Therapeutic Options in Hyperthyroidism
L. Chiovato, F. Santini and A. Pinchera
Toxic diffuse goiter is an autoimmune disease characterized by hyperthyroidism, goiter, ophthalmopathy, and less frequently dermopathy (pretibial myxedema). In this condition, hyperthyroidism occurs from a disturbance of the immune system, resulting in the production of antibodies against the TSH receptor with thyroid stimulating activity F. The prevalence of Graves' disease in the general population is relatively high reaching 1-2 % or more in females, and the female/male ratio is 7/1. It may occur at any age, but the peak incidence is between the 3rd and 4th decade of life.
In toxic multinodular goiter, hyperthyroidism is caused by the presence of autonomously functioning follicles within the thyroid gland. In contrast to the general effect of thyroid stimulating antibody on thyroid tissue in Graves' disease, a variable rate of replication and function in different parts of the gland results in the characteristic structure of this condition. Since hyperthyroidism usually arises from a long-standing multinodular goiter, the prevalence of this disorder largely depends on the iodine intake of a given population, being higher in iodine-deficient areas. In these regions toxic multinodular goiter is responsible of at least 10% of cases of hyperthyroidism among middle-aged and elderly patients.
A third cause of hyperthyroidism is toxic adenoma, a lesion that presents as a solitary hot nodule suppressing the function of the rest of the thyroid. This condition may either result from areas of autonomously functioning thyroid follicles localized in one lobe, or arise as a true benign neoplasm that may be caused by a somatic mutation of the TSH-receptor. This mutation produces a continuous activation of adenylate cyclase irrespective to the TSH control.
| Therapeutic Agent | Action |
|
|
|
| 1) Drugs inhibiting thyroid hormone synthesis, release
or peripheral
conversion of T4 to T3. |
|
| Thionamides | Inhibition of iodide orgnification |
| (methimazole, | Inhibition of coupling of iodotyrosines |
| propylthiouracil, | Inhibition of T4 to T3 conversion (PTU) |
| carbimazole) | |
| Iodide | Inhibition of iodide oxidation and |
| (Lugol's solution, SSKI) | organification |
| Inhibition of thyroid hormone release | |
| Decreased thyroid vascularity | |
| Iodinated constrast | Inhibition of T4 to T3 conversion |
| agents(iopanoic acid, | Release of inorganic iodide and consequent |
| sodium ipodate) | inhibition of thyroid hormone synthesis and secretion |
| Potassium perchlorate | Competitive inhibition of iodide pump |
| (inhibition of iodide uptake and consequent release of iodide from the thyroid) | |
| Glucocorticoids | Inhibition of thyroid hormone secretion (efficiency unknown) |
| Inhibition of peripheral conversion of T4 to T3 | |
| 2) Drugs inhibiting the effects of thyroid hormones on peripheral tissues | |
| Beta-adrenergic | Inhibition of adrenergic effects of thyroid |
| antagonists (propranolol, | hormones |
| metoprolol, nadolol) | Inhibition of peripheral conversion of T4 (atenolol, bisoprolol) |
| to T3 (propranolol) | |
| Calcium antagonists | Anti-arrhythmic effect and reduction of heart (diltiazem, verapamil) rate |
| 3) Ablative forms of treatment. | |
| Radioactive iodide | Destruction of thyroid follicular cells by beta radiation |
| Surgery | Removal of tissue responsible for excessive secretion of thyroid hormones |
|
|
|
The main action of thionamides (methimazole, carbimazole, and propylthiouracil) is to inhibit the organification of iodide and coupling of iodotyrosines, thus blocking the synthesis of thyroid hormones[2-4]. Since carbimazole is almost completely converted to methimazole (MMI) in the body, their effects are comparable. Propylthiouracil (PTU) has the additional effect of inhibiting the conversion of T4 to T3 in peripheral tissues. Despite this property of PTU, in most patients MMI therapy results in a more rapid normalization of serum T4 and T3. This may be due to the greater intrinsic potency of MMI and to its longer duration of action. The main pharmacological features of antithyroid drugs are summarized in Table 3.
| Methimatzole | Propylthiouracil | |
|
|
||
| Relative therapeutic potency | 10-50 | 1 |
| Route of administration | oral | oral |
| Absorption | almost complete | almost complete |
| Serum protein binding | negligible | 75% |
| Serum half-life | 4-6 h | 1-2 h |
| Duration of action | 24 h or longer | 12-24 h |
| Transplacental passage | low | lower |
| Levels in breast milk | low | lower |
|
|
||
Serious side effects (Table 4) are not common with antithyroid drugs, being observed in approximately 3 of every 1000 patients[2-4]. Agranulocytosis (granulocyte count < 500 per cubic ml), the most feared problem, may be observed with both MMI and PTU, but a low dose of MMI is safer than a high dose of either drug. The elderly may be more susceptible to this side effect; however, agranulocytosis can occur in any age group. Agranulocytosis may develop suddenly and usually occurs within the first 3-4 months after starting therapy. Agranulocytosis typically presents with fever and evidence of infection; therefore, all patients taking antithyroid drugs should be instructed to report these symptoms immediately if they occur. In addition to prompt discontinuation of the antithyroid drug, treatment of agranulocytosis involves the administration of broad-spectrum antibiotics and growth factors to stimulate recovery of bone marrow. Patients usually recover within 2 to 3 weeks, but a few deaths have been reported from this complication. Hepatitis, vasculitis, and lupus-like syndromes are rare complications, but make the discontinuation of antithyroid drugs mandatory. Minor side effects are much more frequent, occurring in 1 to 5 % of patients. Among them, pruritus, rash and, less commonly, urticaria are the most prominent manifestations. These side effects may resolve spontaneously despite continued therapy, but in general call for substitution of one thionamide for the other, although cross-sensitivity to these drugs may occur.
Beta-adrenergic antagonist drugs
These drugs are an integral part of the management of hyperthyroidism[2-4]. Blockade of beta-adrenergic receptors rapidly ameliorates some manifestations of thyrotoxicosis, such as tremor, palpitation, and anxiety. Beta-adrenergic antagonists do not affect thyroid hormone synthesis and release, therefore should not be used alone except for short periods before and/or after radioiodine therapy, or in patients with self-limited forms of thyrotoxicosis. Since the introduction of propranolol, a number of new agents became available with a longer duration (atenolol, metoprolol, and nadolol), or with greater cardioselectivity (atenolol, metoprolol, bisoprolol). In practice, any of these drugs is effective, and the choice largely depends on the personal experience of the physician. The usual contraindications of beta-adrenergic antagonists, such as asthma, should be considered. Despite the initial concern, propranolol or other beta-adrenergic antagonists are widely used in thyrotoxic heart disease, in view of the notion that tachycardia and tachyarrhytmias are the most prominent factors involved in this condition.
Iodide
Inorganic iodide given in pharmacological doses (as Lugol's solution or as saturated solution of potassium iodide, SSKI) decreases its own transport into the thyroid, inhibits iodide organification (the Wolff-Chaikoff effect), and rapidly blocks the release of T4 and T3 from the gland[2]. However, after a few days or weeks, its antithyroid action is lost, and thyrotoxicosis recurs or may worsen. The usual dose of Lugol's solution is 3-5 drops three times a day, and that of SSKI is 1 drop three times daily. Short-term iodide therapy is used to prepare patients for surgery, usually in combination with a thionamide drug. Iodide is also used in the management of severe thyrotoxicosis (thyroid storm), because of its ability to inhibit thyroid hormone release acutely.
Oral cholecystographic agents (iopanoic acid and sodium ipodate) have a dual action: they produce a fall in the serum concentration of thyroid hormones, which results from the block of thyroid hormone secretion due to the inorganic iodide released from the drug, and inhibit the peripheral conversion of T4 to T3[2]. Although early reports suggested that these iodinated compounds in doses of 0.5 to 1.0 gram (g) daily could be successfully used as a primary therapy of hyperthyroidism, they proved to be of limited value because of the escape of thyroid hormone synthesis from the effect of iodide. On the other hand because of their rapid effect on serum T3 concentrations, oral cholecystographic agents may be given in conjunction with thionamides for a more rapid normalization of thyroid status.
Perchlorate
Perchlorate interferes with accumulation of iodide by the thyroid[2,3]. In conjunction with thionamides it has successfully been used in the treatment of amiodarone-induced hyperthyroidism. Gastric irritation and toxic reactions (aplastic anemia) limit the long-term use of perchlorate in the management of hyperthyroidism.
Glucocorticoids
Glucocorticoids in high doses inhibit the peripheral conversion of T4 to T3[3]. In Graves' hyperthyroidism, glucocorticoids appear to decrease T4 secretion by the thyroid, but the efficiency and duration of this effect is unknown. In severe hyperthyroidism, short-term glucocorticoid administration may be used as a general supportive treatment. The immunosuppressive effect of glucocorticoids in high doses is commonly exploited in the treatment of ophthalmopathy and dermopathy of Graves' disease, but not in the management of uncomplicated Graves' hyperthyroidism.
The goal of radioiodine therapy of hyperthyroidism is to destroy sufficient thyroid tissue to cure hyperthyroidism with one dose of 131I. Because of radiation-safety restrictions, in some centers, especially in Germany, repeated 2-3 mCi doses of radioiodine are administered. Similar to others, we calculate the dose of radioiodine on the basis of thyroid size and uptake of 131I using the following formula:
Dose (mCi)= estimated thyroid weight (g) x planned dose (µCi/g) / fraction 24-hour radioiodine uptake x 1,000)
In other centers standard fixed doses are given. It is a common experience that small glands appear to be destroyed more readily by radioiodine than larger ones, and that toxic adenoma or toxic multinodular goiter are usually more radioresistant than Graves' glands.The effect of radioiodine is relatively delayed and several months may be required for the complete control of hyperthyroidism. Thus, a course of antithyroid drugs, either before or after (or both in severe thyrotoxicosis) the administration of radioiodine is frequently used in order to avoid the inconveniences of persistent hyperthyroidism.
Possible long-term side effects
In the past, the major concerns with radioiodine therapy derived from the possible carcinogenic effects of ionizing radiation, and from the risks of congenital malformations in offspring of women treated during childbearing years. While there is no doubt that external head and neck radiation is associated with an increased rate of thyroid carcinoma, no association was found in large epidemiological studies between radioiodine administration and thyroid cancer[2]. Similarly, there is no evidence that radioiodine therapy for hyperthyroidism increases the risk of leukemia or solid tumors. A minimal increase in the risk of gastric cancer 10 years or more after treatment was found in a survey in Sweden [5], but not in an epidemiological study in the United States [6]. No association between radioiodine treatment for hyperthyroidism and congenital abnormalities in subsequent offspring has been observed[2]. A rough estimate of the dose to the ovaries is about 0.2 rad/mCi of administered 131I. Thus, the dose to ovaries for a patient receiving 10 mCi of radioiodine is similar to that from a barium enema or an intravenous pyelography [3]. It has been calculated that, if a genetic risk induced by 131I does really exist , this would be only 0.003 % per rad of parental gonadal exposure, and therefore a very small fraction of the spontaneous incidence of genetic disorders[6]. Thus, the experience accumulated in more than 50 years of radioiodine treatment for hyperthyroidism has shown that these potential risks are absent or negligible.
Possible complications of thyroid surgery include thyroid storm, that nowadays is extremely rare, bleeding, injury to the recurrent laryngeal nerve, and hypoparathyroidism. In particular, the risk of laryngeal nerve injury and hypoparathyroidism cannot be disregarded. Although an incidence of these complications lower than 2 % is reported from clinics with wide experience in thyroid surgery, much higher figures up to 10-15 % are encountered in some series. These complications are of course less frequent when lobectomy for toxic adenoma is performed.
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.
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.
1) Large goiter with compression effects;
2) Suspicion of malignancy due to associated cytologically suspect nodules;
3) Reluctance of a patient to receive radioiodine.
Extremely rare or relative indications can be also defined:
1) Pregnant or lactating women who are allergic to thionamides;
2) Likely or proven non-compliance of a patient in taking medication, since the risk that L-T4 replacement will be required may be greater after radioiodine than after surgery. Some thyroidologist advise thyroidectomy in children and adolescents who are allergic or noncompliant with antithyroid drugs. However, subtotal thyroidectomy may be more hazardous in children, in whom acute complications are reported in 16-35 % and permanent complications in up to 8 %[6].
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.
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:
1) The course of Graves' ophthalmopathy is more favorable in patients rendered and maintained euthyroid;
2) Transient exacerbation of ophthalmopathy may occur after radioiodine therapy or thyroidectomy;
3) Systemic glucocorticoid treatment prevents such exacerbation.
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.
Toxic Adenoma
Hyperthyroidism due to toxic adenoma responds well to radioiodine, and the nodule is partially reduced by this form of therapy[2, 3]. In severe hyperthyroidism, pretreatment with thionamides is indicated, but radioiodine should be given before restoration of extranodular thyroid function by TSH. Under these conditions, post-radioiodine hypothyroidism is rare. Relatively high doses of 131I are used, generally 200 µCi/g of estimated nodule weight.
Surgery is a more appropriate choice in large (>5 cm) nodules with associated pressure symptoms. Young age also favors surgery with respect to radioiodine. Lobectomy is indicated in classic toxic adenoma in otherwise normal thyroid glands. When single hyperfunctioning thyroid nodules occur in a multinodular goiter subtotal or near total thyroidectomy is indicated. Hypothyroidism does not occur in patients submitted to lobectomy, but may well occur in those treated with subtotal thyroidectomy. Substitution treatment with L-T4 is mandatory in all cases of hypothyroidism.
Autonomously functioning thyroid nodules (pretoxic adenomas) are rather frequent, mainly in endemic areas. These nodules may remain unchanged in volume and function for years or decades, but their evolution to thyrotoxicosis may be insidious, and is frequently recognized after the appearance of cardiac complications. Because of this, we believe that autonomously functioning thyroid nodules deserve radioiodine or surgical treatment. Most recently percutaneous ethanol injection treatment (PEIT) has been offered as an additional option for both toxic and pretoxic adenoma. PEIT consists in the administration of 98 % ethanol (total amount 1.5 ml per gram of nodular tissue) by a needle inserted into the nodule. Though generally well tolerated, a transient burning sensation is experienced by most patients. More serious side effects are rare, and include transient dysphonia, general malaise, and transient exacerbation of thyrotoxicosis in untreated toxic adenoma. Normalization of thyroid function tests and reduction of the nodular volume have been reported in more than 70 % of patients after 3 to 5 injections. The response to PEIT in large nodules is less satisfactory. PEIT can be proposed as alternative treatment to patients with small toxic adenomas or, more appropriately, with pretoxic nodules. Since the extranodular tissue is unaffected by the treatment, there is no risk of hypothyroidism which, instead, is a relatively common complication of radioiodine administration in patients with pretoxic nodules. The need for repeated injections (up to 8), the relatively high cost, and the possible discomfort associated with intranodular ethanol injection may however limit the use of this form of treatment.
Toxic Multinodular Goiter
Toxic multinodular goiter is more frequent in patients older than age 50, who may have other, nonthyroidal illnesses adding a risk to surgery. Therefore, many patients with toxic multinodular goiters receive radioiodine. Hyperthyroidism is cured in virtually all cases, although more than one dose of 131I may be required. However, the reduction in thyroid size is only partial, because of the presence of intrathyroidal calcifications, fibrosis, and large areas of nonfunctioning tissue. Nevertheless, in patients with large mediastinal goiters, but contraindications to surgery, radioiodine may be used with benefit and partial relieve of pressure symptoms. Prior to 131I administration, coexistent "cold” nodules must be submitted to fine needle aspiration cytology to exclude associated malignancy. Effective doses of 131I are relatively high in this condition. Post-radioiodine hypothyroidism is much less frequent than in toxic diffuse goiter, but may develop at any time after administration of 131I. Pretreatment with thionamides is recommended even in mild to moderate hyperthyroidism to avoid excessive relase of thyroid hormones after 131I.
Surgery is generally regarded as a better option in patients with large goiters, especially if there is evidence of substernal extension and compression of airways and blood vessels. Surgery is also indicated in those instances when radioiodine uptake by the gland is relatively low, as frequently occurs in large multinodular goiters. Control of hyperthyroidism with antithyroid drugs and preoperative iodide is mandatory. Subtotal or near total thyroidectomy is indicated. Thus, hypothyroidism should be expected and adequate L-T4 treatment is required. We consider appropriate the use of partially suppressive doses of L-T4 to prevent recurrences. It is worth mentioning that surgical complications, such as laryngeal nerve paralysis and hypoparathyroidism, are more frequently observed in toxic multinodular goiters, especially if large and substernal, when compared to Graves' disease.
Treatment of ITT is a medical challenge. In this condition all usual forms of treatment of hyperthyroidism have a reduced efficacy, or may not be used at all. Treatment with 131I is not feasible for the low radioiodine uptake and the high stable iodine content of the gland, that will reduce the efficacy of radioiodine. On the other hand, treatment with thionamides (MMI or PTU) has a delayed effect because of the high amounts of preformed thyroid hormones stored in the gland, mainly in goitrous patients. Thus, inhibition of new hormone synthesis by blocking iodine organification requires a longer period of time to control thyrotoxicosis in IIT with respect to the other forms of hyperthyroidism. Thyroid surgery during uncontrolled thyrotoxicosis may be hazardous, especially in patients who have large amounts of stored thyroid hormones with the attendant risk of thyroid storm.
The first step in the treatment is withdrawal of iodine substance. Although their effect may be delayed, full doses of thionamides should be administered for the time required to normalize serum thyroid hormone concentrations. This may take as much as 2 to 4 months. Propranolol or other beta-adrenergic antagonist should be added to the treatment regimen until complete control of hyperthyroidism is achieved. Other general supportive measures should be undertaken, as required. Once euthyroidism is achieved, further therapeutic measures will depend on the underlying disease. The above measures will control IIT in most cases, with the exception of those related to amiodarone, and less frequently to other long-lasting iodinated substances.
Amiodarone-induced thyrotoxicosis (AIT) represents a special problem because it usually occurs in patients with significant heart disease (severe arrhythmias or ischemic heart disease) requiring the administration of this potent antiarrhythmic drug[9]. Furthermore, because amiodarone is stored in adipose tissue, its metabolic disposition is slow, with the result that the release of iodine will continue for up to several months after it has been withdrawn. In AIT, the use of potassium perchlorate in addition to thionamides has been proven useful[9]. The rationale of this treatment derives from the fact that the increased iodine content of the thyroid is the major cause of poor response to antithyroid drugs. Potassium perchlorate competitively inhibits iodide uptake by the thyroid gland and also induces a release of excess intrathyroid iodide which is still not organified. The dose of potassium perchlorate is 600-1200 mg daily together with full doses of thionamides. In many patients with AIT, this treatment will restore euthyroidism within 6 weeks. Administration of potassium perchlorate for periods longer than 6 weeks should generally be avoided because of its renal and bone marrow toxicity. Unless specifically contraindicated, propranolol should be administered together with other supportive measures, as required. After discontinuation of potassium perchlorate, patients with toxic nodular goiter or underlying Graves' disease require a prolongation of thionamide treatment, followed in general by radioiodine administration for the resolution of their disease.
Such vigorous treatment schedule is not required in milder forms of AIT, especially in those with no underlying thyroid disease. In these cases the main pathogenetic factor may well be the direct cytotoxic effect elicited by amiodarone and its derivatives on thyroid cells, resulting in destructive thyroiditis and the subsequent release of preformed thyroid hormones[9]. In keeping with this pathogenic sequence, glucocorticoids have been successfully employed in these cases. In our experience, prednisone at a starting dose of 40 mg/day produces a normalization of serum free T3 in 1to 2 weeks. The absence of preexisting thyroid disease and the finding of very high levels of serum IL-6 are distinctive features of patients with destructive amiodarone-induced thyrotoxicosis, and favor the use of glucocorticoids. A combined regimen of potassium perchlorate, thionamides, and glucocorticoids may be administered to begin with in any patient with severe AIT and high IL-6 serum levels, since thyrotoxicosis may be due to the dual effect of amiodarone. In extremely severe cases, removal of excess thyroid hormones by plasmapheresis has been employed with a transient benefit.
Nowadays, early diagnosis and effective treatment of hyperthyroidism, and adequate preparation of patients undergoing thyroid surgery or radioiodine therapy, have rendered thyroid storm a rare event. However, less severe forms of thyrotoxic crisis are not exceptional, and may represent a medical emergency which requires prompt recognition and adequate treatment. Therapeutic guidelines are directed to:
1) Treatment of underlying nonthyroidal illnesses by specific means, such as digoxin, diuretics, antibiotics, and intravenous fluids, as required;
2) Normalization of body temperature by cooling blankets and/or pharmacological agents such as acetaminophen, chlorpromazine, or meperidine;
3) Inhibition of the synthesis and release of thyroid hormones by thionamides (MMI, PTU), iodides (Lugol's solution, SSKI, intravenous sodium iodide) or iodinated contrast agents (iopanoic acid, sodium ipodate);
4) Inhibition of the peripheral conversion of T4 to T3 by glucocorticoids, iodinated contrast agents, or PTU;
5) Block of the peripheral effects of thyroid hormones by beta-adrenergic antagonists (propranolol, metoprolol, atenolol);
6) Removal of excess thyroid hormones from the circulation by plasmapheresis, peritoneal dialysis, extracorporeal resin perfusion or charcoal plasmaperfusion. All drugs should be employed in maximal doses. Patients require continues monitoring of the electrocardiogram and an intravenous line to administer fluids and drugs. Alternatively drugs can be delivered by a nasogastric tube.
Our protocol for treatment of patients with hyperthyroidism and thyroid crises is as follows: methimazole 40 mg every 12 h, Lugol's solution 20 drops orally every 6 h, propranolol 40 mg orally every 4 h, dexamethasone 2 mg intravenously every 6 h. Doses can be gradually reduced as general conditions improve. If the patient does not respond to this treatment, or presenting symptoms are too severe, direct removal of thyroid hormones from the circulation becomes necessary. In our experience plasmapheresis is an effective mean to achieve this goal. Plasmapheresis should also be used in thyrotoxic crises due to the surreptitious ingestion of thyroid hormones, or in patients whose thyrotoxicosis has been induced by long-lasting iodine substance.
Prof. Aldo Pinchera, M. D., is a leading endocrinologist, especially in thyriodology. He is Chief-Editor of the Journal of Endocrinological investigation and has been member and later Presedent of the European Thyroid Association. He has been awarded scientific prizes many times, both inside and outside Europe. His main research in thyroidology is especially related to thyroid autoimmunity, thyroid carcinoma, endemic goiter and various other clinical and fundamental aspects in thyroidology and other endocrine deseases. He is Professor of Endocrinology and Head of the Institute of Endocrinology of the University of Pisa, Italy, and at the same time Dean for student education.
Dr. Luca Chiovato, M. D., is Assistant Professor of Endocrinology at the Institute of Endocrinology, University of Pisa, Italy. He is a member of the European Thyroid Association and has been awarded for oringinal research in radioimmunoassay techniques. His current research is related to thyroid autoimmunity and thyroid cell biology.
Dr. Ferruccio Santini, M. D., is Resident in Internal Medicine and at the same time working on his PhD in Endocrinology and Metabolism. He is also working at the Institute of Endocinology, University of Pisa, Italy, and is assitant-editor of the Journal of Endocinological investigation. His scientific work is related to metabolism of thyroid hormone, especially focused on deiodination and sulfation pathways.