Sandbox spinalcord
Hyperthyroidism caused by toxic adenoma or toxic nodular goiter rarely remits spontaneously unless the patient has recently been exposed to a provocative iodine load or a solitary hyperfunctioning nodule undergoes hemorrhagic degeneration. Consequently, optimal treatment for most patients entails a permanent therapy, radioiodine or surgery.
Radioactive Iodine and Antithyroid Drugs
RADIOACTIVE IODINE
For most U.S. patients, where even moderately large does of 131 I can be administered on an ambulatory basis, radioiodine represents the most attractive treatment for most patients with toxic adenoma or toxic multinodular goiter. It is generally preferable to surgery when there is no suspicion of coexisting thyroid malignancy, no large goiter threatening local compressive symptoms, no other reason for neck surgery (e.g., primary hyperparathyroidism), no imperative for immediate cure, and whenever the patient’s general health makes him or her a poor candidate for surgery. 111 Radioactive iodine treatment is less attractive in children and adolescents, in whom the radiation dose administered to extranodular tissue approximates that known to be associated with subsequent thyroid cancer. 112 131 I therapy is contraindicated in pregnant women.
It is controversial whether the administered 131 I dose should be determined by some form of simplified dosimetry or an arbitrary dosage used in all patients. Typical dosimetric schemes consider gland size, its fractional uptake of a preceding tracer dose, and a standard administered dose constant (e.g., 0.16 mCi/g of estimated hyperfunctioning tissue). However, controlled studies have failed to show that calculated administered doses of radioiodine are superior to an empirically chosen constant dose for all patients (e.g., 15 mCi). 113 114 115 This is probably due to the result of imprecision in the estimated mass and heterogeneous radioisotope distribution within and lack of data about 131 I retention time in the functioning thyroid tissue. Although radioiodine is largely cleared from the patient within 14 days, resolution of hyperthyroidism typically requires 4 to 8 weeks. Consequently, it may be prudent to use temporary antithyroid drug treatment to achieve euthyroidism, discontinue it for several days before and after 131 I administration, and then resume therapy to maintain normal thyroid function while waiting for the effect of the radioiodine, particularly in older patients and those with cardiac disease. Because propylthiouracil (PTU) has been shown to induce relative resistance to radioiodine in those with Graves’ disease and methimazole has not, the latter is the antithyroid drug of choice for such adjunctive therapy. 116 117 118 119 120 121 122 123 One randomized controlled trial has also confirmed this effect of PTU in toxic multinodular goiter. 124 With typical administered radioiodine doses, such as 10 to 30 mCi of 131 I, hyperthyroidism is cured in 62% to 98% of patients with toxic adenoma or toxic nodular goiter. 125 126 127 128 129 130 The remainder almost invariably respond to a second radioiodine dose, which is typically given no sooner than 4 to 6 months later. Predictors of relative resistance to radioiodine therapy include large goiters and those with a higher fractional thyroid uptake of radioiodine. 131
Potential adverse effects of 131 I therapy for toxic nodular goiter are essentially limited to radiation thyroiditis and postablative hypothyroidism. Radiation thyroiditis can cause anterior neck pain in the week after therapy and exacerbation of thyrotoxicosis because of the release of preformed thyroid hormone from the gland, which typically occurs 2 to 8 weeks after treatment. Pretreatment with an antithyroid drug has been shown to decrease the severity of thyrotoxicosis caused by radiation thyroiditis in Graves’ disease, 132 133 134 135 but this has not been established for toxic nodular goiter. Thyroiditis-related gland swelling with potential worsening of compressive symptoms is a concern that has not actually been realized in studies of radioiodine therapy for nodular goiter. 136 137 Long term, thyroid volume typically decreases by about 40% after 131 I treatment. 138 139
The incidence of postablative hypothyroidism after radioiodine therapy has been reported to be 25% to 50%, which is lower than that encountered after treatment of patients with Graves’ disease. This is presumably because suppressed extranodular thyroid tissue does not take up radioiodine. Radioisotopic distribution within functioning tissue can also be heterogeneous. Postablative hypothyroidism is more common when higher doses of radioactive iodine are administered.
Other sides effects occur rarely. Symptoms related to sialadenitis (e.g., salivary gland swelling and pain) or gastritis (e.g., nausea or vomiting) are uncommon with the usual administered 131 I doses for toxic nodular goiter. Excess risk for other future cancers after radioactive iodine treatment for toxic nodular goiter appears to be absent or extremely low. A Swedish study of 10,552 patients treated for hyperthyroidism (mean dose, 506 MBq), with an average 15-year follow-up, found a standardized incidence ratio of 1.06 (95% CI, 1.01 to 1.11) for any type of cancer occurring 1 year or more after 131 I treatment. Among the 10-year survivors, increased risk of stomach, kidney, and brain cancers was seen, but only the risk for stomach cancer increased over time and with increasing radioactive iodine dose. Thus, these investigators concluded that the overall cancer risk does not increase with increasing 131 I dose or with time since exposure. 140
In another retrospective report by the Cooperative Thyrotoxicosis Therapy Follow-up Study of 35,593 patients with hyperthyroidism treated with 131 I, there was a standardized cancer mortality ratio of 1.16 (95% CI, 1.03 to 1.30) in those with a toxic multinodular goiter. The number of cancer deaths seen in the study was close to the predicted mortality rates in the general population, but there was a small excess mortality caused by breast, lung, kidney, and thyroid malignancies. Radioactive iodine administration was not linked to total cancer deaths (standard mortality ratio [SMR], 1.02; 95% CI, 0.98 to 1.07) or any specific cancer except for thyroid cancer (SMR, 3.94; 95% CI, 2.52 to 5.86). In this study, however, the authors concluded that “in absolute terms the excess number of deaths was small and the underlying thyroid disease appeared to play a role.” 141 Although there are limited data concerning the incidence of infertility, spontaneous abortion, and infants with birth defects in mothers previously treated with radioiodine, there has been no evidence of these deleterious consequences. 142
RECOMBINANT THYROID-STIMULATING HORMONE–STIMULATED 131 I Therapy
The relatively low fractional uptake of radioiodine by nodular goiters can limit the effectiveness of 131 I therapy and increase the administered dose requirement. Consequently, in recent years, recombinant TSH (thyrotropin alfa, rTSH, Thyrogen) has been investigated as an off-label approach to increasing thyroidal radioiodine uptake for the treatment of hyperthyroidism and goiter size in patients with toxic nodular goiter. rTSH has also been used to facilitate goiter shrinkage with 131 I in patients with nontoxic nodular goiter, in whom rTSH permits a 50% to 60% reduction in the administered 131 I dose 143 144 while producing a more substantial decrease in goiter volume. Studies in nontoxic nodular goiter patients have demonstrated the importance of using a rTSH dose less than that used for thyroid cancer testing (e.g., a single 0.01- to 0.45-mg rTSH dose). 144 145 146 Larger rTSH doses have been reported to induce severe thyrotoxicosis or gland swelling with increased obstructive symptoms. rTSH-stimulated 131 I therapy has also been used for older patients with clinical or subclinical hyperthyroidism caused by large multinodular goiters. In such patients, the relatively low fractional uptake of radioiodine by the thyroid reduces the cure rate after 131 I. In one study of 41 patients with clinical or subclinical hyperthyroidism caused by large multinodular goiter, patients who were randomly assigned to receive 0.45 mg rTSH before 131 I had a greater reduction in goiter volume at 1 year, 58% versus 40%. However, rTSH pre-treated patients also had a higher rate of postradioiodine hypothyroidism, 65% versus 21%, 147 probably because rTSH enhanced uptake in previously suppressed regions of the gland. Because of its risk of exacerbating hyperthyroidism, rTSH is generally inadvisable when administering a larger 131 I dose is an option, especially in older patients and those with underlying heart disease.
ANTITHYROID DRUGS
The thionamide antithyroid drugs—methimazole and propylthiouracil in the United States and carbimazole in Europe and Asia—have limited roles in the management of patients with nontoxic nodular goiter. Unlike hyperthyroid Graves’ disease, thyroid autonomy in toxic nodular goiter rarely remits unless it has been provoked by an iodine load. Furthermore, because of the substantial store of previously synthesized thyroid hormone that can be present in the large gland of a patient with toxic nodular goiter, thionamide therapy alone may not control hyperthyroidism completely for weeks or months.
Nonetheless, there remain certain indications for short-term antithyroid drug therapy. First, thionamides can be useful for the initial control of hyperthyroidism that is severe or complicates cardiac or other conditions in a fragile patient. By restoring euthyroidism, such thionamide pretreatment can then make subsequent surgery or radioiodine therapy safer. Second, PTU is the immediate treatment of choice for pregnant patients with hyperthyroidism, although toxic nodular goiter is rare in this population. Third, a time-limited course of antithyroid drugs can sometimes be useful to evaluate the clinical status of patients with subclinical hyperthyroidism who have nonspecific symptoms, such as nervousness or insomnia, that may or may not improve with definitive treatment of mild hyperthyroidism. If a patient experiences an improvement in symptoms or sense of well-being when thyroid function has been restored to normal on thionamide therapy, then the case for radioiodine therapy or surgery is stronger.
The specific mechanisms of action, doses, and side effects of the thionamide antithyroid drugs have been extensively reviewed.