Abstract
Introduction
Methods
The task force was represented by both adult and pediatric endocrinologists, nuclear medicine experts, and endocrine surgeons from the United States and Western Europe. The guidelines begin with an explanation about the methods of development of evidence based on facts. The ratings of the recommendations are based on the best scientific evidence combined with the experience of seasoned clinicians, also considering the pragmatic realities of implementation. The strength of recommendation is indicated by numbers 1 (strong) or 2 (weak). In Appendix A of the guidelines, a total of 100 resolutions are detailed. The strength of recommendation is categorized as strong for the vast majority of the resolutions, whereas it is ranked as weak only for 19. The panel indicated that the recommendations were strongly supported by evidence in more than 80% of the topics. Quality of the evidence is denoted by the (+) sign. The final document was approved by the ATA and AACE and endorsed by a large number of associations from the United States, Europe, United Kingdom, and Latin America.
Results
The background section of the guidelines cites the several conditions that can lead to thyrotoxicosis. It gives special emphasis to GD, the most common cause of thyrotoxicosis in the United States. Although less common than GD, the prevalence of toxic MNG increases with age and, in countries with long-standing iodine deficiency, is relatively frequent in adults (3,4). In the elderly with MNG, thyrotoxicosis may be severe and can trigger cardiac arrhythmias with potential fatal outcome (3). It usually occurs after abrupt increase of nutritional iodine but may also be induced by iodinated contrast media and iodinated medicines, such as iodine preparations for pulmonary diseases and amiodarone. Additional comment on the management of toxic MNG will be presented in the section that discusses with this topic.
Assessment of disease activity, biochemical evaluation, and etiology
Determination of serum triiodothyronine concentration may be helpful in the diagnosis of thyrotoxicosis when functional autonomous nodules are present. In centers where radioactive iodine uptake and scan are unavailable, use of flow Doppler ultrasound may be useful in delineating the characteristics of the thyroid (5). Determination of serum levels of thyroid antibodies, such as thyroid-stimulating antibodies (thyrotropin receptor antibodies, TRAb), may be determinant in cases in which the involvement of autoimmunity is unclear (6).
Management of GD
Although radioiodine (131I) is widely accepted as a simple and cost-effective therapy, ATDs, radioiodine, and surgery have all been extensively used for the treatment of GD. Radioiodine cures thyrotoxicosis by destroying thyroid tissue, but in patients with GD, the underlying immunological disturbance remains (6). There is some evidence suggesting that ATDs may have an immunomodulatory effect, reflected by a decrease in serum TRAb activity; expression of human leukocyte antigen HLA class II, cytokines, and chemokines (6,7); and induced apoptosis of thyroid lymphocytes. However, there are also convincing data pointing away from these immunosuppressive actions (6). By contrast, a peak of elevation in serum TRAb has been documented after 131I therapy (6,7), an autoimmune surge that may have an impact in women of child-bearing age (6). ATDs improve the clinical course of thyrotoxicosis and may prevent progression of Graves' ophthalmopathy (GO) (8). Major limitations associated with ATDs are lack of compliance, low remission rates following treatment discontinuation, and the occurrence of adverse side effects.
The evidence that prolonging the usual therapy duration of 12 to 18 months could reduce the relapse rate associated with ATD discontinuation is inconsistent. In some settings, long-term ATD therapy has wider acceptance because it is considered to be safe. Alternatively, long-term, low-dose ATD therapy has been addressed in a few studies (9,10). For those who relapse, the likelihood of remission during a second course of ATD is low. A therapeutic dose of radioiodine is usually administered when patients relapse after ATD discontinuation. Serum thyrotropin (TSH), TRAb, and lipids levels were higher in the radioiodine-treated patients as compared with low-dose ATD therapy (10). The task force has thoroughly discussed all the aspects of GD management in the guidelines and finalized this topic with clear-cut and practical resolutions.
Surgery for GD
In exceptional circumstances when it is not possible to render a patient euthyroid prior to a planned thyroidectomy, a rapid presurgical treatment with beta blockers, methimazole, prednisone, and potassium iodide for 7 to 10 days may be instituted. In many countries, highly trained thyroid surgeons are not immediately available when a patient with GD is ready for surgery. In other settings, there is a long waiting list for thyroid surgery in public hospitals because trained surgeons are busy operating on thyroid cancer patients. An alternative to this relatively common situation is therapy with radioiodine.
Toxic nodular goiter and toxic MNG management
Most patients with hyperthyroidism associated with toxic MNG or toxic adenoma are treated with radioiodine. According to the panel, the use of recombinant human TSH (rhTSH) preceding radioiodine treatment is not indicated in these patients since it may lead to exacerbation of the hyperthyroid state (11). The combination of rhTSH before radioiodine has been strongly advocated for the elderly, particularly those at high surgical risk and for patients with long-standing MNG who refuse surgery and hospitalization (12). In some countries, an off-label low dose of rhTSH may be administered, followed by radioiodine, mostly on an outpatient basis (4). This therapeutic modality may not be feasible in countries in which rhTSH has not been approved for therapeutic purposes.
Prior to rhTSH and radioiodine therapy, patients should receive medical management tailored to their needs, age, and presence of comorbid conditions. Poor or inadequate therapeutic decisions may result in increased heart rate, atrial fibrillation, and heart failure (4). Therefore, careful use of all therapeutic resources, including low-iodine diet, methimazole, and beta blockers, should be considered before treatment of subclinical or clinical hyperthyroidism due to toxic MNG with radioiodine in patients pretreated or not with rhTSH (4).
The guidelines state judiciously that advanced age, significant comorbidity, and lack of access to a high-volume thyroid surgeon should favor radioiodine treatment for toxic MNG. Most highly populated countries (China, India, Brazil, Indonesia, and others) have a history of chronic iodine deficiency, which fosters a higher prevalence of MNG in the elderly. The development of hyperthyroidism secondary to toxic nodules and iodine-induced hyperthyroidism is always a possibility in this group (3). Our option for most of these patients would be radioiodine, since the access to seasoned thyroid surgeons for all patients is not feasible. It should also be considered that potential complications following near-total/total thyroidectomies by surgeons who are not high-volume thyroid specialists are higher both in frequency and may impact future quality of life of the patients. This should be considered when the option for radioiodine versus surgery is being weighed (13 –15). If total thyroidectomy has been indicated for toxic MNG, it is widely accepted that thyroid hormone replacement should be started after surgery, followed by constant monitoring of serum free T4 and TSH levels. It should be noted, however, that the dose requirement of LT4 is lower in elderly patients.
GD in children and adolescents
The optimal management of GD in children and adolescents is a matter of debate. Nevertheless, the recommendations of the guidelines have been carried out successfully. Therapy with ATDs often requires a prolonged course in order to achieve disease remission, which usually occurs in less than 30% of the patients. Although long-term ATD compliance is challenging, most children are initially treated with ATDs due to controversies regarding the use of radioiodine in this population (16). Interestingly, a study assessing 4510 thyrotoxic children in China (17) has shown a smaller incidence of adverse effects (1.5%) associated with radioiodine treatment (administered to 41.5% of the children) compared with those treated with ATDs (administered to 28.4% of the children, rate of adverse events 9.3%). Among surgically treated children (30.4%), postsurgical complications were found in 13.9%. The incidence of congenital abnormalities in the offspring of those treated with radioiodine also was low (1.98%) compared with other modalities of treatment. The relapse rate was 6.3% with radioiodine, 48.4% with ATDs, and 10% with surgery. We can conclude from these findings that radioiodine is a safe and efficient therapy also in this age group. Treatment should be planned to deliver a high, single dose of radioiodine in order to induce hypothyroidism. This approach will help reduce radiation to residual thyroid tissue and prevent recurrence (16). Still, use of radioiodine requires close follow-up due to the risk of development of hypothyroidism. As far as surgical therapy goes, it must be performed by an experienced surgeon in pediatric thyroidectomy, as reinforced by the task force.
Subclinical hyperthyroidism
There is emerging evidence that untreated long-term subclinical hyperthyroidism may cause clinical consequences, including atrial fibrillation, diastolic dysfunction, osteoporosis, and in some studies, higher rates of cardiovascular disease and death (18). Recommendations for clinicians include careful evaluation of the real risks, particularly in patients above 65 years of age, as well as in younger patients who have comorbidities. Patients with serum TSH persistently lower than 0.1 mU/L may be treated. According to a recent recommendation, patients with serum TSH between 0.1 and 0.4 mU/L may also be treated in special situations (18).
Pregnancy and hyperthyroidism
GD occurs in about 0.1% to 0.4% of pregnancies, posing significant challenge in the management of these patients and requiring cooperation of obstetricians, endocrinologists, and neonatologists. Transient gestational hyperthyroidism, with a prevalence of 2% to 3% in Europe and higher in Asia and South America, depends on high serum human chorionic gonadotropin levels, which are generally above 200 UI/mL. An important issue is the new specific proposal for evaluation and intervention in pregnant women with GD, summarized in Table 9 of the guidelines.
Noncontrolled trials have been conducted in GD during pregnancy but this condition may expose the mother and fetus to a high risk for adverse outcomes (19). Women with GD and persistently high levels of TRAb should be evaluated carefully throughout pregnancy because maternal TRAb cross the placental barrier, and 1% to 5% of neonates of GD mothers have hyperthyroidism (19).
The treatment of choice for GD occurring during pregnancy is the use of ATDs, while radioiodine therapy is an absolute contraindication. Experts of the task force strongly recommend propylthiouracil (PTU) as the drug of choice before pregnancy as well as during the first trimester (19,20). At the beginning of the second trimester, when the fetal organs have already developed, PTU may be switched to methimazole because PTU has been associated with hepatotoxicity (21). The goal of treatment is to achieve subclinical hyperthyroid and avoid maternal hypothyroidism. Concerns have been raised about the use of methimazole during pregnancy (22), but despite the need for more studies in this important area, congenital abnormalities seem to be associated with the hyperthyroidism rather than the drug (23). Thyroidectomy should be performed in the second trimester, but the use of a saturated solution of potassium iodide should be avoided. In women with high levels of TRAb, there is a risk of fetal thyroid dysfunction, and serial fetal ultrasound may be useful in showing major evidence of fetal thyroid disease, such as intrauterine growth limitation, tachycardia, cardiac failure, hydrops, advanced bone age, and goiter.
Hyperthyroidism and GO
The actual risk of GO progression after radioiodine therapy is relatively small, as highlighted by the task force. Clinicians should identify which patients are at higher risk for progression and introduce glucocorticoid prophylaxis (24). In one study, serum TRAb levels were positive in 97% of the patients with GO and correlated with activity and severity of the disease (25). In a recent retrospective study in which the block-replacement therapy (methimazole 30 mg plus thyroxine) was used for GD patients with moderate to severe GO, 63% of the patients (46 of 73) achieved remission after a mean follow-up of 51 months. No substantial worsening of GO was observed, even in patients who relapsed and were then treated with radioiodine (8). Serum TRAb levels do, in fact, tend to decrease following long-term block-replacement therapy compared with levels in patients receiving only ATD (26). Still, there is a need for well-designed trials analyzing the benefits of block-replacement therapy on the progression of GO. The recommendations by the task force for hyperthyroid patients with GO reflect a great advance in information in this area with increased usefulness for the management of the patients.
Footnotes
Conclusions
The management guidelines for hyperthyroidism and other forms of thyrotoxicosis fulfill all the desirable criteria requested for an effective practitioners' guidance. The various items to be discussed were precisely defined, technical remarks were given, the literature search was extensive and accurate, recommendations (100) were corroborated by available evidence considered valid, and controversial issues and areas were clearly indicated where a consensus was not possible. A total of 14 tables were added to the text and will facilitate consultation. The format and presentation of both the text and the tables are conductive for ready reference. We are all grateful to the task force for this excellent, updated contribution to the care of our patients with hyperthyroidism and other cases of thyrotoxicosis.