Long-term Antithyroid Drug Therapy Research Articles

Long-Term Antithyroid Drug Therapy in Smoldering or Fluctuating-Type Graves' Hyperthyroidism with Potassium Iodide.

Graves' hyperthyroidism is characterized by stimulation of the thyroid gland by thyroid-stimulating hormone receptor antibodies (TRAbs). Antithyroid drug (ATD) continuation is recommended as long as the thyroid gland is stimulated. Goiter size, thyroidal 123I uptake, serum thyroglobulin level, and TRAb positivity are reliable markers of thyroid stimulation. Attention must also be paid to the responsiveness of the thyroid gland due to the high prevalence of painless thyroiditis and spontaneous hypothyroidism during treatment. TRAbs disappeared at <5 years entering remission in 36.6% of patients (smooth-type), while re-elevation of TRAb activity occurred in 37.7% (fluctuating-type) and remained positive for >5 years in 21.1% (smoldering-type). Seven percent of patients remained positive for TRAbs for >30 years, requiring life-long ATD treatment. Remission occurred after median 6.8 years (interquartile range, 4.0 to 10.9) of ATD treatment in 55% of patients. However, late relapse may occur after stressful events (dormant type). In apparently intractable Graves' disease (GD) with a large goiter (>40 g), 131I therapy should be considered. For initial and long-term ATD treatment, we must choose effective, safe, and economical drugs such as 100 mg potassium iodide (KI), although KI sensitivity varies in patients with GD. Thionamide, which has notorious side effects, is added only during the KI-resistant period.

Approach to the Patient Considering Long-term Antithyroid Drug Therapy for Graves' Disease.

Antithyroid drugs (ATD) are the treatment of choice for the majority of patients with Graves' hyperthyroidism worldwide. However, relapse of hyperthyroidism after withdrawal of arbitrarily chosen conventional 12 to 18 months of therapy is very common. In the last 2 decades, many studies have shown that treatment with long-term ATD (LT-ATD) is effective and safe in the maintenance of euthyroidism. In addition, it has been reported that serum TSH receptor antibody may not decrease permanently before 5 to 6 years of ATD treatment, and clinical trials have shown that ≥5 years of ATD treatment is accompanied by remission in the majority of patients with Graves' hyperthyroidism. The objective of this article is to discuss the optimal time to withdraw of conventional ATD therapy, to illustrate the decision-making of the management of recurrent hyperthyroidism, to review the proper management of LT-ATD, and to generate suggestions for lifelong ATD treatment by discussing 4 scenarios of decision-making in patients with Graves' disease.

Advantages and disadvantages of surgery, radioactive iodine, and long-term anti-thyroid drug therapy for Graves' hyperthyroidism

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1402838: Thyroid Stimulating Hormone-Secreting Adenoma: A Rare Case of Hyperthyroidism

TSH-secreting adenomas account for only 0.5 to 3 % of all functioning pituitary tumors. We present this case report to highlight the importance of early diagnosis and prevention of severe complications. A 48-year-old postmenopausal female with a history of hypothyroidism was referred to our clinic for a second opinion. The patient had been stable on levothyroxine for over 10 years. Routine blood work was significant for elevated TSH and free T4. Despite adjustments to her levothyroxine, TSH and free T4 remained elevated. Her prior endocrinologist discontinued the levothyroxine and ordered an MRI brain, which showed an 8mm pituitary adenoma. The patient was referred to a neurosurgeon for evaluation, which then prompted the second endocrinology evaluation. Patient denied any palpitations, weight loss, heat intolerance, headaches, vision changes, or galactorrhea. Lab work repeated off of thyroid supplementation showed persistent elevated TSH at 6.5 mIU/L and free T4 at 2.1 ng/dL. Differential diagnosis included thyroid hormone resistance versus interference to thyroid assays versus TSHoma. The patient tested negative for the thyroid hormone resistance beta mutation, deeming thyroid hormone resistance unlikely. She tested negative for the human anti-mouse antibody, making interference to thyroid assays unlikely. Her alpha subunit level was normal, after which TSHoma was not a certainty. Since the diagnosis was unclear, patient was advised to follow up closely. Repeat MRI showed the tumor was now 1.2cm. Due to the increase in size, she was advised to proceed with trans-sphenoidal surgery (TSS). Pathology stained for TSH, confirming it was a TSH-secreting adenoma. After TSS, TSH normalized and free T4 was low, requiring the patient to be restarted on levothyroxine. TSH-secreting adenomas are quite rare, accounting for less than 1% of all cases of hyperthyroidism. Common clinical features include goiter, visual field defects, headache, menstrual disturbances, and galactorrhea. The presence of high free T4 and T3 and measurable serum TSH in the presence of a macroadenoma on MRI present strong evidence of a TSHoma. Definitive therapy includes transsphenoidal resection. Long-acting somatostatin analogs or dopamine agonists are used to restore euthyroidism prior to surgery. Long-term antithyroid drug therapy or thyroid ablation is not recommended because prolonged decreases in thyroid hormone secretion can stimulate TSH secretion and tumor growth. If TSHomas are left untreated, they can grow aggressively and impinge on nearby structures. Complications include visual field defects due to optic nerve compression, galactorrhea due to pituitary stalk compression, hypopituitarism leading to blood pressure dysregulation and decreased sexual function, and cardiac arrythmias leading to blood clots, stroke, and heart failure. Therefore, when hyperthyroxinemia is present with an elevated TSH, TSHoma should be considered. Even when alpha subunit levels are low or normal, TSHoma is still a possibility. Further investigation and close monitoring should be done to confirm diagnosis and prevent negative outcomes.

Approach to the Patient: Management and the Long-term Consequences of Graves' Disease in Children

In children, Graves' disease (GD) is the most common cause of hyperthyroidism. Most pediatric patients with GD will not go into lasting remission, even following many years of antidrug therapy. Thus, most pediatric patients will require radioactive iodine (RAI) or surgery. When antithyroid drugs are used, methimazole is the drug of choice. When methimazole is used in children, up to 20% will have minor adverse reactions and serious adverse events occur in up to 1%. RAI is an effective form of therapy when the thyroid size is less than 80 g. Because of concerns of whole-body radiation exposure, it is recommended that RAI be avoided in children under 5 years of age, and dosages less than 10 mCi be used between 5 and 10 years of age. Surgery is an effective treatment in children if performed by a high-volume thyroid surgeon. Because of the scarcity of high-volume pediatric thyroid surgeons, a multidisciplinary approach using pediatric surgeons and endocrine surgeons can be considered. Whereas there is a trend toward long-term antithyroid drug therapy in adults, for several reasons, this approach may not be practical for children. Determining the optimal treatment for the pediatric patient with GD, requires consideration of the risks and benefits relating to age and likelihood of remission.

Long-term antithyroid drug therapy.

Over the last 1-2 decades, patients and physicians have preferred antithyroid drug therapy as the initial treatment of Graves' disease, rather than radioactive iodine or surgery. More recently, the concept of long-term antithyroid drug therapy (LTADT; >24 months of treatment) has also become increasingly popular. Data from cohort studies and a prospective randomized trial suggest that LTATD therapy is safe and is associated with a higher chance of remission from Graves' disease than is shorter-term therapy. Also, LTADT may be associated with better quality of life and other clinical outcomes compared to radioiodine and surgery. Long-term antithyroid drug therapy is appropriate for children and young adults. This approach is a reasonable option in those who are doing well on a stable low dose of antithyroid drug therapy, and especially those who wish to avoid definitive treatment with radioactive iodine or surgery, given their inherent risks and need for lifelong hormonal replacement therapy.

Management of Graves’ Hyperthyroidism: More Than a Century of Progression

Context: 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. Evidence Acquisition: We searched PubMed for English language articles using pertinent search terms. Results: 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. Conclusions: 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.

Long-Term Treatment with Antithyroid Drugs: Efficacy and Safety

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

The Concept of Cure in Thyroid Diseases

: “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.

Long-Term Treatment of Hyperthyroidism with Antithyroid Drugs: 35 Years of Personal Clinical Experience.

Background: None of the current therapeutic approaches for management of Graves' disease has been able to re-establish normal thyroid function in all patients. Objective: To describe the author's 35 years of personal experience in the management of Graves' hyperthyroidism and, in doing so, review current articles published on the long-term medical treatment of hyperthyroidism. Methods: All published articles related to ≥4 years of continuous antithyroid drug (ATD) treatment were searched. Findings were added and compared with studies published by the authors on the same topic. Results: Long-term ATD treatment is effective and safe, both in children and adults, for treatment of hyperthyroidism. Treatment of Graves' patients with ATDs >60 months causes euthyroidism up to 4 years after discontinuation of ATDs in the majority of patients. Long-term ATD therapy is not inferior to radioiodine therapy and may sometimes even be superior in some aspects, when considering serum lipid profile, cardiac function, mood, and cognition. Conclusions: Long-term ATD therapy for Graves' hyperthyroidism is efficient and safe and induces control of hyperthyroidism, without rendering the patient hypothyroid in the majority of patients.

Antineutrophil Cytoplasmic Antibody-Positive Small-Vessel Vasculitis Associated with Antithyroid Drug Therapy: How Significant Is the Clinical Problem?

The aim of this review was to delineate the characteristics of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis associated with antithyroid drugs (ATD). A PubMed search was made for English language articles using the search terms antithyroid drugs AND ANCA OR ANCA-associated vasculitis. The literature includes approximately 260 case reports of ANCA-associated small-vessel vasculitis related to ATD, with 75% of these associated with thiouracil derivatives (propylthiouracil [PTU]) and 25% with methyl-mercapto-imidazole derivatives (MMI/TMZ). The prevalence of ANCA-positive cases caused by ATD varied between 4% and 64% with PTU (median 30%), and 0% and 16% with MMI/TMZ (median 6%). Young age and the duration of ATD therapy were the main factors contributing to the emergence of ANCA positivity. Before ATD therapy initiation, the prevalence of ANCA-positive patients was 0-13%. During ATD administration, 20% of patients were found to be positive for ANCA. Only 15% of ANCA-positive patients treated with ATD exhibited clinical evidence of vasculitis, corresponding to 3% of all patients who received ATD. Clinical manifestations of ANCA-associated vasculitis related to ATD were extremely heterogeneous. When vasculitis occurred, ATD withdrawal was usually followed by rapid clinical improvement and a favorable prognosis. ANCA screening is not systematically recommended for individuals on ATD therapy, particularly given the decreasing use of PTU in favor of TMZ/MMI. Particular attention should be given to the pediatric population with Graves' disease who receive ATD, as well as patients treated with thiouracil derivatives and those on long-term ATD therapy.

Thyroid-Stimulating Hormone Receptor Antibody Assays: Recommendation for Correct Interpretation of Results in Graves Disease

To the Editor: In Graves disease, the clinical uses of thyrotropin receptor [thyroid-stimulating hormone receptor (TSH-R)1] antibody (TRAb) measurements have been reported in the Thyroid Guidelines of the American Thyroid Association (1). First, TRAb measurements are used to investigate the etiology of hyperthyroidism when the diagnosis is not clinically obvious; second, a declining TRAb concentration during long-term antithyroid drug therapy is suggestive of remission, although TRAb measurements can be misleading in 25% of such patients; third, TRAb is used in the follow-up of pregnant women with a history or recent onset of Graves …

Rapid preoperative preparation for severe hyperthyroid Graves' disease.

Thyroidectomy (TX) is no longer the preferred choice for the therapy of hyperthyroid Graves' disease but is an alternative in patients who are noncompliant with or have reactions to antithyroid drugs, have moderate to severe ophthalmopathy, have large goiters, or who refuse (131)I therapy and/or long-term antithyroid drug therapy. Seventeen clinically and biochemically severely thyrotoxic patients (16 female, mean age of 35 yr), all but one with large goiters, underwent TX after rapid preparation. The potent inhibitors of the deiodination of T(4) to T(3), iopanoic acid (IOP) (500 mg twice a day) and dexamethasone (DEX) (1 mg twice a day), were given with propylthiouracil or methimazole, when possible, and beta-blockers. Thyroid function tests were obtained before treatment and at TX. All patients were thyrotoxic (mean +/- SE: T(4), 21.6 +/- 1.2 micro g/dl; free T(4) index (FTI), 10.3 +/- 0.8; total T(3), 510 +/- 48 ng/dl). IOP and DEX rapidly lowered T(3) values (P < 0.0001; total T(3), 147 +/- 13 ng/dl) with a smaller but significant (P < 0.05) decrease in T(4)/FTI (T(4), 17.9 +/- 1.3 micro g/dl; FTI, 7.9 +/- 0.6). All patients were clinically euthyroid before surgery. None developed hypoparathyroidism, laryngeal nerve damage, or worsening of ophthalmopathy after surgery. The restoration of hyperthyroid Graves' disease to euthyroidism is rapidly accomplished with IOP and DEX, beta-blockers, and, when possible, antithyroid drugs. This is especially relevant in noncompliant patients with large goiters.

ANTITHYROID DRUGS FOR THE TREATMENT OF HYPERTHYROIDISM CAUSED BY GRAVES' DISEASE

Therapy for Graves' disease is not straightforward and often involves complex decision making. Long-term antithyroid drug therapy is appealing because it is nonablative, but it is not for everyone. The physician must weigh the advantages and disadvantages of antithyroid drug treatment and help the patient arrive at an individualized therapeutic strategy that is appropriate and cost-effective.

Current Management of the Patient with Autonomously Functioning Nodular Goiter

Autonomously functioning thyroid nodules (AFTNs) are presumably independent of TSH for growth and function and appear "hot" on scintiscan because they selectively concentrate radionuclide to a greater extent than the remaining thyroid gland, which is controlled by the normal TH-TSH feedback mechanism. Such autonomously functioning tissue may occur in "patchy" areas, as a solitary nodule, or as multiple nodules (classic Plummer's disease), with the mass of hyperfunctioning tissue and the related secretion of thyroid hormones determining whether the patient is euthyroid or hyperthyroid. Important diagnostic tests include a 99mTc thyroid scan, T4 RIA, T3 uptake, FTI, TSH RIA, and occasionally T3 RIA ("T3 thyrotoxicosis"). Solitary autonomous nodules in adult patients characteristically progress slowly over many years, with toxicity rarely developing in nodules less than 2.5 cm in diameter and occurring primarily in nodules 3 cm or larger and in older patients. The decision to treat a solitary nodule depends upon the size and degree of function of the nodule and the patient's age. Surgery and radioactive iodine are effective therapies. Hyperfunctioning thyroid nodules in children and adolescents (under age 18) have a more rapidly progressive course than those in adults and should be treated by thyroid lobectomy at the time of diagnosis. Subtotal thyroidectomy is the preferred treatment for most patients with toxic multinodular goiter, because it achieves prompt control of the hyperthyroidism and removes the goiter. Radioiodine therapy and long-term antithyroid drug therapy are alternative forms of treatment for patients who are poor surgical risks or who develop recurrent hyperthyroidism following thyroid surgery.

Controversies in Clinical Thyroidology

This book is the written counterpart of a panel discussion. It consists often chapters each addressing a specific clinical question. One of the editors presents the issues to be discussed by the various commentators and relates his personal experience. In turn, several invited contributors reply to the specific questions posed by the editor. A summation of each chapter follows. Four chapters contain material of direct relevance to the general surgeon. Chapter 3 asks whether all autonomously functioning thyroid nodules should be ablated to prevent subsequent development of thyrotoxicosis. Chapter 4 questions routine ablative therapy of hyperthyroidism in women of childbearing age. Chapter 8 is concerned with the efficacy and safety of needle aspiration of cystic thyroid nodules. Chapter 9 discusses the requirement for excision of thyroid nodules appearing after radiation therapy to the head and neck. Three chapters on Graves' disease consider use of long-term antithyroid drug therapy, long-term treatment

CORRELATION OF HLA AND THYROID ANTIBODIES WITH CLINICAL COURSE OF THYROTOXICOSIS TREATED WITH ANTITHYROID DRUGS

The prevalence of HLA-B8 in thyrotoxic (Graves' disease) patients who relapsed after withdrawal of antithyroid drugs was high (69%) compared with that in patients who remained in remission (40%) and in healthy controls (28%). B8-positive patients were 1·8 times more likely to relapse after withdrawal of drug therapy than B8-negative patients. The persistence of thyroid microsomal antibodies after withdrawal of therapy correlated significantly with the presence of HLA-B8. This association was more pronounced in patients who remained in remission. From this it might be assumed that B8 is also associated with the persistence of thyroid T.S.H. (thyroid-stimulating hormone) receptor stimulating antibodies. In view of these findings, it is suggested that patients who are thyrotoxic might be typed for HLA, and those who are B8-negative could be given a trial of long-term antithyroid drug therapy.

Auto-immune thyroiditis

The study of thyroid auto-immunity is still in its early stages and much work remains to be done. Thus, it is still uncertain whether the thyroid auto-antibodies arise because of some subtle alteration in the chemical constitution of the thyroid auto-antigens, because of failure to acquire tolerance or because of some derangement of the antibody-forming mechanism which renders it incapable of recognizing self; or whether the thyroid auto-antibodies merely reflect the pathologic changes brought about by other immunity mechanisms such as “cell-bound” or “delayed” hypersensitivity. Nevertheless, the auto-immune concept has had important repercussions in the diagnosis and treatment of thyroid disease. Auto-immune thyroiditis can readily be differentiated from other forms of thyroid disease on the basis of a combination of clinical and laboratory findings including serologic, biochemical and radioiodine tests. The precipitin test is the most reliable laboratory test, but the occasional occurrence of a positive test in thyroid neoplasm makes it necessary to carry out thyroid biopsy when the clinical findings are equivocal. The Hyland Laboratories T-A test provides a rapid screening procedure for auto-immune thyroiditis, but false positives may occur in patients with rheumatoid arthritis. On the other hand, the tanned red cell hemagglutination and complement fixation tests are too sensitive for routine diagnostic purposes. Increases in gamma globulin, abnormal flocculation tests, and an accelerated erythrocyte sedimentation rate are of diagnostic value in auto-immune thyroiditis and the results of routine radioiodine tests may be helpful, although occasionally misleading in the euthyroid patient who manifests symptoms of thyrotoxicosis. In the difficult case additional radioiodine tests, such as the perchlorate discharge, thyroxin or triiodothyronine suppression, and thyrotropin stimulation, or stable iodine studies may be necessary to establish the diagnosis without recourse to thyroid biopsy. The treatment of choice in auto-immune thyroiditis is thyroxin in a daily dose of between 0.2 and 0.3 mg. by mouth. This results in a variable but significant shrinkage of the goiter and a return toward normal of the biochemical abnormalities. Thyroxin should be prescribed to all patients irrespective of their clinical status and should be continued indefinitely. In rare instances surgical intervention will be necessary to relieve pressure symptoms or when a thyroid neoplasm is suspected. There is now good evidence that hypothyroidism without goiter, i.e., “primary” hypothyroidism, and auto-immune thyroiditis are variants of the same pathologic process, and that the chronic thyroiditis present in the thyrotoxic gland is a focal lesion of the same type. Patients with thyrotoxicosis who have positive precipitin tests have severe and extensive thyroiditis present in the gland and should be treated with long-term antithyroid drug therapy. Thyrotoxic patients with positive tanned red cell and complement-fixation tests are also best treated with antithyroid drugs, unless there is a definite indication for surgery or radioiodine therapy.