Discontinuation Of Methimazole Research Articles

7375 Severe Hypoglycemia In Graves’ Hyperthyroidism: A Rare Consequence Of Methimazole Induced Insulin Autoimmune Syndrome

Abstract Disclosure: J. Ratnasingam: None. N. Ismail: None. Y. Ng: None. T. Sarvanandan: None. N. Hee: None. Q. Lim: None. L. Lim: None. S. Paramasivam: None. P. Sthaneshwar: None. S. Vethakkan: None. Background: Islet autoimmune syndrome (IAS) is a rare disease characterized by elevated insulin autoantibodies (IAA), triggered by genetic, environmental or drug (sulfhydryl containing) factors. We describe a case of Graves’ hyperthyroidism who developed IAS with methimazole. Clinical Case: A 28-year-old Malaysian-Chinese woman presented with tremors and palpitations. She weighed 56 kg, had no palpable goiter or thyroid eye signs. The diagnosis of Graves’ disease was confirmed with ft4 66.5 (11.5-22.7)pmol/L and TSH <0.01 (0.55-4.78)mIU/L with elevated thyroid stimulating immunoglobulin of 5.4 (< 0.55)IU/L. She was treated with methimazole 20mg BID and Propranolol 20mg TID. After 5 weeks of methimazole, she experienced recurrent episodes of sweating and presented with a generalized tonic-clonic seizure with capillary blood glucose of 27mg/dL. Seizures aborted after resuscitation with dextrose. There was no history of fever, exposure to insulin or other drugs, weight gain, family history of diabetes or alcohol use. CT brain and other parameters were normal and she had no other apparent cause of seizures. During the hypoglycemic episode; with the plasma glucose of 32 mg/dL, she had disproportionately high insulin: 9309 (3-25)mIU/L relative to C-peptide: 18.6 (0.9-7.1)ng/mL, with appropriate cortisol levels of 958 nmol/L. Sulphonylurea screen and pancreatic imaging was negative. Low insulin recovery was documented following PEG precipitation suggesting the presence of anti-insulin antibody. Elevated serum IAA levels at >20 (<2.4)U/mL with positive HLA-DRB1*04:06, confirmed the diagnosis of IAS. Multiple small, low carbohydrate and frequent meals were prescribed to prevent hypoglycemia and methimazole was discontinued as she had mild hyperthyroidism at this point (ft4 20.6 pmol/L, TSH <0.01mIU/L). Three days after discontinuation of methimazole, hypoglycemia completely resolved without need for dextrose infusion or corticosteroids. She received immediate 131-iodine therapy and developed hypothyroidism within two months, requiring levothyroxine replacement. She had not reported any hypoglycemia since and repeated IAA titre significantly diminished to 3.2 U/mL two months after discontinuation of methimazole. Conclusion: Methimazole-induced IAS is a rare cause of insulin mediated hypoglycemia, caused by cleaving of the disulphide bonds of insulin by the drug, leading to a cascade of autoimmune response in susceptible individuals. This is the first reported Malaysian case of methimazole- induced IAS. To date, this condition have almost always been reported in East- Asians in whom the DRB1*0406 genotype is relatively common. Unprovoked hypoglycaemia in a patient on anti-thyroid medications should prompt clinicians to consider methimazole-induced IAS. Presentation: 6/1/2024

SAT548 Incidental Papillary Thyroid Carcinoma Diagnosed After Total Thyroidectomy For Recurrent Grave's Disease

Abstract Disclosure: S.U. Perez-Martinez: None. S. Bao: None. Introduction: Whether Graves’ disease (GD) increases the risk of thyroid cancer (TC) has been a long-time topic of debate. Some studies reported increased risk of TC in GD, particularly when patients with GD have thyroid nodules. Other studies suggested the prevalence of incidental differentiated TC in GD is comparable to euthyroid goiter. Here we present a case of a 39-year-old female with a thyroid nodule and recurrent GD who underwent total thyroidectomy (TT) and was found to have a 0.4cm incidental papillary TC. Clinical case: 39 year-old female patient was diagnosed with hyperthyroidism due to GD and a 1.26x2.04x2.88cm complex right thyroid nodule at age 28, based on laboratory and thyroid ultrasound (US) studies, respectively. Fine needle aspiration showed a follicular lesion favoring colloid nodule. Patient preferred conservative measures at that time. She was treated with methimazole for 3 years and went into remission. Her thyroid nodule was monitored with serial thyroid US (every 1-2 years) for 7 years and remained stable. However, 7 years after discontinuation of methimazole, she developed recurrent hyperthyroidism, with laboratory findings of suppressed TSH of <0.04 (normal 0.35-5.5 mcu/mL), elevated free T4 of 2.4 (normal 0.8-1.8 ng/dL) and Thyroid Stimulating Immunoglobulin of 8.01 (normal < 0.054 IU/L). Patient was restarted on Methimazole 10mg daily. Her TSH remained to be low at < 0.015 (normal 0.35-3.6 mcu/mL) 4 months later, at which point more definitive treatment options including radioactive iodine ablation or TT were again discussed, and the patient opted to undergo TT, which was performed successfully 2 months later. Surgical pathology was consistent with GD, an encapsulated, fibrotic, and calcified nodule consistent with infarcted follicular lesion but also a 0.4cm incidental Papillary TC in right thyroid lobe. Surgical margin was clean, no extrathyroidal extension, one perithyroidal lymph node was negative for malignancy. Patient has been doing well afterwards. Discussion: The prevalence and clinical significance of incidental differentiated TC in patients with GD have been controversial topics. Incidence of TC in GD was mostly reported to be 7-17%, but may be as high as 42%, based on thyroidectomy studies. However, a recent retrospective multicenter study suggested the concomitant TC in GD was considerably lower. No difference in TC aggressiveness, US findings, or prognosis were observed between nodular GD and non-nodular GD groups. The clinical outcomes of TC were also excellent. A Cleveland Clinic study suggested nodule size > 1cm predicted incidental TC whereas Thyroid Stimulating Immunoglobulin titers and disease duration did not. These data argue for screening patients with GD more aggressively for TC or treating GD patients with coexisting thyroid nodule more aggressively; as in our case, even if incidental TC was found, prognosis is favorable. Presentation Date: Saturday, June 17, 2023

Abstract #1382972: Between a Rock and a Hard Place: A Case of Amiodarone Induced Thyrotoxicosis Presenting with Methimazole Induced Agranulocytosis

Amiodarone is a frequently used anti-arrhythmic drug which may often cause thyroid dysfunction. Management of amiodarone induced thyrotoxicosis (AIT) often hinges on distinguishing between type I and II AIT which is not often possible. When antithyroid drugs (ATD) are used, higher than average doses are often needed, increasing risk for complications. We report a case of a 67-year-old man who presented with palpitations, tremors, hyperdefecation and weight loss, consistent with thyrotoxicosis. He had been treated with amiodarone for paroxysmal atrial fibrillation (a-fib) for several years. Admission labs showed TSH < 0.01 uIU/ml (0.36-3.74 uIU/ml), free T4 3.32 ng/dL (0.76-1.46), total T3 237 ng/dL (86-192), negative thyrotropin receptor blocking antibodies < 1.10 IU/L (0.0-1.75), thyroglobulin antibodies < 20 IU/mL (0.0-40.0) and thyroid peroxidase antibodies < 10.0 IU/mL (0.0-35.0). Thyroid ultrasound showed a mildly enlarged, heterogeneous thyroid without discrete nodules and normal vascularity. He was treated empirically for both type I and type II AIT with methimazole 40 mg and prednisone 40 mg. Despite treatment, he returned with similar complaints one month later. EKG showed a-fib with a heart rate of 120 bpm. Repeat labs showed TSH < 0.01 uIU/ml, free T4 4.01 ng/dL and total T3 146 ng/dL. His overall evaluation was consistent with impending thyroid storm. CBC was notable for a WBC and ANC of 4.0 10ˆ3 cells/μL and 520 cells/μL respectively, which decreased further to a nadir of 2.6 10ˆ3 cells/μL and 62 cells/μL the following day. The inability to use ATDs in the setting of severe agranulocytosis made thyroidectomy an attractive option. His WBC improved with discontinuation of methimazole and resolved completely a day after administration of G-CSF. He was treated with potassium Iodide, prednisone, cholestyramine and metoprolol in preparation for surgery. He did well after surgery and was discharged home in stable condition on postoperative day two. AIT types I and II are distinct clinical entities. First line treatment consists of ATDs for AIT type I, and steroids for AIT type II. In the acute setting it may be difficult to distinguish between both types and some patients may have features of both. Importantly, a 10-fold increased risk for ATD associated agranulocytosis has been reported in patients with AIT compared to thyrotoxicosis due to other etiologies. Higher doses of ATDs are often required in AIT and the risk for agranulocytosis from ATDs is likely dose dependent. Although neutropenia resolves in most patient in 1-3 weeks after cessation of ATDs, use of G-CSF may shorten recovery times, decrease risk for infections and shorten hospital stays.

Long-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ Disease

Clinical ThyroidologyVol. 35, No. 02 HyperthyroidismFree AccessLong-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ DiseaseGiuseppe BarbesinoGiuseppe BarbesinoThyroid Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.Search for more papers by this authorPublished Online:8 Feb 2023https://doi.org/10.1089/ct.2023;35.54-56AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Lertwattanarak R, Kunavisarut T, Sriussadaporn S 2022 Benefits of Long-term continuation of low-dose methimazole therapy in the prevention of recurrent hyperthyroidism in Graves' hyperthyroid patients: A randomized prospective controlled study. Int J Endocrinol 2022:1705740. PMID: 36267362.SUMMARYBackgroundThe management of Graves’ disease (GD) hyperthyroidism has been evolving over the past two decades. The traditional standard of care suggested treatment with methimazole for 12 to18 months followed by radioactive iodine (RAI) treatment or surgery (1) in patients not achieving remission, where remission is defined as the ability to maintain euthyroidism after discontinuation of methimazole. This recommendation is supported by the recognition that longer courses of antithyroid drugs do not increase the rate of lasting remissions after discontinuation (2). This strategy has become less attractive owing to increasing evidence that RAI can cause or worsen thyroid eye disease (3) on the one hand and on the other to concerns about quality of life with hypothyroidism, even when thyroid hormone is optimally replaced (4). This study (5) was conducted to understand whether long-term therapy with low-dose methimazole could protect GD patients from relapses of hyperthyroidism.MethodsThis was a randomized controlled study in adult GD patients who had been euthyroid while taking methimazole for at least 6 months prior to randomization. The patients were randomly assigned to either continue methimazole at low doses (2.5–5 mg daily) or discontinue methimazole. The subjects’ thyroid function was then monitored every 6 months for 36 months. Standard diagnostic criteria for GD were adopted for inclusion. Patients who had already experienced a relapse were excluded. The primary outcome measured was the cumulative incidence of relapsing hyperthyroidism in the two groups.ResultsNinety-two patients were randomly assigned to the discontinuation group and 92 to the low-dose treatment group. Except for minor differences, the two groups were very similar for most epidemiologic parameters (86% female vs. 84% and mean [±SD] age, 39.9±10.9 vs. 42.2±14.9 years), indicating a reliable randomization process. The average duration of methimazole therapy prior to randomization was 37 months in the discontinuation group and 32 months in the low-dose group (not statistically different). In the discontinuation group, the number of relapses increased progressively and uniformly during the study time, reaching 41.2% at 36 months. In the low-dose group, the rate of relapse was 11%, and it was reached 18 months after randomization, with no additional relapses after that time. There were no recorded side effects during the study period.ConclusionsIn patients with GD, long-term treatment with 2.5 to 5 mg of methimazole daily is safe and effective in preventing the relapse of hyperthyroidism. This strategy is a valid alternative to RAI therapy and thyroidectomy in patients who want neither and yet worry about relapses of hyperthyroidism.COMMENTARYGraves’ disease, like many other autoimmune diseases, is often characterized by flares and remissions (6). Patients taking methimazole are typically treated for 12 to 18 months, after which a discontinuation trial is performed, in the hope of a lasting remission. Measuring serum TSH receptor antibodies (TRAbs) before antithyroid drug discontinuation helps to identify patients who are at high risk for early relapses in the 3 to 6 months after discontinuation (7). However, 20 to 30% of patients negative for TRAbs will still relapse months to years after the discontinuation (8,9). This observation, and mounting diffidence towards RAI therapy and surgery, has led to increased interest for long-term methimazole treatment. The data so far available have been mostly retrospective, or have addressed only select patient groups (for example, patients who already have experienced a relapse) (10). Like other endocrinologists, I have been advising some of my patients with GD who appear to be “currently” in remission, to continue methimazole indefinitely at very low doses, typically 2.5 mg daily. This article provides good-quality evidence to support such a practice, which I will continue to apply, especially to older patients and patients who had experienced particularly intense symptoms from the hyperthyroidism at the time of its first presentation.Disclosures: The author has no relevant conflicts of interest to declare.

Efficacy of methimazole before the administration of radioactive iodine in the management of Graves' disease: a systematic review and meta-analysis.

The efficacy of anti-thyroid drugs in conjunction with radioactive iodine therapy in the management of Graves' disease is still controversial. To compare the efficacy of pretreatment with methimazole before the administration of radioactive iodine for the treatment of Graves' disease. A systematic review and meta-analysis was conducted at a teaching/tertiary hospital in Ibadan, Nigeria. A systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases was performed from inception to December, 2021. Five studies with 297 participants were included. There was no difference in the risk of persistent hyperthyroidism when radioactive iodine was used in conjunction with methimazole compared with when radioactive iodine was used alone (relative risk: 1.02, 95% confidence interval, CI: 0.62-1.66; P = 0.95, I2 = 0%). Subgroup analysis based on the duration between discontinuation of methimazole and the administration of radioactive iodine showed a lower risk of persistent hyperthyroidism when methimazole was discontinued within 7 days before radioactive iodine use, although this did not reach statistical significance (risk ratio: 0.85, CI: 0.28-2.58). The use of methimazole before radioactive iodine administration was not associated with an increased risk of persistent hyperthyroidism. Concerns about medication toxicity and adverse effects should be considered when clinicians make decisions on combination therapies for the treatment of Graves' disease. CRD42020150013, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150013.

Metimazol ile Oluşturulan Sıçan Hipotiroidi Modelinde Kognitif Fonksiyonlar, Anksiyete ve Depresyon Benzeri Davranışların Değerlendirilmesi: Pilot Çalışma

Hipertiroidizm tedavisinde yaygın olarak kullanılan metimazol, deneysel çalışmalarda geçici hipotiroidizm modeli oluşturmak için kullanılmaktadır. Çalışmamızda metimazol ile oluşturulan sıçan hipotiroidi modelinde kognitif fonksiyonların değerlendirilmesi ve hipotiroidinin anksiyete ve depresyon benzeri davranışlar üzerine etkisinin belirlenmesi amaçlanmıştır. Oniki adet erişkin dişi/erkek Wistar sıçan (250-300 g) iki gruba ayrılarak bir gruba 4 hafta süre ile içme suyu içinde %0,02 metimazol verilerek hipotiroidizm oluşturulmuş, diğer gruba normal içme suyu verilmiştir. Dört hafta sonunda, Morris su labirenti, yükseltilmiş artı labirent, kuyruk suspansiyon testi, pasif sakınma testi uygulanmıştır. Metimazol kesildikten 8 hafta sonra serum serbest T4 ve TSH düzeyleri ölçülmüş ve tiroid dokusu histopatolojik olarak değerlendirilmiştir. Morris su labirenti testinde sadece 1. günde gruplar arasında anlamlı fark izlenmiştir (p &lt; 0,001). Pasif sakınma testinde ise gruplar arasında anlamlı fark görülmemiştir (p = 0,477). Yükseltilmiş artı labirentte hipotiroid sıçanlar açık alanda daha fazla süre geçirmiş (123,5 ± 35,5 sn vs. 12,5 ± 7,9 sn; p = 0,012); açık ve orta alana daha fazla sayıda giriş yapmıştır (sırasıyla, 3,0 ± 0,4 vs. 0,7 ± 0,5; p = 0,006, 6,2 ± 1,2 vs. 2,8 ± 0,7; p = 0,042). Kuyruk suspansiyon testinde hipotiroid grubun hareketsiz kaldığı süre, ötiroid gruba göre anlamlı olarak daha uzun bulunmuştur (186,2 ± 19,5 sn vs. 110,3 ± 26,2 sn; p = 0,043). Histopatolojik incelemede, hipotiroid grubunda kolloid vakuolizasyonu izlenmiş, ancak serum serbest T4 ve TSH düzeylerinde gruplar arasında fark görülmemiştir. Sonuç olarak, sıçanda metimazol hipotiroidi modeli öğrenme ve bellekte bozulma oluşturmaksızın, anksiyeteyi azaltıp depresyona eğilimi artırmaktadır. Bu zeminde, hipotiroidi ve kognitif fonksiyon ilişkisini aydınlatmaya yönelik ileri çalışmalar planlanmalıdır.

Antithyroid Drug-Induced Lupus Erythematosus and Immunoglobulin A Deficiency

Patient: Male, 32-year-oldFinal Diagnosis: Drug induced lupus erythematosusSymptoms: Lymphadenopathy • proteinuria • rashMedication: —Clinical Procedure: Renal biopsySpecialty: Endocrinology and Metabolic • Immunology • General and Internal MedicineObjective:Rare co-existance of disease or pathologyBackground:Antithyroid drugs, namely methimazole, are well-known causes of drug-induced lupus erythematosus. This is, however, an infrequent adverse effect. Selective Immunoglobulin A (IgA) deficiency, in contrast, is the most common primary immunodeficiency. Patients with IgA deficiency are at risk of developing infectious diseases, but also autoimmune diseases such as Grave’s disease or systemic lupus erythematosus.Case Report:We report a case of methimazole-induced lupus erythematosus in a 32-year-old man with renal involvement and concomitant selective IgA deficiency. Symptoms promptly resolved after treatment with hydroxychloroquine and corticosteroids after discontinuation of methimazole. Lupus nephritis required treatment with cyclophosphamide followed by maintenance therapy with mycophenolate mofetil.Conclusions:Drug-induced lupus erythematosus usually develops after a few months or years of exposure to the causative agent. No specific symptoms exist. The diagnosis is not based on particular specific tests, but relies on a set of arguments evoking the role of the medication inducing the condition. The first step in treatment is to stop the causative drug. The therapeutic management of the various manifestations does not differ from that of idiopathic systemic lupus erythematosus. We briefly discuss the relationship between drug-induced lupus erythematosus, Grave’s disease, and IgA deficiency, and suggest that IgA deficiency may act as a potential risk factor. Testing for IgA deficiency could be helpful in patients being treated with drugs known to be associated with drug-induced lupus erythematosus.

LARGE, RECURRENT PLEURAL EFFUSION FROM IATROGENIC METHIMAZOLE-INDUCED HYPOTHYROIDISM

SESSION TITLE: Medical Student/Resident Disorders of the Pleura Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pleural effusion is a recognized but uncommon manifestation of hypothyroidism. We describe a large, recurrent unilateral effusion attributed to iatrogenic hypothyroidism from methimazole. The effusion resolved with methimazole discontinuation and without the need for hormone replacement therapy. CASE PRESENTATION: An 84 year-old female with remote history of hyperthyroidism treated with methimazole and partial thyroidectomy presented with three days of dyspnea. Evaluation revealed a large unilateral pleural effusion. Diagnostic and therapeutic thoracentesis removed a 1.4L collection that was borderline exudative by Light’s criteria. Her dyspnea transiently resolved but recurred within 5 days. Repeat thoracentesis removed an additional 1.2 liters of exudative fluid. Cytologic and microbiologic studies were unremarkable. However, serum TSH and free T4 were noted to be 56.9 and 0.6, respectively, consistent with hypothyroidism. It was discovered that her primary provider had started methimazole 3 months prior, after misinterpreting routine results as recurrence of her hyperthyroidism when they were actually indicative of subclinical hypothyroidism (TSH/FT4 4.25/0.9, respectively). Methimazole was discontinued upon this discovery. In follow up visits, her thyroid function tests normalized without the need for hormone replacement therapy, and the pleural effusion never recurred. DISCUSSION: Hypothyroidism is rare but recognized cause of pleural effusions (1). Case studies have documented pleural effusions directly related to hypothyroidism, including some attributable to methimazole, which in turn has been theorized to be mediated by a drug-induced ANCA-vasculitis mechanism (2). Our patient developed a large, recurrent, unilateral pleural effusion when methimazole was erroneously prescribed for subclinical hypothyroidism. Her subsequent hospitalization with dyspnea that led to the recognition of iatrogenic hypothyroidism. After repeated diagnostic and therapeutic thoracenteses, her clinical course finally improved after discontinuation of the offending agent and without the need for hormone replacement therapy. Our case reinforced the connection between hypothyroidism and pleural effusions, including those from methimazole-induced hypothyroidism. It also re-emphasizes the importance of appropriate outpatient monitoring and interpretation of thyroid function labs (3). CONCLUSIONS: Pleural effusions can arise due to hypothyroidism, including iatrogenic hypothyroidism secondary to methimazole. The fluid collection may be massive and lead to significant symptoms, but the clinical course appears to be self-limited once the offending agent is removed. Thyroid function tests should be appropriately monitored after the initiation of anti-thyroid drugs like methimazole to avoid complications. Reference #1: Gottehrer A, Roa J, Standford GG, Chernow B, Sahn SA. Hypothyroidism and Pleural Effusions. Chest. 1999;98(5):1130-1132. Reference #2: Gaspar-da-Costa P, Duarte Silva F, Henriques J, do Vale S, Braz S, Meneses J, et al. Methimazole associated eosinophilic pleural effusion: a case report. BMC Pharmacol Toxicol. 2017 Mar 21;18(16). Reference #3: Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014 Dec 1;24(12):1670-1751. DISCLOSURES: No relevant relationships by Tydus Thai, source=Web Response No relevant relationships by Kenneth Wei, source=Web Response

Increased Remission Rates After Long-Term Methimazole Therapy in Patients with Graves' Disease: Results of a Randomized Clinical Trial.

Background: Studies differ regarding whether, compared with courses of conventional duration, longer-term antithyroid drug treatment increases frequency of remission in patients with Graves' hyperthyroidism. We prospectively conducted a randomized, parallel-group study comparing relapse rates in patients receiving longer-term versus conventional-length methimazole therapy. We also sought variables associated with relapse following the latter. Methods: We enrolled 302 consecutive patients with untreated first episodes of Graves' hyperthyroidism. After 18-24 months of methimazole, 258 patients (85.4%) were randomized to an additional 36-102-month courses ("long-term group": n = 130; scheduled total time on methimazole: 60-120 months) or discontinuation of methimazole ("conventional group": n = 128). Patients were followed 48 months postmethimazole cessation. We performed Cox proportional hazards modeling to identify factors associated with relapse after conventional courses. Results: Methimazole was given for 95 ± 22 months in long-term patients and 19 ± 3 months in the conventional group. Fourteen patients experienced cutaneous reactions and 2 liver enzyme elevations during the first 18 months of treatment; no further methimazole-related reactions were observed despite therapy for up to another 118 months. Hyperthyroidism recurred within 48 months postmethimazole withdrawal in 15% (18/119) of long-term patients versus 53% (65/123) of conventional group patients. In the conventional group, older age, higher triiodothyronine or thyrotropin receptor antibody concentrations, lower thyrotropin concentration, or possession of the rs1879877 CD28 polymorphism or the DQB1-05 HLA polymorphism were independently associated with relapse. Conclusion: Administration of low-dose methimazole for a total of 60-120 months safely and effectively treats Graves' hyperthyroidism, with much higher remission rates than those attained by using conventional 18-24-month courses.

SAT-599 Propylthiouracil-Induced Anaphylaxis with Subsequent Tolerance of Methimazole

Background: Although the thionamides have been associated with adverse effects such as cutaneous reactions, hepatotoxicity, and agranulocytosis, anaphylaxis is rarely reported (1). We describe the case of a patient with Graves’ disease, who developed anaphylaxis after treatment with propylthiouracil (PTU), and who subsequently tolerated methimazole. Clinical Case: A 38-year-old woman presented to the emergency department with worsening palpitations, weight loss, and tremor. She was found to be severely thyrotoxic with TSH < 0.01 (normal 0.27-4.20 mU/L), free T4 > 100 (normal 12.0-22.0 pmol/L), free T3 44.2 (normal 3.1-6.9 pmol/L), and TSH receptor antibody 4.0 (normal < 1.8 IU/L). Past medical history was significant for beta-thalassemia trait and two previous early pregnancy losses. Treatment options were reviewed, and initial therapy with an antithyroid medication was recommended. The patient was started on propranolol 20 mg PRN and PTU 100 mg PO TID, chosen because she hoped to become pregnant once euthyroid. She was discharged home with outpatient endocrinology follow-up. After the first dose of PTU, she developed acute onset tongue, lip, and facial swelling, with full-body urticaria. She immediately returned to the emergency department, where she became hypotensive and sustained a syncopal episode. She was treated for anaphylaxis with epinephrine, prednisone, diphenhydramine, and ranitidine. The case was reviewed with specialists from allergy, nuclear medicine, and surgery. In general, it is not recommended to use another antithyroid medication after a severe allergic reaction to the initial agent, as there is a chance of cross-reactivity. Thyroidectomy and radioiodine ablation were deemed risky due to severe thyrotoxicosis and the possibility of precipitating thyroid storm. For this reason, she was challenged with gradually increasing doses of methimazole under close monitoring. She tolerated 1 mg and 5 mg of methimazole while in hospital, and was eventually up-titrated to a total daily dose of 20 mg. There was a resultant reduction of free T4 to 29.9 pmol/L and free T3 to 7.83 pmol/L. Radioiodine ablation was arranged with discontinuation of methimazole one week prior. Thyroid uptake and scan showed 24hr uptake of 87.6% (normal 15-35%) and a diffusely enlarged thyroid gland. She was prescribed 370 megabecquerels of I-131, and was counselled to delay pregnancy for a minimum of six months after therapy and until normalization of TSH. Conclusion: This is the first reported case of anaphylaxis secondary to PTU and subsequent tolerance of methimazole. It highlights challenges that can occur in the management of patients with severe thyrotoxicosis, and the importance of multidisciplinary care in this situation.

Development of Agranulocytosis after Discontinuation of Methimazole: An Unusual Case.

Agranulocytosis is a rare and critical adverse effect of antithyroid drugs (ATD). The occurrence of agranulocytosis in continuous ATD treatment patients is well known; however, a case of ATD agranulocytosis occurring following the discontinuation of methimazole (MMI) treatment is not a usual situation. We herein describe a case of a 41-year-old woman who was previously administered methimazole (MMI) for ten days and developed ATD-induced agranulocytosis and symptoms of an upper respiratory tract infection after three weeks following discontinuation of MMI treatment. A thorough hematologic and serological evaluation did not disclose an alternative cause for the agranulocytosis. After receiving empirical antibiotic treatment, she responded successfully with clinical improvement of her symptoms and resolved neutropenia on the seventh day. This case is atypical because agranulocytosis developed after discontinuation of MMI, which strengthens the importance of remaining alert for signs of agranulocytosis even after discontinuation of ATD treatment.

Methimazole-Induced Goitrogenesis in an Adult Patient With the Syndrome of Resistance to Thyroid Hormone.

Patients with the syndrome of resistance to thyroid hormone (RTH) have clinical (tachycardia and anxiety) and biochemical (elevated thyroid hormones level) features of hyperthyroidism. Based on previous reports in pediatric patients with the RTH, antithyroid treatment in these patients is not indicated. Clinical and biochemical sequel of antithyroid therapy in an adult patient with RTH was not previously reported. A 63-year-old African American female with history of RTH was treated with a therapy consisting of methimazole 15 mg daily and atenolol. Methimazole treatment resulted in reduction in thyroid hormone level while the patient’s TSH increased with a peak of 24.88 mIU/L. Having achieved biochemical euthyroidism, the patient developed thyroid gland enlargement associated with progressive symptoms of dysphagia and dyspnea. Examination demonstrated globally enlarged firm thyroid gland with areas of nodularity in both lobes. A computed tomography of the neck showed enlarged thyroid gland with extension around bilateral sternocleidomastoid muscles and compression onto the trachea. Methimazole therapy was discontinued and patient was treated just on atenolol. Over 12 months following discontinuation of methimazole, the patient experienced marked clinical and radiographic improvement of the goiter size associated with TSH reduction to 1.26 mIU/L and modest free thyroxine increase as expected in RTH. It seems appealing to treat patients with the RTH with antithyroid medications. However, in these patients decrease in thyroid hormone levels will stimulate TSH production, which can, in turn, predispose to goiter formation. Our report supports prior observations in children with RTH that treatment with methimazole is not indicated in adult patients with RTH.

A Case of Methimazole-Induced Chronic Arthritis Masquerading as Seronegative Rheumatoid Arthritis

We report a 40-year-old woman with onset of oligoarthritis shortly after initiating treatment with methimazole for Graves disease. Over the course of 7 years, her arthritis became progressively severe, leading to a diagnosis of seronegative rheumatoid arthritis. Treatment with disease-modifying antirheumatic agents and surgical intervention was contemplated. Ultrasound and magnetic resonance imaging revealed exuberant synovitis, involving right elbow and knees. Upon withdrawal of methimazole, prompt resolution of all signs and symptoms of arthritis was observed within several weeks. Following a MEDLINE search of available literature concerning antithyroid drug-induced arthritis, it is evident that this case represents the lengthiest duration of inflammatory arthropathy ever described in a patient that nonetheless was rapidly reversible with discontinuation of methimazole.

Graves' disease and treatment effects on warfarin anticoagulation.

Background. Hyperthyroidism causes an increased hypoprothrombinemic response to warfarin anticoagulation. Previous studies have demonstrated that patients with hyperthyroidism require lower dosages of warfarin to achieve a therapeutic effect. As hyperthyroidism is treated and euthyroidism is approached, patients may require increasing warfarin dosages to maintain appropriate anticoagulation. We describe a patient's varying response to warfarin during treatment of Graves' disease. Case Presentation. A 48-year-old African American female presented to the emergency room with tachycardia, new onset bilateral lower extremity edema, gradual weight loss, palpable goiter, and generalized sweating over the prior 4 months. She was admitted with Graves' disease and new onset atrial fibrillation. Primary stroke prophylaxis was started using warfarin; the patient developed a markedly supratherapeutic INR likely due to hyperthyroidism. After starting methimazole, her free thyroxine approached euthyroid levels and the INR became subtherapeutic. She remained subtherapeutic over several months despite steadily increasing dosages of warfarin. Immediately following thyroid radioablation and discontinuation of methimazole, the patient's warfarin dose and INR stabilized. Conclusion. Clinicians should expect an increased response to warfarin in patients with hyperthyroidism and close monitoring of the INR is imperative to prevent adverse effects. As patients approach euthyroidism, insufficient anticoagulation is likely without vigilant follow-up, INR monitoring, and increasing warfarin dosages.

Two Cases of Methimazole-Induced Insulin Autoimmune Syndrome in Graves' Disease

We report here the cases of two females with Graves' disease who developed insulin autoimmune syndrome after treatment with methimazole. The patients exhibited a sudden altered mental state after treatment with methimazole for approximately 4 weeks. Patients had hypoglycemia with serum glucose below 70 mg/dL, and laboratory findings showed both high levels of serum insulin and high titers of insulin autoantibodies. The two women had never been exposed to insulin or oral antidiabetic agents, and there was no evidence of insulinoma in imaging studies. After glucose loading, serum glucose, and total insulin levels increased abnormally. One of the patient was found to have HLA-DRB1*0406, which is known to be strongly associated with methimazole-induced insulin autoimmune syndrome. After discontinuation of methimazole, hypoglycemic events disappeared within 1 month. Insulin autoantibody titer and insulin levels decreased within 5 months and there was no further development of hypoglycemic events. We present these cases with a review of the relevant literature.

A randomized trial evaluating a block-replacement regimen during radioiodine therapy

Lack of consensus regarding the antithyroid drug regimen in relation to radioiodine ((131) I) therapy of hyperthyroidism prompted this randomized trial comparing two strategies. Patients with Graves' disease (GD, n = 51) or toxic nodular goitre (TNG, n = 49) were randomized to (131) I either 8 days following discontinuation of methimazole (-BRT, n = 52, median dose: 5 mg) or while on a continuous block-replacement regimen (+BRT, n = 48, median dose 15 mg methimazole and 100 μg levothyroxine). results: Patients in the +BRT group required more radioactivity. In this group, thyroid function did not change in the early post (131) I period, while serum-free T3 index was higher in the -BRT group (P < 0·05). One year posttherapy, the fraction of cured patients (euthyroid or hypothyroid) was 48% and 61% in the +BRT and -BRT group, respectively (P = 0·014 unadjusted; P = 0·004 adjusted), but the outcome depended on the type of disease. In GD, treatment failure in the +BRT group correlated positively with the 24-h thyroid (131) I uptake (P = 0·017), while no correlations existed in the -BRT group. In addition to +BRT allocation, patients with TNG were at higher risk of treatment failure with lower thyroid radiation doses (P = 0·048), higher doses of methimazole (P = 0·026) and lower levels of serum TSH (P = 0·009). A continuous block-replacement regimen results in a stable thyroid function during (131) I therapy but is hampered by the higher amounts of radioactivity required. The study demonstrates that the outcome in GD is highly unpredictable, while treatment failure in patients with TNG is correlated with a number of factors.

Improvement of idiopathic thrombocytopenic purpura by antithyroid therapy

Here we report a case of idiopathic thrombocytopenic purpura accompanied by Graves' disease. Improvement in thyroid function with methimazole led to the spontaneous recovery of the platelet count from 8 x 10(9)/L to 84 x 10(9)/L. Furthermore, the second fall and recovery of the platelet count well coincided with the recurrence of hyperthyroidism after the discontinuation of methimazole and its normalization by resumption of the drug, respectively. These parallel fluctuations of platelet and thyrotropin because of the cessation and resumption of antithyroid therapy suggests that correction of hyperthyroidism may be beneficial to the control of an imbalance in the immune system which impairs not only thyroid but also the platelet.

Simple and reliable method for predicting the remission of Graves' disease: revised triiodothyronine-suppression test, indexed by serum thyroxine.

To find a simple and reliable method for predicting the long-term remission of Graves' disease, we studied the outcome of 182 methimazole-treated patients with Graves' disease, whose thyroidal RAIU became < 12% after T3 administration. The patients were treated with methimazole over 2 years. T3 suppression test was done 6 months after the disappearance of TSH-receptor antibody (TRAb); the patients took T3 for 14 days, and on the 14th day, blood was obtained for serum T3, T4, and TSH determination, and RAIU was measured. These 182 patients were followed for 5 years after methimazole withdrawal. We divided the 182 methimazole-treated patients, whose thyroidal RAIU became < 12% after T3 administration, into two groups based on the outcome after the discontinuation of methimazole; 40 patients (22%) had an overt recurrence (group A) and the other 142 (78%) did not (group B). The degree of serum T4 suppressibility by T3 was less in group A than in group B. In group A, the number of the patients with a serum T4 < 60% of the pre-T3 levels is less than that with a serum T4 > or = 60%, but, in group B the former is more than the latter. The serum T4 < 60% of the pre-T3 level was significantly associated with the remission.(ABSTRACT TRUNCATED AT 250 WORDS)

Age‐Related Therapeutic Response to Antithyroid Drug in Patients with Hyperthyroid Graves' Disease

To determine whether there is an age-related difference in the therapeutic response to antithyroid drugs in hyperthyroid Graves' disease. Retrospective analysis of treatment duration and recurrence rate. Two hundred and twenty-two patients who have triiodothyronine-suppressible thyroids within 4 years of methimazole treatment. Serum thyroid hormone levels, serum thyrotropin receptor antibody titer, and thyroidal radioiodine uptake. A longer period of methimazole treatment was needed to normalize serum thyroid hormone levels and to restore normal thyroidal triiodothyronine suppressibility in young than in aged patients. There was an average 10-month lag between normalization of thyrotropin receptor antibody titer and restoration of thyroidal triiodothyronine suppressibility in both young and aged patients. Recurrence after discontinuation of methimazole was more frequent in young than in aged patients. Aged patients with hyperthyroid Graves' disease show a more favorable response to antithyroid drugs than young counterparts.

Serum Soluble CD8 Concentration Is an Indicator of Disease Activity in Patients with Graves' Disease

Cell-mediated immunity is important in the pathogenesis of Graves' disease. Activation of T cells is apparently associated with the release of soluble CD8 (sCD8) and CD4 (sCD4) molecules from the corresponding T cell subset. To test the possibility that the concentrations of these molecules may be related to Graves' disease activity, we measured serum sCD8 and sCD4 concentration in 58 Graves' patients using ELISA technique before and after treatment with methimazole as well as in 10 patients with toxic nodular goiter. sCD8 was significantly elevated in thyrotoxic patients [609.9 +/- 118 (SD) U/ml] compared to controls (264.1 +/- 98.8, p < 0.001) and normalized when patients became euthyroid as a result of methimazole treatment (278.7 +/- 89.1). The mean sCD8 concentration in the patients with toxic nodular goiter was 302 +/- 28 U/ml, no different from control. The sCD4 level in the Graves' disease group was not different from control values and did not change significantly with treatment. Correlations were found between the levels of serum thyroid hormone(s) and sCD8 concentration but not with anti-TSH receptor antibodies in the 50 patients with Graves' disease. In addition, serum sCD8 studied prospectively in eight patients after discontinuation of methimazole, increased before the rise in serum T4, and well before the clinical relapse of thyrotoxicosis. It is concluded that sCD8 is a useful marker for the activation of CD8+ cells in Graves' disease.