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Radioiodine as a first choice treatment
The choice of treatment for Graves' hyperthyroidism involves both physician's prejudice and patient's preference. In the past, it was accepted that any patient presenting for the first time with hyperthyroidism of moderate severity due to Graves' disease should be given a chance to go in remission with a course of antithyroid drugs. In 1987 a survey of practice in Europe showed that 77 % of physicians still preferred this type of treatment in female patients in their forties, even if no further pregnancy was planned[3]. In a younger patient (such as a 19 year-old woman), the percentage of European thyroidologists who selected antithyroid drugs as primary treatment rose to 95 %. By contrast, when similar index cases were submitted to North American physicians, radioiodine was selected by 69 % of them in the older patient, and by 27 % in the 19 year-old hyperthyroid female. There was a consensus on both sides of the Atlantic for a relative lack of role of thyroidectomy for small or medium size hyperthyroid Graves' goiters. Our policy is to give radioiodine as a first choice treatment for Grave's hyperthyroidism, once euthyroidism has been restored and maintained by a short course (3 to 6 months) of antithyroid drugs. We do advise this type of treatment in all middle-age and elderly people, and we offer this option to young adults. Our preference for this treatment strategy derives from two considerations: 1) the recurrence rate of hyperthyroidism after antithyroid drugs is high, 2) radioiodine therapy for hyperthyroidism is effective, inexpensive, and safe. 1) The remission rate after antithyroid drugs is unsatisfactory. Although remission rates in the order of 50-60 % after 5 years have been reported in some series, in other studies hyperthyroidism recurred in 60 % to 90 % of patients during the same follow-up period[2-4]. Thus, some figures indicate a remission rate after antithyroid drugs similar to the apparent spontaneous rate of remission of the disease observed in patients treated with propranolol alone. Moreover, the remission rate after thionamide therapy appears to be declining, probably due to the increased intake of iodine, which has occurred in most industrialized countries in the last 10-15 years[2]. We also observed such decline in the remission rate, that in our clinic ranges between 20 to 30 % after a 18-24-month course of thionamides. 2) Hyperthyroidism is cured by one or more radioiodine doses in all patients with Graves' disease, although most of them ultimately develop thyroid failure. Hypothyroidism is presently regarded as a common outcome of radioiodine treatment rather than a complication. As discussed below, it can be easily and economically controlled with L-T4 substitution treatment. If we take into account the possible side effects of long-term thionamide administration, the risks of recurrent thyrotoxicosis, or the complications of thyroid surgery, radioiodine appears a relatively safe form of treatment for Graves' hyperthyroidism. Acute complications of radioiodine are extremely rare if patients are rendered euthyroid with antithyroid drugs for a period sufficient to deplete intrathyroidal stores of hormones. On the other hand, there is no epidemiological evidence that radioiodine therapy for hyperthyroidism is associated with a higher risk for future carcinogenesis, or with a risk of congenital malformations or any other abnormality in the offspring of women treated during childbearing years. Adjunctive treatment to radioiodine In patients given radioiodine as the sole form of treatment euthyroidism may not be achieved for several months. Because of this slow response, we advise pretreatment with antithyroid drugs in all patients with Graves' hyperthyroidism. Once euthyroidism has been restored, we continue the thionamide treatment for several weeks in order to deplete the intrathyroidal hormone stores. The antithyroid drug is withdrawn 7 to 10 days before radioiodine therapy. Thereafter, a beta-adrenergic antagonist is usually administered for 3 to 6 weeks to control the transient thyrotoxicosis that may occur after radioiodine due to the release of preformed thyroid hormones. Reactivation of thyroid hyperfunction following withdrawal of antithyroid drugs may also occur before the destructive effect of radioiodine takes place. This may require a short-term treatment with thionamides. We try to delay the reinstitution of antithyroid drugs for at least 1 week and possibly 2 weeks after radioiodine since thionamides may reduce the effectiveness of 131I treatment[2]. As discussed in a following paragraph, radioiodine therapy may lead to worsening of Graves' ophthalmopathy, when present. This worsening can be prevented by concomitant glucocorticoid therapy, beginning after radioiodine administration. Regimen and post treatment thyroid function In the past an effort was made to calibrate the dose of 131I to cure hyperthyroidism, but to avoid hypothyroidism. This attempt was effective to a variable extent in reducing the development of hypothyroidism early after 131I, but not in avoiding late-onset hypothyroidism. In fact, the cumulative incidence of post-radioiodine hypothyroidism steadily increases with a rate of 2-3 % of new cases per year (2, 3). The overall incidence of post-radioiodine hypothyroidism approaches a total of 50 % at 5 years and 70 % at 10 years[2, 3]. Even in patients given lower doses of 131I, the incidence of hypothyroidism is at least 50 % by 25 years[4]. Because of these considerations, in many centers including our own radioiodine doses are calculated with the aim to avoid failures and to produce early-onset rather than late-onset hypothyroidism. To this purpose, we use relatively high doses of 131I: 150-200 µCi/g of estimated thyroid weight ( in practice 10-18 mCi). In our experience, nearly 70 % of patients are cured after one dose of 131I, 25 % require a second dose, and rare patients need a third or fourth dose. Large goiters, rapid iodine turnover, and adjunctive therapy with MMI shortly after radioiodine are associated with a higher rate of persistence of hyperthyroidism. The decision to give a second dose of 131I is usually not made before 6-12 months after the first one. Long-term follow-up of patients treated with 131I for hyperthyroidism is mandatory. Once recognized, hypothyroidism should adequately be treated with L-thyroxine (L-T4). Early onset hypothyroidism may not be permanent. In these cases, L-T4 substitution should be initiated at submaximal doses. If during this incomplete substitution TSH remains elevated for more than 2 months, hypothyroidism is likely to be permanent. Antithyroid Drugs as an Alternative Treatment Despite our attitude for the use of radioiodine as a primary treatment for Graves' hyperthyroidism, in clinical practice a considerable percentage of patients, mainly young women in childbearing age, will refuse this therapeutic option. Reluctance to ablate the thyroid, fear of subsequent hypothyroidism, anxiety about possible radiation-induced carcinogenesis, or concern for the genetic risks to future generations are the main reasons for this refusal. In these instances, a course of antithyroid drugs should be offered as an alternative therapeutic option. Antithyroid drug treatment is usually started with 20-40 mg/day of MMI or with 200-400 mg/day of PTU. We generally prefer MMI over PTU because MMI is more potent, restores euthyroidism more quickly, and in moderate doses is associated with lower risk of agranulocytosis than PTU. Doses of MMI above 40 mg/day are rarely (if ever) necessary. On the other hand, lower doses of MMI (10-20mg/day) may be sufficient to induce euthyroidism, although after longer periods of administration. Once euthyroidism has been restored in the following 4 to 6 weeks, two treatment strategies can be used: 1) progressive reduction of the dose of thionamide to the minimal amount that maintains euthyroidism; 2) administration of a fixed, relatively high dose of the antithyroid drug in combination with L-T4 to prevent iatrogenic hypothyroidism. The rationale for the latter therapeutic option derives from the possible immunosuppressive effect of MMI, and from studies suggesting a greater remission rate of hyperthyroidism in Graves' patients treated with high doses of thionamides (60 mg vs. 15 mg of MMI per day)[3]. A very high remission rate has also been reported in Japanese patients treated with MMI for six months, and then given a combination of MMI and L-T4 for a further year, followed by L-T4 alone for three years. However, the latter results have not been reproduced so far. Despite the alleged advantages of a combined regimen of thionamides and L-T4, we prefer the strategy of adjusting the dose of MMI (or PTU) to maintain euthyroidism. This is because of the following arguments that derive from a recent prospective randomized trial of low (10mg/day) versus moderately high doses (40mg/day) of MMI [7]. In this study: 1) TSH-receptor antibodies decreased similarly in patients treated with low or high doses of MMI; 2) the relapse rate within 1 year after a 12-month course of treatment was almost identical in the two groups; 3) the relapse rate was also similar in patients receiving less than or more than 50 µg of L-T4/day to maintain euthyroidism while given a fixed dose of MMI; 4) the rate of adverse reactions was greater in the group of patients receiving MMI at 40 mg/day. One factor that affects the likelihood of remission after antithyroid drugs is the duration of treatment[2, 3]. With a short course of antithyroid drugs (3-6 months), long-lasting remissions occur in approximately 25 % of patients, whereas this proportion is increased when treatment is maintained for 18 to 24 months or longer. However, a significant proportion of patients cannot be "cured” even with a course of thionamides longer than 8 years. For this reason, we continue antithyroid drugs for 18 months, after which the patient must be reevaluated regularly. To rationalize the duration of thionamide therapy, it would be helpful to have on-treatment criteria or tests to anticipate the outcome of thyroid function after stopping medication. Size of goiter under antithyroid drugs, T3-suppression of 99mTc uptake, TRH-test, HLA-DR3 typing, T3/T4 ratio, TSH-receptor antibody or thyroid-peroxidase antibody levels, serum Tg concentrations, thyroid echogenicity by ultrasound, circulating activated T-cells or T-cells subset ratios, have been proposed as predictors of remission or relapse after discontinuation of thionamides[2]. However, no test or combination of tests has the required sensitivity and specificity to be useful in individual patients. In our experience features during therapy that suggest that a patient will probably undergo a relapse of hyperthyroidism include: 1) the presence of a large goiter that fails to shrink or even increases in size under antithyroid drugs; 2) persistence of a high T3/T4 ratio; 3) requirement of moderately high doses of thionamides to maintain euthyroidism; 4) failure of thyroid stimulating antibody to disappear from the serum during treatment. Positivity of thyroid stimulating antibody (TSAb) before discontinuation of thionamides signifies almost certain future relapse. However, if TSAb disappears, there is still about a 20% to 50 % chance of recurrence of hyperthyroidism[1]. Relapse usually occurs within 3 to 6 months after therapy is discontinued, and more than two-thirds of patients who relapse will do so within 2 years. Scanty data are available on long-term outcome in patients undergoing prolonged remission, but some eventually develop autoimmune hypothyroidism (burned out hyperthyroidism)[3], while others will experience a new attack of hyperthyroidism. If hyperthyroidism does recur, it is our policy to strongly advise radioiodine treatment in all patients except children and adolescents. A considerable percentage of young adults may again refuse radioablation of the thyroid, and in these cases a second course of thionamides is acceptable. However, the risk of relapse after a second course of antithyroid drugs appears similar to that after a the first one. Role of Thyroidectomy Thyroidectomy, either subtotal or near total, is the oldest means of treating Graves' hyperthyroidism[2-4], but nowadays it is restricted to special cases. The following indications for surgery are accepted by most experts in the treatment of Graves' hyperthyroidism:
Postoperative thyroid function largely depends on the extent of thyroidectomy and duration of follow-up. Insufficient tissue removal results in persistent hyperthyroidism or in later relapse of hyperthyroidism. This may occur in 5 to 10% of patients within 5 years, and in up to 40% within 30 years after thyroidectomy[2-4]. Recurrence of hyperthyroidism is particularly undesirable, since a second operation is technically more difficult than the first one and involves a higher risk of complications. With few exceptions, therefore, such patients should be treated with radioiodine. Removal of too much tissue results in postoperative thyroid failure. In the first year after surgery, hypothyroidism has been reported in percentages of patients that range from 5 % to 60 %[2-4]. Late onset cases develop in an additional 1-3 % per year. Hypothyroidism is easily and economically treated with L-T4 replacement therapy, thus thyroid failure after thyroidectomy for Graves' hyperthyroidism should not be considered a real complication. |
