In a recent editorial [1], Dr. Cooper makes several assertions about our article [2] that we believe deserve further consideration. He suggests that the incremental changes we observed in 17 patients after antithyroid drugs were stopped weighted by the inclusion of patients who were not rendered euthyroid before discontinuation of antithyroid drug therapy. This speculation is unsupported by data and overlooks our detailed analysis, which showed no statistical relation between basal and subsequent peak hormone levels after the discontinuation of antithyroid therapy. As shown in Figure 1, the fold increase in free thyroxine levels after antithyroid therapy was discontinued had no correlation with basal hormone levels; in fact, the largest incremental increase occurred in a patient pretreated to the lowest thyroid hormone levels before receiving Iodine-131. Similar results were obtained for changes in free triiodothyronine levels.

View larger version (10K): [in this window] [in a new window]   Figure 1. Relation between basal level and fold increase in free thyroxine (T4) level after the discontinuation of antithyroid drug therapy. Fold increase represents the peak level during the study period before administration of Iodine-131 divided by the basal level at study entry (r = –0.34;P = 0.18).

Dr. Cooper also suggests that our study lacked suitable controls. This statement appears to be rooted in a misinterpretation of our original hypothesis. Our stated study objective was "to determine the relative effects on thyroid hormone levels of discontinuing antithyroid drug therapy and subsequent ablation with radioiodine in patients with hyperthyroid Graves disease." The short-term changes observed after discontinuation of antithyroid drug therapy were compared with those occurring after Iodine-131 was administered. This analysis allowed an assessment of relative changes in mean hormone levels during these two phases of therapy. No attempt was made to use the four patients not receiving pretreatment as a control group. The fact that these patients had dramatic, statistically significant decreases in thyroid hormone level after Iodine-131 is noteworthy, however, and leads us to concur with Dr. Cooper's recommendation for a randomized trial to compare the short-term effects of Iodine-131 in patients with and without pretreatment with antithyroid drugs.

On the basis of our results, Dr. Cooper offers an alternative to conventional approaches for discontinuing antithyroid drug treatment before Iodine-131 ablation. He suggests that antithyroid drug therapy should be discontinued as soon as 2 to 3 days before Iodine-131 ablation therapy. This period is considerably shorter than most current recommendations, which range from at least 3 days to 5 days [3]. We believe that the absence of data to support this position suggests a need for further study before the position is adopted, particularly in light of increasing evidence that pretreatment with antithyroid drugs decreases the remission rate after administration of Iodine-131 for Graves disease [4]—a finding that might suggest a need for increasing rather than decreasing the period of discontinuing antithyroid drug therapy. It should also be noted that as early as 3 days from the last dose of antithyroid drugs, our patients already had significant elevations in free and total triiodothyronine levels. Moreover, the action duration of antithyroid drugs may be as great as 60 hours [5], and the brief interruption of therapy suggested by Dr. Cooper might therefore be associated with both inadequate Iodine-131 uptake and reduced therapeutic benefit.

Finally, despite several decades of experience, two important questions remain regarding pretreatment with antithyroid drugs before ablation with Iodine-131 in patients with Graves disease. First, does this practice do any harm? Our study provides convincing evidence that pretreatment and abrupt discontinuation of antithyroid drug therapy before ablation with Iodine-131 may result in a rapid increase in free thyroid hormone levels. Elderly or sick patients may be at greater risk for thyroid storm in this setting [2]. In addition, pretreatment with antithyroid drugs may diminish the long-term effectiveness of Iodine-131 therapy. Second, does pretreatment with antithyroid drugs provide any benefit? As Dr. Cooper points out, it is possible that pretreatment with antithyroid drugs, although exposing patients to an exacerbation of thyrotoxicosis before Iodine-131 administration, paradoxically protected these patients from significant further increases after Iodine-131 administration. This theory remains to be tested. We hope that our study will lead to an increased awareness of the potential harmful effects of pretreatment with antithyroid drugs before Iodine-131 ablation for Graves disease and that it will serve as an impetus for further study—particularly regarding the efficacy of this common practice. Only then will a rational assessment of the risk–benefit ratio associated with antithyroid drug pretreatment be possible.