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15 August 1994 | Volume 121 Issue 4 | Pages 281-288
Purpose: To evaluate treatments for hyperthyroid disease.
Data Sources: Selected studies published during the last 20 years addressing the diagnosis, causes, and treatment of hyperthyroid disease.
Study Selection: Studies were chosen based on their usefulness in addressing specific points in the treatment of hyperthyroid disease.
Data Extraction: Various treatment principles extracted from the references form the basis for the conclusions and recommendations made here.
Results: Hyperthyroid disease is a common endocrine disease. Although Graves disease is the most common cause of thyrotoxicosis, other primary and secondary causes exist. With classic signs and symptoms accompanied by confirmatory laboratory measures of thyroid hyperfunction, the diagnosis can be established firmly. Radioiodine is the preferred method to treat Graves disease; however, recent data concerning treatment with a combination of propylthiouracil and thyroxine require further evaluation to establish its efficacy. Radioiodine is also the preferred treatment for the other forms of hyperthyroid disease; however, patient-specific considerations in both may require patient-tailored therapies.
Conclusions: Hyperthyroid disease can be treated definitively for most patients. Palliative therapy with ß-adrenergic blockade is useful in some patients. Further studies are needed to determine whether more recently described treatments have improved efficacy and whether therapy directed specifically at the underlying immunologic cause of Graves disease can be used successfully.
Hyperthyroid disease results from various disorders (Table 1); the most common is Graves disease, an autoimmune disorder mediated by an IgG antibody that binds to and activates thyroid-stimulating hormone (TSH) receptors (thyrotoxin receptor antibody) on the surface of thyroid cells [2]. Other common types of hyperthyroid disease include toxic nodular goiter (multinodular goiter) and toxic adenoma (hyperfunction of a single thyroid nodule). Sufficient highly sensitive and specific serum tests of thyroid function exist to diagnose this disease with certainty [3]. Clinical assessment of the presence and severity of hyperthyroid symptoms confirms laboratory findings and further guides the physician in selecting and timing treatment [4]. Although treatments of various forms of primary hyperthyroid disease share many components, specific considerations depend on the underlying cause. DIAGNOSIS AND TREATMENT
Treatment of Hyperthyroid Disease
Successful treatment regimens can be designed if we understand the causes of hyperthyroid disease and the cellular action of thyroid hormone that produce its characteristic signs and symptoms. We describe the treatment options available to manage hyperthyroid disease, defined for this review as the production of excessive amounts of thyroid hormone by a hyperfunctional thyroid gland. We also discuss treatment of thyrotoxicosis resulting from forms of thyroiditis, the excessive intake of thyroid hormone, and other less common causes of hyperthyroid disease [1].
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Treatment of Graves Disease
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Adrenergic signs and symptoms include tachycardia, tremor, increased systolic blood pressure, hyperreflexia, eyelid lag, staring, palpitations, depression, nervousness, and anxiety [5, 6]. These signs and symptoms respond to ß-adrenergic blocking drugs with rapid improvement [4]. Thyroid hormone effects include increased oxygen consumption, hyperphagia, weight loss, some psychological disturbances, and possibly some component of tachycardia and enhanced cardiac contractility with decreased systemic vascular resistance [6-8]. In a recent study, patients receiving levothyroxine (T4) in a dose sufficient to suppress TSH showed cardiovascular changes similar to those seen in patients with Graves disease [9, 10].
Thyroid hormone has a relatively long half-life in serum (euthyroid, 8 days; hyperthyroid state, 3 to 5 days) and exerts many of its cellular effects at the nuclear level [11]. These actions arise through the binding of triiodothyronine (T3) to specific nuclear receptors [12], which in turn regulate gene transcription and promote synthesis of specific proteins. As a result of this mechanism of action and the large store of preformed hormone in the thyroid gland, treatment for Graves hyperthyroidism inherently requires a relatively long (weeks to months) delay between the start of therapy and substantial improvement or amelioration of signs and symptoms. This is particularly true with chronic hyperthyroid disease, as found in patients with Graves disease.
The autoimmune mechanisms involved in the pathogenesis of Graves disease have been well studied [2]. Specific portions of the TSH receptor extracellular domain may be involved in thyrotoxin receptor antibody binding and activation [13]. Idealized therapy would interrupt the excessive thyroid gland stimulation by a specific immunologic antagonist. An immunologic component of Graves disease is also the probable cause of the ophthalmopathy, lymphadenopathy, splenomegaly, and infiltrative dermopathy [1, 2]. No specific therapies are available for these additional manifestations. Therefore, management of primary hyperthyroid disease must focus on two broad categories of therapeutic options: definitive therapy with normalization of serum thyroxine (T4) and T3 concentrations, and palliative therapy that interrupts the adrenergic-like symptoms and signs without necessarily correcting abnormal thyroid gland function or cellular hormone action. When excess T4 and T3 levels resolve spontaneously (subacute thyroiditis), only palliative or no specific therapy is indicated. The decision to treat depends primarily on the degree of symptoms manifested by the patient [4, 6].
Definitive Therapy
Definitive therapies for Graves disease are surgery, antithyroid drugs (thionamides), and radioiodine. Before discussing these treatments, we should address the persistent controversy characterizing therapeutic decision making when considering variables such as the patient's age and sex. Two separate studies that surveyed the preference for treatment of Graves disease revealed that practices vary widely among cohorts of physicians and among physicians of different countries [14, 15]. Between 1984 and 1991, the approach to treating hyperthyroid disease changed substantially among physicians in the United States [15], with a shift toward radioiodine and away from antithyroid drugs.
Surgery
Described in 1900, surgery was the first definitive therapeutic option to treat the hyperthyroidism of Graves disease, and it antedates the use of thionamides and radioiodine, which were not introduced until the 1940s. Success depended on meticulous preoperative and intraoperative management. However, physicians recognized that to induce and maintain anesthesia safely and to prevent intraoperative and postoperative complications, including cardiovascular dysfunction and thyroid storm, patients had to be brought as close to a euthyroid state as possible. Treatment with iodine for several weeks before surgery decreased the severity of the hyperthyroid condition and the vascularity [3] of the Graves hyperthyroid thyroid gland, a finding confirmed by recent studies [16].
Today, preoperative therapy includes pretreatment with thionamides to decrease serum T4 and T3 to normal levels, and, for patients with Graves disease, addition of iodine in the form of 5 to 10 drops per day of Lugol's solution for 4 to 7 days before surgery. Alternative methods to prepare patients with hyperthyroid disease for surgery include use of ß-adrenergic blockade alone or combined with iodine [17]. Although these alternative treatments can be used successfully, generally they should be reserved for special situations such as in patients with allergies to thionamides or when time is insufficient for effective antithyroid drug therapy. The margin of safety associated with normalization of serum T4 and T3 levels with either propylthiouracil or methimazole suggest that this is the recommended preoperative preparation.
To treat Graves disease with surgery, a modified subtotal thyroidectomy is preferred [18]. Surgery has been advised when use of neither antithyroid therapy nor radioiodine are optimal. It is usually reserved for children who have not responded well to antithyroid drugs or when radioiodine is not accepted by the patient or is ineffective. Surgery is not recommended for adults with Graves disease, except for those with a very large goiter or when thyroid cancer is confirmed or suspected. A small but unavoidable number of surgical and anesthetic complications, including hemorrhage, hypoparathyroidism, hoarseness (vocal cord paralysis), and, very rarely, death [16-18] has made surgery a less desirable alternative form of definitive therapy. Surgical treatment has been associated classically with a high incidence of recurrent hyperthyroid disease if too much thyroid tissue was left and with a high incidence of postoperative hypothyroidism if too much tissue was removed. Long-term follow-up to rule out late hypothyroid disease is necessary, but a recent 4-year prospective study of 55 patients having modified subtotal thyroidectomies showed that more than 90% of them were euthyroid at 4 years. The study was not associated with any deaths and had a low rate of postoperative complications [18]. The low rate of postoperative hypothyroid disease in this study contrasts with earlier reports in which its incidence increased progressively for 10 years after surgery [19]. When hypothyroidism does occur, replacement with levothyroxine is sufficient to maintain the euthyroid state [20].
Antithyroid Drugs
Antithyroid drugs derived from thionamides include propylthiouracil and methimazole and are used frequently to treat hyperthyroid disease primarily due to Graves disease [21]. They have relatively mild and infrequent side effects, are easy to use, have predictable therapeutic actions, and are inexpensive. In most patients, thyroid function returns to normal within several weeks to several months. The usual starting dose of propylthiouracil is 100 to 150 mg given orally every 8 hours, although larger doses may be necessary. For methimazole, the commonly used starting dose is 20 to 30 mg given once daily. When the patient becomes euthyroid, the dose is decreased to the lowest amount that will maintain normal T4 and T3 levels. Although an increase in TSH to the normal range in this setting is desirable, TSH suppression may persist long after the serum T4 levels are corrected [22]. Therefore, therapeutic efficacy and dosage adjustment are best assessed by monitoring clinical signs and symptoms and serum T4 and T3 levels routinely.
Although they share many similarities, propylthiouracil and methimazole differ in several ways. Methimazole has a longer duration of action and is most often given once daily, potentially increasing patient compliance. Propylthiouracil crosses the placenta less readily and is found in breast milk in smaller amounts than is methimazole, making it the preferred drug for pregnant or breast-feeding women if antithyroid drug therapy is necessary [21, 23]. Propylthiouracil at total daily doses greater than approximately 450 mg/d inhibits hepatic conversion of T4 to T3, although the extrathyroidal, hepatic action of propylthiouracil [5] and a resulting decrease in serum T3 level were reported within 4 to 8 hours after the oral administration of a single 200-mg dose [21]. This characteristic can be useful for patients with severe thyrotoxicity (as with thyroid storm) in whom rapid lowering of the serum T3 level is clinically appropriate [24].
Both propylthiouracil and methimazole inhibit specific steps in thyroid hormone biosynthesis, organ function, and coupling within the thyroid gland. Other mechanisms of action within the pathway of thyroid hormone biosynthesis have also been suggested [21]. Propylthiouracil and methimazole may alter the immunogenicity of thyroid tissue, increasing the likelihood of remission from Graves disease [22].
Graves disease may be present during gestation [25]. For the factors noted previously, the preferred treatment for pregnant women is propylthiouracil, which has little or no reported teratogenicity [21, 25]. The goal of treatment is to decrease the total serum T4 and serum T (3) values to levels appropriate for pregnancy (approximately 50% greater than normal) and to reduce the propylthiouracil dosage as quickly as possible to the lowest level that controls the hyperthyroid condition [25] to minimize any effects on neonatal thyroid function. In general, starting doses of propylthiouracil are approximately 300 mg/d and can be reduced to 100 mg or less at the time of parturition as the patient responds [23]. Breast-feeding during treatment is permitted with appropriate surveillance of the infant [25]. Surgical correction of Graves disease is rarely advocated but can be done in the second trimester; radioiodine treatment is contraindicated because the Iodine-131 crosses the placenta and, after the 11th week of gestation, could damage the fetal thyroid gland. Postpartum radioiodine therapy is also contraindicated during breast-feeding. To obviate the need to treat hyperthyroid disease during pregnancy, many physicians recommend radioiodine as definitive treatment of Graves disease well before planned conception [23].
Early in pregnancy, especially with multiple fetuses or when the serum human chorionic gonadotropin level is high, biochemical hyperthyroid disease accompanied by hyperemesis (hyperemesis gravidarum) can occur. Stimulation of the TSH receptor by human chorionic gonadotropin appears to mediate these changes [26]. In addition to hyperemesis, patients may show various degrees of thyromegaly and thyrotoxic symptoms. Most often this does not require antithyroid therapy, and with time these changes resolve spontaneously. Although ß-adrenergic blockade may yield clinical improvement, the overall clinical assessment most often precludes treatment of these patients.
Side effects of antithyroid therapy occur in fewer than 5% of patients [22]. Some of the minor reactions are self-limited and include a bitter taste, nausea, minor skin reactions, and a mild decrease in total leukocyte count. These do not necessarily require drug discontinuation, and sometimes prescribing an alternate drug is useful. In contrast, more severe skin eruptions, including urticaria and diffuse erythema, and arthralgias, arthritis, and temperature increases require drug discontinuation. Agranulocytosis occurs in fewer than 0.5% of patients. Although some authors have suggested that leukopenia predates the onset of agranulocytosis [27], most reports indicate that true agranulocytosis (absolute polymorphonuclear leukocyte counts of less than 0.2 x 109 L) occurs precipitously, and routine surveillance is not useful in predicting an idiosyncratic response. This reaction appears to be immune mediated, with antipolymorphonuclear leukocyte antibodies circulating in serum [28]. Although agranulocytosis has been reported to be more common with higher doses of methimazole and in older patients, researchers have not noted a similar relation to propylthiouracil therapy [22]. The onset of fever with sore throat and other signs of infection should alert patients and physicians to the possibility of leukopenia. Occurrence of agranulocytosis mandates prompt discontinuation of the drug. These hematologic changes usually resolve within 7 to 10 days after drug withdrawal. During this period, in-hospital antibiotic therapy is advised. Although concomitant corticosteroid [7] administration has been reported to shorten the duration of methimazole-induced leukopenia [29], the value of this form of treatment must still be confirmed. Although potentially of benefit, a therapeutic role for any of the various granulocyte-stimulating factors in this clinical setting remains to be established. The occurrence of agranulocytosis with any of the thionamide formulations should preclude the use of other agents within the same class of drugs, and alternative definitive therapy must be considered in this circumstance.
Recognition of the unpredictability and previous reports of a low probability of long-term disease remission have dampened enthusiasm regarding the usefulness of propylthiouracil and methimazole as single agents for definite therapy for Graves disease. The reported rates for long-term disease remission after thiourea therapy range from 14% to 80%; the lower rate was reported in the early 1970s, and the higher rates were observed in patients treated for longer periods (1 to 2 years) and in geographic areas with lower levels of dietary iodide. A reasonable treatment course should range from 6 to 18 months [21] to maximize the chance of remission from Graves disease.
There is no reliable way to preselect patients for antithyroid therapy based on a recognized marker for the likelihood of achieving remission. Criteria such as patient age, disease duration, goiter size, degree of thyroid function abnormalities, or magnitude of clinical symptoms, although possibly related to outcome, do not have significant predictive value [22]. With an increased understanding of the immunologic basis for Graves disease [2, 13], several immune-related markers have been studied before implementing therapy to identify patients most likely to benefit from antithyroid therapy. Unfortunately, no pretreatment combination of HLA typing, antithyroid antibody titers, or thyrotoxin receptor antibody titers has consistently predicted therapeutic outcome. Nevertheless, the failure of thyrotoxin receptor antibody titers or thyroid gland size to decrease during therapy is linked to a high degree of disease persistence or recurrence [30].
A recent study of a large number of Japanese patients focused on the ability of methimazole to decrease thyrotoxin receptor antibody levels in the presence or absence of concomitant levothyroxine administration [31]. All patients were treated with 10 mg of methimazole three times a day for 6 months and then with 10 mg once a day and were divided into two groups, one to receive a fixed dose (100 µg) of T4 and the other group to receive a placebo. The combined use of T4 with methimazole for 1 year was followed by a significantly lower rate of disease relapse (approximately 3% compared with 35%, respectively) when followed for the subsequent 3 years [31]. This degree of success in achieving disease remission is much greater than any previously reported but must be confirmed because different patient populations may respond in different ways.
Radioiodine
Radioiodine (Iodine-131) has been used to treat hyperthyroid disease for almost 50 years. Experience in more than 500 000 patients has shown that it is safe in the amounts used to treat this condition and that early concerns regarding the possibility of radiation-induced leukemia, thyroid cancer, or unwanted genetic effects were unfounded [32]. The gonadal radiation dose from radioiodine to treat Graves disease has been estimated to range from 0.8 to 1.4 rem, a value not different from that associated with commonly used radiographic procedures such as abdominal computed tomography and barium enema. Offspring of patients who received substantially higher doses of radioiodine to treat thyroid cancer do not show increased teratogenicity [33].
Researchers use several methods to calculate the dose of radioiodine, which usually ranges from 5 to 15 mCi [32]. Symptoms improve in most patients in 4 to 6 weeks, thyroid function test results improve in 6 to 8 weeks, and most parameters of hyperthyroidism return to normal by 10 to 12 weeks [33, 34]. When a more rapid clinical response is desired, higher doses of radioiodine can be given.
Because of the inherent delay in achieving a therapeutic response with Iodine-131, ancillary treatment with a ß-adrenergic-blocking drug [4, 5] is often desirable. In patients being treated with thionamides to control hyperthyroid disease, this drug can be discontinued for 4 or 5 days before radioiodine dosing, although this is not necessary [35]. However, previous thionomide therapy may decrease the effectiveness of radioiodine therapy. Although worsening of hyperthyroid symptoms has been reported after radioiodine treatment (radiation thyroiditis), this is uncommon [36] and usually can be managed with ß-adrenergic blockade.
Clinical evidence of therapeutic efficacy is shown by a decrease in thyroid gland size, a decrease in symptoms, weight gain, and a decrease in serum T4 and T3 levels. If, after 3 to 6 months, the thyroid gland has not decreased in size, symptoms persist, and serum T4 and T (3) levels are unaffected, a second treatment dose, usually equal to or larger than the first dose, can be given [32].
The primary drawback of radioiodine treatment of Graves disease is the high incidence of subsequent hypothyroidism [34]. Depending on the therapeutic strategy, researchers estimate that permanent hypothyroidism occurs in as many as 50% to 80% of patients. Low-dose radioiodine treatment decreases the incidence of post-therapeutic hypothyroid disease, and there is an almost linear relation between the amount of administered radioiodine and the development of subsequent hypothyroid disease [32, 34]. Administration of smaller amounts of Iodine-131, however, increases the chances of treatment failure and the need for repeated radioiodine administration. Because most treated patients with Graves disease (regardless of treatment used) ultimately become hypothyroid, we prefer to tell patients to expect this as an acceptable late result of treatment and that they should be prepared to receive post-therapeutic levothyroxine replacement. Through this approach and by using larger administered amounts of radioiodine, we can avoid an unduly high rate of treatment failures. Cogent arguments have been made to base therapy on the radiation dose delivered to the thyroid [34].
A recent study suggested that development or exacerbation of Graves ophthalmopathy is more likely after radioiodine therapy compared with other forms of treatment [37]. In that study, only patients older than 35 years received radioiodine, and in most the degree of orbital tissue involvement or progression was mild. The study was not well controlled and additional factors may have affected this observation, including the occurrence of post-treatment hypothyroidism, a greater percentage of tobacco use, and the duration of time until the patients became euthyroid. A separate report showed no difference in ocular disease in patients treated with radioiodine [38].
Glucocorticoids used before radioiodine therapy for Graves disease change the expression of serum immune markers without altering the clinical response. Whether this additional treatment can decrease the subsequent development of ophthalmopathy, as was recently reported [39], the prevalence of post-therapeutic hypothyroid disease must be studied further. We do not routinely recommend that patients with mild or stable ophthalmopathy receive glucocorticoid therapy before radioiodine treatment.
After treatment with radioiodine, patients should be followed closely to evaluate their thyroid function. If hypothyroidism develops, with serum T4 and T3 levels decreasing to values less than normal and a substantial increase in TSH, life-long thyroid hormone replacement may be necessary. In a small subset of patients, hypothyroid disease is transient, and the thyroid gland appears to repair itself sufficiently to maintain a chemical and clinically euthyroid state without thyroid hormone supplements. Rarely, perhaps as an extension of this process, hyperthyroid disease may reappear.
Thyroid cancer occurring in patients with Graves disease has been studied [40]. Differentiated (papillary) thyroid cancer appears to be more prevalent in patients with surgically treated Graves disease than in normal patients. Treatment with radioactive iodine does not appear to increase this prevalence further. Therefore, nodular disease of the thyroid that persists after radioiodine therapy for Graves disease should be evaluated in a manner similar to that recommended for the general population [1, 40].
Although radioiodine is the preferred treatment for young adults and older patients, investigators still disagree about therapy in adolescent patients. Despite the lack of evidence to support a teratogenic effect of radioiodine or long-term genetic damage [32, 33], many physicians still use antithyroid therapy in young people, often for many years. Because most of these patients ultimately require an additional form of definitive therapy [22, 23], initial treatment with radioiodine may be justified. Careful discussion with patients and their families is necessary to resolve any concerns related to this treatment.
Palliative Therapy
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The most frequently used palliative therapy is ß-adrenergic blockade. Successful blockade can be accomplished with various selective and nonselective ß-adrenergic blocking drugs, including propranolol, atenolol, and esmolol [4-7]. Therapeutic end points include decreased or normalized resting heart rate, decreased tremor, increased muscle strength, and an overall improvement in the patient's sense of well-being [4, 7]. Treatment has no effect on serum T4 levels, radioiodine uptake, goiter size, or any of the thyroid hormone or immunologically mediated manifestations.
Hyperthyroid disease has profound effects on the cardiovascular system [41]. Even mild degrees of chronic chemical hyperthyroidism resulting from exogenous thyroxine therapy can enhance left ventricular performance and work and lead to cardiac hypertrophy [8, 10]. Tachycardia, increased cardiac output, and a widened pulse pressure occur in all patients.
Atrial fibrillation can result from thyrotoxicosis. Congestive heart failure may occur, particularly in older patients with underlying heart disease [4, 8]. When treating patients with hyperthyroid disease and congestive heart failure, the physician must recognize that it is a form of high-output failure, with left ventricular contractile function, including both systolic and diastolic performance, almost always enhanced [10]. In a few patients, persistent, exaggerated tachycardia may lead to left ventricular dysfunction as the mechanism of congestive failure. Although the exact mechanism for this rate-related myopathic process is not completely understood, therapeutic measures to reverse the tachyarrhythmia can rapidly improve ventricular contractility [41, 42].
Treatment of patients with hyperthyroid disease, tachycardia, and signs of heart failure using ß-adrenergic blocking drugs leads to clinical and hemodynamic improvement in most cases [5, 41]. However, ß-adrenergic blockade should not be prescribed without serious consideration for patients with hyperthyroid disease who have congestive heart failure. Administration of the ß-adrenergic blocking drug in this setting should be monitored closely by hemodynamic measurements in case the heart failure worsens secondary to ß-adrenergic blockade. Treatment with esmolol, a ß-adrenergic blocking drug with a short half-life, may be more appropriate, because any untoward effects rapidly dissipate [43]. Clinical indications for coexistent left ventricular dysfunction due to ischemic or hypertensive heart disease warrant use of standard heart failure treatment agents, including digitalis and diuretics. The therapeutic goal in this setting is to improve clinical and cardiovascular performance while alternative forms of antithyroid treatment are used. A history of asthma or obstructive airway disease is a contraindication to use of ß-adrenergic blockade [1].
Anticoagulation
As noted previously, atrial fibrillation can be a cardiovascular manifestation of hyperthyroid disease [8]. Various studies suggest a prevalence rate of 10% to 25%, with older patients being more commonly affected [44]. Because atrial fibrillation may lead to systemic embolism, some investigators suggest that patients with hyperthyroid disease and atrial fibrillation receive anticoagulation [44]. Additional review of large series of patients with atrial fibrillation did not reveal clinical evidence for systemic embolization either before or after radioiodine therapy [36]. Anecdotal reports indicate that anticoagulation with warfarin may predispose the thyroid gland to hemorrhage after radioiodine treatment. Therefore, in patients without organic heart disease (mitral valvular disease) or congestive heart failure, anticoagulation is not routinely recommended. Antiplatelet therapy with aspirin may be used, although it has not been tested adequately.
In patients who remain in atrial fibrillation for more than 3 to 4 months after reaching a euthyroid state, spontaneous reversion to sinus rhythm is unlikely [45]. In such patients, we recommend anticoagulation followed by elective cardioversion.
Iodide and Iodide-containing Substances
Administration of a large dose of iodine was one of the earliest treatments for hyperthyroid disease. Because iodide can inhibit almost all the steps in T4 and T3 biosynthesis and release, this therapy can decrease serum T4 and T3 levels within 24 hours. In most cases, thyroid hormone levels cannot be reduced to normal values and the effect may be relatively short lived. Some patients treated with iodides may have a worsening of chemical and clinical indices of hyperthyroid disease within 7 to 10 days after drug withdrawal [22]. Iodide also has limitations in the management of hyperthyroid disease because it increases the iodide content of the thyroid gland, rendering it resistant to therapy with either radioiodine or thionamides.
Therefore, antithyroid drugs should be given before iodide (even if only 1 to 2 hours) to prevent new hormone stores from incorporating iodide.
Some conditions exist for which iodide therapy can be useful. In thyroid storm, potassium iodide, given intravenously as 1 to 2 g during 24 hours, provides prompt improvement and is one of the cornerstones, in conjunction with antithyroid drugs, of early therapy [24]. Iodides may be used after radioiodine therapy to speed the return of thyroid function to normal and to improve hyperthyroid symptoms more rapidly [34]. In preparation for elective surgical resection of the thyroid gland in Graves disease, iodide treatment decreases the vascularity of the gland, which may improve the surgical field [16]. In patients with untreated hyperthyroid disease who have emergency nonthyroid surgery, the combination of iodides with ß-adrenergic blocking drugs are useful to prevent worsening of the condition and to control the disease during surgery. In contrast to patients with Graves disease, those with hyperthyroid disease and nodular goiter or adenomas may not benefit or their clinical conditions may worsen with iodide therapy (see sections that follow). We do not recommend using iodide to manage hyperthyroid disease routinely.
Serum T3 levels predictably decrease in patients receiving iodinated radiologic contrast agents [46]. Subsequent reports showed that this was a result of inhibition of the hepatic 5'-monodeiodinase enzyme that is responsible for most T4 to T3 conversion. Although theoretical considerations suggest potential clinical usefulness, recent studies found that these agents were ineffective in long-term therapy [47]. The effects of lithium on the thyroid gland are similar in many ways to those of iodine [48]. Thyroid gland function and serum T4 and T3 levels decrease in response to 500 mg to 1 g of lithium given in a period of 24 hours. Although posing a consideration for euthyroid patients receiving lithium therapy, this has no utility for the treatment of hyperthyroid disease.
Treatment of Hyperthyroid Disease of Other Causes
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Hyperthyroid disease may result from autonomous function of nodular thyroid tissue in one dominant or many nodules [1, 49]. These patients have thyrotoxic signs and symptoms similar to those of Graves disease but tend to be somewhat older and not to have the ocular or dermatologic stigmata of Graves disease. Although sharing many common treatment principles, the approach to therapy for these patients differs in certain respects. Radioiodine is a preferred therapy for most patients, although larger therapeutic doses and sometimes multiple treatments are needed [34]. Post-therapy hypothyroid disease occurs less commonly than with Graves disease because previously suppressed non-nodular thyroid tissue can avoid radioiodine-mediated damage and subsequently regain function. This is especially true in the treatment of patients with solitary toxic adenomas [49].
In patients with goiters causing tracheal deviation or esophagealcompression, surgical therapy may be preferred. Although radioiodine effectively treats hyperthyroid disease, it may not reliably reduce the size of the thyroid goiter to a functionally or cosmetically acceptable extent [34]. Before choosing surgery, patients should be made clinically and chemically euthyroid. Although antithyroid drugs are useful to achieve this goal, propylthiouracil and methimazole are not used in the long-term treatment of toxic nodular goiter because they do not induce disease remission [21]. Treatment with iodine is not used before operation because in these patients it may worsen clinical chemical parameters of hyperthyroid disease.
Thyroiditis
In addition to the chronic forms of hyperthyroid disease, Graves disease, toxic nodular goiter, and toxic multinodular goiter, three self-limited forms of thyrotoxicosis, subacute thyroiditis (painful), silent thyroiditis, and postpartum thyroiditis deserve special mention [1, 49]. These three causes of thyrotoxicosis [16] result from an inflammatory injury-mediated release of preformed thyroid hormone from the thyroid gland [50, 51]. Because of the relatively acute and self-limited duration of signs and symptoms, definitive therapy is rarely, if ever, needed. Beta-adrenergic blockade and, with subacute thyroiditis, anti-inflammatory drugs sufficiently control the most troubling symptoms until the thyrotoxicity resolves. Minimal or absent thyroid radioiodine uptake is diagnostic, and many patients enter a transient hypothyroid phase during the recovery period [1, 50].
Neonatal Thyrotoxicosis
Neonatal hyperthyroid disease is a rare condition that occurs in 1 of 25 000 pregnancies. Although seen most often in infants of women with a history of Graves disease [25], it can occur in the offspring of euthyroid women, presumably as a result of the transplacental passage of thyrotoxin receptor antibody [52]. As in the adult disease, cardiovascular signs are common with neonatal thyrotoxicosis. After confirmation of the diagnosis by determination of serum T4, serum T3 radioimmunoassay, and TSH levels, therapy with a combination of thionamides and ß-adrenergic blockade is recommended. The latter is useful to control fetal tachycardia, which may be evident antepartum and account for considerable morbidity if not treated.
Iodine-Induced Hyperthyroid Disease
Excessive iodine ingestion can cause hyperthyroid disease, with an increased synthesis and release of T4 and T3 in some patients with underlying thyroid abnormalities [53]. It appears more commonly in Europe, South America, and other areas where levels of iodine are deficient [53]. In the United States, it is sometimes observed after administration of iodine contrast dyes and with drugs such as amiodarone [55]. Except for rare patients in whom iodine unmasked underlying Graves disease [53], most cases are self-limited and do not require definitive therapy. Amiodarone may cause thyrotoxicosis in 2% of treated patients and occasionally this can be chronic, resistant to propylthiouracil therapy, and require alternative therapy [56].
Thyrotoxicosis Factitia
Thyrotoxicosis factitia is characterized by the surreptitious administration of excessive thyroxine; its treatment is discontinuation of the drug. The clinical clues to excess thyroxine therapy or ingestion include the absence of thyromegaly, minimal to absent radioactive iodine uptake, and a low serum thyroglobulin level [57].
To minimize disease recurrence in patients treated for thyroid cancer, thyroxine therapy is purposefully given in doses sufficient to suppress endogenous TSH release. This can cause overt (symptomatic) or subclinical hyperthyroid disease [9]. The systemic effects of excessive thyroxine therapy are similar to those of spontaneous primary hyperthyroid disease [41, 57]. Although TSH suppression is desirable when treating thyroid cancer, it should be avoided in patients receiving thyroxine replacement for hypothyroid disease. Thyroid hormone preparations containing T3 are not recommended because they can cause thyrotoxicosis as a result of widely fluctuating serum T3 levels, and they have no advantage over preparations containing only L-thyroxine. Therapy requires only a change in thyroid hormone formulation, dosage adjustment, or discontinuation of treatment as indicated [57].
Thyrotropin-producing Pituitary Adenoma
Thyroid-stimulating hormone-producing pituitary adenomas are the least common type of pituitary neoplasm, and the excess TSH production by pituitary thyrotroph cells is a rare cause of hyperthyroid disease [58, 59]. Because a sensitive TSH assay is readily available, patients with increased serum TSH levels are easily identified [3]. In this setting, the "inappropriately high" TSH mediates the hyperthyroid condition. These cases are characterized by mild to modest hyperthyroid symptoms, a modest-sized goiter, the absence of the immunologic stigmata of Graves disease (see previous explanation), and most importantly an increased TSH associated with high serum levels of T4 and T3 [58]. When assayed, secretion of the TSH 
-subunit is found to be increased [59]. Although almost always benign, thyrotroph adenomas may be large and locally invasive and may cause other anterior pituitary dysfunctions. Treatment requires anatomic evaluation of the pituitary, followed by short-term control of the hyperthyroid condition (using thionamides) and ultimately neurosurgical resection of the adenoma. Early diagnosis and treatment, especially of microadenomas, appear to offer the best chance for cure [59].
With inappropriate TSH secretion but no anatomic evidence of a pituitary adenoma, thyrotroph resistance to thyroid hormone action is suggested [60]. When this is part of a generalized thyroid hormone-resistant state, often no therapy is needed. In contrast, selective pituitary resistance can produce classic but often modest signs of hyperthyroid disease and may benefit from palliative therapy with ß-adrenergic blockade. Rarely, if ever, is definitive therapy directed to the thyroid gland necessary.
Author and Article Information
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References
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