs 3% of cases) but in the majority of cases (65%) any detereoration resolved within 3 months ( 3). In the first prospective randomized trial comparing the three treatment modalities, surgery was shown to be quicker than either thionamides or radioiodine in establishing euthyroidism and to have the lowest 2 year failure rate (6% vs 21% for radioiodine and 40% for drugs) ( 46). No significant complications were noted in 67 operations performed by 7 experienced surgeons. This study was unique in its assessment of issues such as patients satisfaction and days sick leave taken. On such criteria surgery scored as well as radioiodine or drugs and indeed was the quickest in the patients' perception of speed of recovery ( 46). In other published series, rates of postoperative haemorrhage (0–1.3%), recurrent laryngeal nerve palsy (0–4.5%) and permanent hypocalcaemia (0.6%) have been similarly low ( 11), but the risks are likely to be higher in less experienced centres. Overt, late hypothyroidism is common after surgery with rates reaching 30% or more at 5 years, although with much variation between centres. Subclinical hypothyroidism is even more common (up to 46%) but often self-limiting ( 40; 7; 22; 12; 11; 32). Recurrent hyperthyroidism late after subtotal thyroidectomy is rarer but rates may reach as high as 10% or more at 5–10 years ( 7; 22; 11; 32). As a result, the optimal size of thyroid remnant (usually 5–10 g) continues to be debated. Total thyroidectomy with thyroxine replacement has been proposed by expert centres to avoid the problem of recurrent hyperthyroidism ( 32), but in many hands this is likely to increase the risk or periopertaive complications to unacceptable levels. Most relapses following thionamide therapy occur within the first 12 months ( 44; 48; 18; 47). In a 15 year follow-up study by Hedley of 434 patients, 40% relapsed during the first year following medical therapy, this figure rising to 58% at 5 years and 61% at 10 years. In this series, 95% of all relapses occurred within 5 years with negligible increase in relapses after 10–15 years ( 18). Sugrue et al. however, did notice an increase from 50 to 62% in relapses between 5 and 8 years after drug therapy in patients treated for prolonged periods of time (mean 3.8 years). Ninety percentage of patients treated for less than 2 years in this study relapsed within 5 years with no further rise after this time ( 40). Late (20–30 years) hypothyroidism after thionamide therapy does occur ( 53), but, like late recurrence of hyperthyroidism after surgery or radioiodine, appears to be rare. In contrast, hypothyroidism rates rise steadily after radioiodine, reaching 18% at 5 years and 42% at 10 years, with values up to 90% for higher dose therapy ( 12; 14). According to these data, patients are at risk of changing thyroid function at anytime after treatment with all three modalities unless they have become permanently hypothyroid and are maintained on a full dose of thyroxine replacement. Nonetheless, more than 90% of patients who have become euthyroid within 1 year of surgery or radioiodine are unlikely to have a recurrence of hyperthyroidism and the same is true for 80–90% of patients 5 years after thionamide therapy. All 3 treatment modalities for Graves' disease have their advantages and disadvantages ( Table 4). Absolute contraindications for each modality are few. Patient preference and local expertise are therefore important factors and Table 4 may prove useful in guiding patient choice. Thionamides are the treatment of choice for initial therapy of severely toxic or medically unfit patients. Time to euthyroidism and risk of side-effects can be minimized by commencing therapy with more than 20 mg but less than 60 mg of methimazole/carbimazole with reassessment of thyroid function at 4–6 weeks. Long-term remission rates of around 60% should be achievable using at least 12 months and preferably 18–24 months of therapy. Block-replace/continued high dose therapy is convenient and may shorten the period of treatment required but has not been shown to improve long-term outcomes. The addition of thyroxine alone confers little benefit. If radioiodine is chosen, pretreatment with thionamides, if required, should be stopped 7 days before administration. Consideration should be given to block-replace thionamide therapy starting 4 days after treatment to avoid large swings in thyroid function and to steroid cover for patients with pre-existing ophthalmopathy. Surgery should be considered as primary therapy in good operative centres for severely toxic young patients with a large goitre who want rapid resolution of the condition, once thyroid function has been controlled with drugs. Table 5 summarizes the important issues that remain to be addressed. Studies to examine these should be multicentre, prospective and randomized where possible. If high dose block replace therapy can shorten the time required for thionamide treatment to 6 months, this has important practical implications. The value of extending drug therapy beyond 18 months in patients who remain anti-TSH receptor antibody positive has also yet to be established. Combination therapy with thionamides to induce and maintain euthyroidism before and after therapy with radioiodine may prove more acceptable to patients than radioiodine alone. Finally, the maintenance of large registries to study long-term outcome remains essential to inform current practice.