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Hyperthyroidism and Ophthalmopathy
Relief of thyrotoxicosis by any form of treatment is generally associated with an amelioration of eye signs caused by excessive sympathetic activity. On the other hand, it is still debated whether treatment of hyperthyroidism with antithyroid drugs, radioiodine or surgery, has any role in the appearance of Graves' ophthalmopathy or can modify its course when pre-existing. In our opinion[1], currently available evidence indicates that:
It is also reasonable to believe that elimination of thyroid autoantigens by radical means (radioiodine, thyroidectomy, or both) may favor a remission of the autoimmune reaction against orbital antigens. Not yet sufficiently documented, clinical experience suggests that repeated recurrences of hyperthyroidism may adversely affect the course of ophthalmopathy. Based on these considerations, we favor the following therapeutic approach in patients with Graves' hyperthyroidism and ophthalmopathy: 1) In any case: rapid restoration of euthyroidism by antithyroid drugs, followed by radical treatment of hyperthyroidism by thyroidectomy or radioiodine, as indicated; 2) In patients with mild or moderate ophthalmopathy: protection from possible exacerbations of ophthalmopathy after radioiodine or surgery with a short-term course of glucocorticoids; 3) In patients with severe ophthalmopathy: radical treatment of hyperthyroidism associated with specific therapy for eye disease consisting in orbital irradiation and high-dose systemic glucocorticoids; 4) Careful monitoring of post-treatment thyroid status to promptly correct intervening hypothyroidism. Hyperthyroidism in Pregnancy Thyrotoxicosis occurs in every 500-1500 pregnancies, and in most cases is due to Graves' disease; toxic multinodular goiter is much less common[2, 3, 8]. Hyperthyroidism during pregnancy does not warrant abortion, but requires prompt and effective treatment. There is a higher incidence of abortion, preterm delivery, lower-birth-weight infants and neonatal mortality in pregnancies complicated by maternal hyperthyroidism. In addition hyperthyroidism may precipitate heart failure, and thyroid storm may occur during labor and delivery in a thyrotoxic woman. All these complications are much less frequent when thyrotoxicosis is recognized and treated before pregnancy as opposed to during pregnancy. Nevertheless, control of maternal thyrotoxicosis at any time during gestation is critical to improve the outcome of pregnancy. Thionamides are the first choice treatment in a pregnant woman with hyperthyroidism. Radioiodine therapy is contraindicated during pregnancy, and surgery is restricted to exceptional cases. Inadvertent administration of radioiodine to pregnant women by 10 weeks of gestation, when the fetal thyroid gland has developed, results in congenital hypothyroidism. Clinical improvement with thionamides occurs after the first week, and euthyroidism may be reached after 4 to 6 weeks of therapy. Both PTU and MMI cross the placenta, and in excessive doses may cause hypothyroidism and goiter in the fetus and in the neonate. Because PTU is less lipid-soluble and more highly protein bound, its placental transfer appears to be lower, so that the preferential use of this drug in pregnancy has been advocated by some, mainly in United States[2]. However, a study at term showed no difference between PTU or MMI in suppressing fetal thyroid function (2, 3, 8). In our view the physician should use during pregnancy the same drug, MMI or PTU, he is more accustomed to. The drug chosen should be given at the lowest possible dose (but not higher than 10 mg MMI or 100 mg PTU daily as maintenance dose) to maintain maternal free T4 and free T3 in the high normal range. In general, this will ensure euthyroidism in the fetus since free T4 levels in mother serum are correlated with fetal free T4 levels, as assessed in cord blood. Due to physiological changes of TSH secretion during the various phases of pregnancy, serum TSH is not a reliable index to judge the adequacy of treatment. In any case, high levels of serum TSH are indicative of excess treatment and require a prompt adjustment of the dose of thionamides. Because of the well known immunosuppressive effect of pregnancy, partial and transient remission of Graves' disease may occur. Accordingly, control of hyperthyroidism may be achieved with a relatively low dose of thionamides, and then maintained with a minimal amount of these drugs. Often antithyroid drugs may even be discontinued in the last few months of gestation. On the other hand, relapse of hyperthyroidism is frequent in the post-partum period. A blocking-replacement regimen of high dose thionamides combined with L-T4 replacement therapy is contraindicated in pregnancy, since L-T4 will keep the mother euthyroid, but the differential placental transfer will result in fetal hypothyroidism. Iodide must also be avoided because of the risk of fetal hypothyroidism and goiter due to Wolff-Chaikoff effect. A lactating mother receiving antithyroid drugs may transfer thionamides to her infant in breast milk, and MMI more so than PTU. Low doses of thionamides, up to 15 mg of MMI or 150 mg of PTU, given to the mother during breast-feeding apparently do not affect thyroid function in the infant. Under these conditions breast-feeding can be allowed, provided that the infant's thyroid function is monitored. An increase in congenital malformations has been reported in infants of hyperthyroid mothers[8]. In a study of infants of mothers with Graves' disease, those mothers rendered euthyroid with MMI had the same low rate of fetal abnormalities seen in euthyroid untreated mothers (<1 %). In contrast, hyperthyroid, untreated mothers had the highest incidence of fetal anomalies (6 %). These findings suggest that uncontrolled maternal hyperthyroidism may cause fetal malformations and that the benefit of MMI outweighs any possible teratogenic effect related to this drug. Aplasia cutis in offspring of MMI-treated mothers is an extremely rare occurrence[2], and per se should not justify the choice of an alternative drug during pregnancy. Subsequent intellectual development of children exposed to antithyroid drugs in utero is normal. The use of beta-adrenergic antagonists in pregnancy is not advisable since it may be associated with a small placenta, intrauterine fetal growth retardation, impaired response to anoxic stress, postnatal bradycardia, and hypoglycemia in the offspring. Surgical treatment is only exceptionally indicated, and may be considered in cases of poor compliance, severe drug allergy, very large goiter, associated thyroid malignancy, or necessity to use high doses of thionamides to maintain euthyroidism. Thyroidectomy is most safely performed in the second trimester. Complications of surgery, such as vocal cord paralysis or hypoparathyroidism, are disabling and difficult to treat during pregnancy. L-thyroxine therapy for the mother may be required postoperatively. Management of hyperthyroidism in women of childbearing age planning subsequent pregnancy remains controversial. Once hyperthyroidism has been controlled with antithyroid drugs, and euthyroidism is maintained with a low dose of thionamides, pregnancy can be allowed. This regimen, however, requires compliant and cooperative patients. Alternatively, the radioiodine option should be offered, since there is no evidence for an association between 131I treatment for hyperthyroidism and congenital abnormalities in subsequent offspring. We allow pregnancy one year after radioiodine therapy, once thyroid function is normalized. Subtotal thyroidectomy is advocated by others, because of more rapid restoration of euthyroidism. Neonatal and Fetal Hyperthyroidism Neonatal thyrotoxicosis may occur in association with maternal Graves' disease and it is due to the transplacental transfer of TSAb[2, 3]. Neonatal hyperthyroidism requires early and vigorous treatment with thionamides. MMI (0.5-1.0 mg/kg/day) or PTU (5 to 10 mg/kg /day) must be administered every 8 hours. Propranolol may be added to slow pulse rate and to reduce hyperactivity. Iodine (1 drop of Lugol's solution equivalent to 8 mg of iodine every 8 hr) is also used in addition to thionamides to inhibit the release of preformed thyroid hormones. As an alternative form of treatment, sodium ipodate alone, 0.5 g doses every 3 days, has been reported to rapidly normalize serum T4 and T3 in thyrotoxic neonates. In severely ill infants, glucocorticoids may be added as a general supportive measure and to block conversion of T4 to T3. Hyperthyroidism may occur in utero during fetal life, mainly if high levels of TSAb are present in maternal serum. Fetal thyrotoxicosis is suggested by a heart rate over 160 per minute after 22 weeks of gestation. In this instance, in utero treatment of hyperthyroidism may be accomplished by giving antithyroid drugs to the mother. The dose of thionamides should be adjusted to maintain a fetal heart rate of about 140 beats/min. Hyperthyroidism in Children and Adolescents Graves' disease is the main cause of hyperthyroidism in children and adolescents. In this age group the peak incidence of the disease is between 11 and 15 years, but it may even occur in children under 5 years. Antithyroid drugs, radioiodine and surgery, have been successfully used in children[2, 3], but, similar to others, we favor thionamides as first choice treatment. Radioiodine has been proven to be effective, and safe in children with hyperthyroidism, but its long-range potential for radiation oncogenesis and gonadal damage remains to be established[2]. Current data indicate that the incidence of thyroid cancer, leukemia, or other cancers is not increased, nor is there evidence of reproduction abnormalities in females. However, long-term follow-up studies on radioiodine therapy in children, i.e. in patients who have a 60-70 year life expectancy are still limited. Because of this, most children in our institution are treated with thionamides for long periods (3-4 years) in the attempt to induce a stable remission. This has been reported to occur in 34 % to 64 % of children, higher rates been associated with longer treatment periods [2]. Long-term courses of therapy imply close medical supervision, since compliance of patients (and families) may be low in this age group. Positive TSAb tests under therapy indicate that remission has not been achieved, and are an indication to continue antithyroid drug treatment. Relapses of hyperthyroidism are again managed with thionamides. In practice, we make an effort to maintain control of hyperthyroidism with antithyroid drugs up to the completion of physical growth and sexual development, i. e. after 18-19 years of age. At this stage the same treatment strategies discussed for adults are applied. Thyroidectomy is rarely performed in children and adolescents because permanent complications occur with a relatively high rate in this age group [6], and have a great relevance (hypoparathyroidism) in the developmental age. Recurrences of hyperthyroidism following subtotal thyroidectomy in children are also more frequent than in adults. Nevertheless, very large goiters or poor compliance to antithyroid drugs may indicate the need for surgical treatment. Similar to adults, thyroid surgery in childhood and adolescence requires careful medical preparation and an experienced surgeon. Major toxic-effects of thionamides are not infrequent in children. In such cases, as in the presence of associated heart disease or major nonthyroidal illness, we prefer radical treatment with radioiodine. As in adults, hypothyroidism is a common event following radioiodine or surgery. Prompt L-T4 substitution therapy is mandatory in this age-group, even if serum TSH is only slightly elevated. Whatever treatment for hyperthyroidism is selected, children and adolescents require a life-long follow-up to promptly detect relapses of hyperthyroidism or the development of hypothyroidism. Hyperthyroidism in the Elderly The frequent coexistence of hyperthyroidism and cardiac disease in the elderly represent a major challenge for the physician. The therapeutic intervention is directed to rapidly control hyperthyroidism, to avoid future relapses, and to prevent additional heart complications. Accordingly, the treatment plan involves: 1) prompt restoration of euthyroidism with antithyroid drugs; 2) rapid control of thyrotoxic symptoms with beta-adrenergic antagonists; 3) definitive, ablative treatment of hyperthyroidism with high doses of radioiodine, generally preferred to surgery; 4) protection of the heart from the possible radioiodine-induced transient thyrotoxicosis with beta-adrenergic antagonists and/or dexamethasone; 5) resumption of thionamides 2 weeks after radioiodine to control hyperthyroidism while waiting for the complete effect of radioiodine; 6) strict control of thyroid state in the next 12 months; 7) cautious tapering of antithyroid drugs until discontinuation. Hypothyroidism, that is the desirable outcome of treatment in these patients, should be corrected with the minimal amount of L-T4 sufficient to maintain serum TSH in the normal range. |
