International Journal of Endocrinology and Metabolism
Volume:18 Issue: 3, Jun 2020

 There are three therapeutic modalities for the management of Graves’ disease (GD), including thyroid surgery, radioactive iodine (RAI), and antithyroid drugs (ATDs). We aimed to briefly review the history of these treatment strategies and their advantages and disadvantages.

 We searched PubMed for English language articles using pertinent search terms.

Each treatment modality for GD is accompanied by several advantages and disadvantages. Nowadays, ATDs are the most commonly prescribed therapy for GD worldwide. The lack of well-designed, large RCTs comparing three different treatments for hyperthyroidism concerning various short-term and long-term outcomes has led to remarkable uncertainty in the preference of each of these treatments, as is evident in relevant guidelines from different societies. Recently, the efficacy and safety of long-term use of ATDs have been documented.

Pros and cons of each therapeutic modality for Graves’ hyperthyroidism should be taken into account during the physician-patient discussion to select the primary treatment. Considering recent data about the long-term efficacy and safety of ATDs, it seems that the appropriate selection of Graves’ patients for long-term ATD therapy can be a new avenue in the treatment and even cure of GD.

Cure” has been referred to maintaining a healthy situation before the occurrence of the illness. With emerging non-communicable chronic diseases, many treatment approaches and management of these disorders have been found to control the disease, despite the fact that the status of the human body does not return to like it was before the illness. Patients become asymptomatic, but their body composition, cellular, and humoral factors differ from healthy individuals. In this article, it has been discussed that after treatment of thyroid diseases, only in few conditions the status of thyroid returns to the healthy situation after discontinuation of therapy and majority of thyroid illnesses are managed as “controlled”, meaning that patients become asymptomatic. However, their thyroid structure, function, and biochemical factors fundamentally change. Therefore, patients may need additional permanent treatment to attain euthyroidism and especial follow-up for recurrence of the disease. For example, for Graves’ hyperthyroidism, all three forms of therapeutic approaches fail to re-establish continuous normal thyroid function in all patients. Long-term anti-thyroid drug therapy appears to cause an increase in the number of patients with Graves’ disease to attain a cure without further treatment.

 Antithyroid drugs (ATD) are the first-line treatment for Graves’ disease (GD); however, relapse following treatment is approximately 30% - 40% in the first year, and 50% - 60% in the long term. Identification of risk factors that predict relapse, after discontinuing ATD, plays an important role in guiding therapeutic options.

 PubMed was used to search for studies published in English between 1995 and 2019. The following search terms were used: Graves’ disease, antithyroid drugs, relapse, recurrence, and outcome. The reference lists from review articles were also included in the search in order to find older journals.

Factors associated with a high recurrence rate, as reported in most studies, were divided into phenotype and genotype predictors. Phenotype factors included large goiter size, persistence of high TSH receptor antibody (TRAb), severe hyperthyroidism, smoking, younger age, male sex, and prior history of recurrence. Genotype factors included human leukocyte antigen (HLA), CD40, CTLA-4, PTPN22, Tg, and TSHR genes. In a subgroup analysis by age, genetic factors were better predictors in the younger group, while clinical signs were more useful in the older group. The reliability of using individual baseline risk factors to predict subsequent relapse is poor; however, predictive scores calculated by grouping single risk factors might help to predict future outcomes.

Longer normalization time of TRAb, the persistence of a palpable goiter, and harboring genetic risk factors in younger patients are associated with high recurrence rate of GD. Multi-marker prediction models have been proposed and validated to improve the predictive value of relapse after ATD withdrawal.

Graves’ disease is an autoimmune disease caused by thyrotropin receptor antibodies (TRAb). These antibodies can be measured and used for the diagnosis, prediction of remission, and risk of Graves’ orbitopathy development. There are three treatments for Graves’ disease that have remained unchanged for the last 75 years: Antithyroid drugs, radioiodine, and surgery. Antithyroid drugs are the first treatment option worldwide and are usually used for 12 - 18 months. Recent reports suggest the use of antithyroid drugs for more than 18 months with better outcomes. This review focuses on two aspects of treatment with antithyroid drugs: The impact of using antithyroid drugs for more than 12 - 18 months on remission rates and the trend of TRAb during prolonged antithyroid drug treatment.

 A review was performed in Medline on the published work regarding the duration of ATD treatment and remission of Graves' disease and also ATD treatment and TRAb status during the 1990 - 2019 period.

Remission rates are variable (30% - 80%), and many clinical and genetic factors serve as predictors. The long-term use of antithyroid drugs appears to increase remission rates. TRAb values usually decline during ATD treatment, but the trend could occur in two ways: Becoming negative or showing a fluctuating pattern. However, approximately 10% of the patients will remain TRAb-positive after five years of treatment with antithyroid drugs.

Antithyroid drugs can be used for long periods with an increase in remission rates, and a gradual decrease in TRAb levels, with the disappearance of TRAb in 90% of the patients after 60 months.

Medical therapy of hyperthyroidism has been the Astwood’s gift to medicine. However, controversy remains about its mechanisms of action, the ideal treatment duration, and its proper use in pregnancy. The concept that hyperthyroidism could be controlled ‘indefinitely’ with antithyroid drugs (ATDs) is also a topic of current debate. The purpose of this review was to highlight the pros and cons of long-term ATD therapy.

 PubMed, Scopus, Web of Science, and Google Scholar databases were searched for retrieving studies conducted on long-term treatment with ATDs up to Jan 2020. The final selection of the papers was made based on their relevancy with the safety and efficacy of long-term treatment with ATDs.

The main drawback of the ATD treatment is the high relapse rate after drug discontinuation. On the other hand, ATDs may have a favorable immunosuppressive effect, either primarily, in the diminution of thyroid-specific autoimmunity, or secondarily, as a result of controlling the hyperthyroid state, hence keeping patients in a euthyroid state for a prolonged period to diminish autoimmunity and hyperthyroid relapse. This often calls for long-term use of methimazole, but with the lowest possible dose to minimize the risk of side effects. Emerging evidence demonstrates that the long-term treatment with ATDs has relatively few adverse events, most of which arise within the starting months of treatment and in subjects on larger doses. Hence, once we have reached the end of a conventional course of ATD treatment (12 - 18 months), the hazard is eliminated, and adverse events are very rare to occur. Therefore, by continuing low-dose ATD, we could safely maintain the patient’s euthyroid status.

Long-term ATD treatment is safe, especially at a low dose. It can be considered as the preferred treatment for selected hyperthyroid patients.

 Thyroid hormones can affect the development and function of the central nervous system and various other organs. As such, the pathologic excess of these hormones, known as thyrotoxicosis, can be the source of significant damage during childhood and adolescence. The objective of this study was to review the management of Graves’ disease (GD) in the pediatric age group, especially concerning long-term antithyroid drug (ATD) treatment.

 A thorough search of literature published from 1980 to 2019 was performed in PubMed only for English language literature. The following key terms were used: “Graves’ disease, hyperthyroidism, thyrotoxicosis in children, thyrotoxicosis remission, thyrotoxicosis relapse, definite therapy, radioactive iodine, thyroidectomy, anti-thyroid drugs, propylthiouracil, methimazole, and carbimazole”. We also did a thorough search in review articles, observational studies, open-label/controlled randomized/non-randomized trials, and meta-analyses, as well as the articles cited by textbooks, chapters, and review articles, which led us to locate older sources of information on the topic.

More than 90% of thyrotoxicosis in the pediatric age group is attributable to GD. A host of strategies, including ATDs, radioiodine therapy, and surgery, are employed to treat this entity. However, there is still significant controversy regarding the most optimal strategy. Current evidence suggests that ATDs are the best initial treatment in pediatric patients with GD. Although ATDs are widely used, the duration of their administration is controversial and varies significantly between protocols. A major problem is the high relapse rate (up to 70%), but extending the duration of such treatment could potentially bring the remission rate up to 88%. Indications for using radioactive iodine treatment include the lack of remission following years of receiving ATDs, poor compliance, and the emergence of a major side effect. In pediatric patients aged five-years-old or younger who suffer from very large goiter, severe ophthalmopathy, and persistent hyperthyroidism, as well as those with the lack of response to or showing adverse effects of ATDs, it is advisable to consider total or near-total thyroidectomy.

Antithyroid drugs are the mainstay of treatment of juvenile GD, and long-term methimazole therapy increases the remission rate in pediatric GD.

Trends in serum thyroid-stimulating hormone (TSH) and TSH receptor antibody (TRAb) changes during antithyroid drug treatment, and long-term prognosis were evaluated in Graves’ hyperthyroidism (GD).

In 609 GD patients initially treated with 15 mg of methyl-mercapto imidazole (MMI), the changes in serum TRAb and long-term prognosis were compared in the TSH-normalized group (A) and the TSH-suppressed group (B and C) during the initial 180 days of treatment.

Early responses to MMI during 180 days of treatment were as follows: 48 cases (7.9%) became hypothyroid with elevated TSH (A1), and 188 cases (30.9%) became euthyroid with normal TSH (A2). Among patients with continuously suppressed TSH, the free T4 (fT4) level was low in 31 cases (5.1%) (B1-inappropriately suppressed TSH), fT4 and fT3 were normal in 185 cases (30.4%) (B2), fT4 was normal, but fT3 remained high in 84 cases (13.8%) (B3), and fT4 remained high in 73 cases (12.0%) (C-refractory). Serum TRAb became negative after < 5 years then remained negative in 25% - 51% of the cases (smooth type), became negative after < 5 years then became positive again in 30% - 43% of the cases (fluctuating type), and remained positive after > 5 years in 10% - 42% of the cases (smoldering type). In total, remission occurred after 6.2 (3.0 - 10.4) years of treatment in 42%, possible remission on a small maintenance dosage of antithyroid drug occurred in 13%, and spontaneous hypothyroidism occurred in 4.4% of the cases. The smoldering type was more frequent in the B1 and C groups than in others, and remission was less frequent. The difference in the long-term prognosis depending on the early response to MMI disappeared after excluding the ablated patients. Without ablation, remission or spontaneous hypothyroidism could be expected in 60% - 75% of patients after tenacious treatment for > 10 years.

Prolonged suppression of serum TSH may suggest active TRAb activity during treatment, and continuous TRAb positivity for more than 5 years suggests persistent GD activity.