Ghid ATA 2016 Htyr

THYROID SPECIAL ARTICLEVolume 26, Number 10, 2016 ª American Thyroid Association ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2016.0229 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis Douglas S. Ross,1* Henry B. Burch,2** David S. Cooper,3 M. Carol Greenlee,4 Peter Laurberg,5{ Ana Luiza Maia,6 Scott A. Rivkees,7 Mary Samuels,8 Julie Ann Sosa,9 Marius N. Stan,10 and Martin A. Walter11 Downloaded by 5.2.156.233 from online.liebertpub.com at 01/28/18. For personal use only. Background: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search sup- plemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves’ hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multi- nodular goiter or toxic adenoma using radioactive iodine or surgery; Graves’ disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves’ orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves’ hyper- thyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice. 1 Massachusetts General Hospital, Boston, Massachusetts. 2 Endocrinology – Metabolic Service, Walter Reed National Military Medical Center, Bethesda, Maryland. 3 Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 4 Western Slope Endocrinology, Grand Junction, Colorado. 5 Departments of Clinical Medicine and Endocrinology, Aalborg University and Aalborg University Hospital, Aalborg, Denmark. 6 Thyroid Section, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 7 Pediatrics – Chairman’s Office, University of Florida College of Medicine, Gainesville, Florida. 8 Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, Oregon. 9 Section of Endocrine Surgery, Duke University School of Medicine, Durham, North Carolina. 10 Division of Endocrinology, Mayo Clinic, Rochester, Minnesota. 11 Institute of Nuclear Medicine, University Hospital Bern, Switzerland. *Authorship listed in alphabetical order following the Chairperson. **One or more of the authors are military service members (or employees of the U.S. Government). The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense or the United States Government. This work was prepared as part of the service member’s official duties. {Deceased. 1343 1344 ROSS ET AL. DEDICATION of interest at the initial meeting of the group and periodi- These guidelines are dedicated to the memory of Peter cally during the course of deliberations. Funding for the Laurberg, our friend and colleague, who died tragically during guidelines was derived solely from the general funds of the their preparation. ATA, and thus the task force functioned without com- mercial support. INTRODUCTION The task force reviewed the 2011 guidelines and pub- lished editorials regarding those guidelines. It then de- T hyrotoxicosis is a condition having multiple eti- ologies, manifestations, and potential therapies. The term ‘‘thyrotoxicosis’’ refers to a clinical state that results veloped a revised list of the most common causes of thyrotoxicosis and the most important questions that a practitioner might pose when caring for a patient with a from inappropriately high thyroid hormone action in tis- particular form of thyrotoxicosis or special clinical con- sues generally due to inappropriately high tissue thyroid dition. One task force member was assigned as the primary hormone levels. The term ‘‘hyperthyroidism,’’ as used in writer for each topic. One or more task force members these guidelines, is a form of thyrotoxicosis due to inappro- were assigned as secondary writers for each topic, pro- priately high synthesis and secretion of thyroid hormone(s) by viding their specific expertise and critical review for the the thyroid. Appropriate treatment of thyrotoxicosis requires primary writer. The relevant literature was reviewed using an accurate diagnosis. For example, thyroidectomy is an ap- a systematic PubMed search for primary references and propriate treatment for some forms of thyrotoxicosis and not reviews published after the submission of the 2011 guidelines, for others. Additionally, b-blockers may be used in almost all supplemented with additional published materials found on forms of thyrotoxicosis, whereas antithyroid drugs (ATDs) are Downloaded by 5.2.156.233 from online.liebertpub.com at 01/28/18. For personal use only. focused PubMed searches. Recommendations were based on useful in only some. the literature and expert opinion where appropriate. A pre- In the United States, the prevalence of hyperthyroidism is liminary document and a series of recommendations con- approximately 1.2% (0.5% overt and 0.7% subclinical); the cerning all the topics were generated by each primary writer most common causes include Graves’ disease (GD), toxic and then critically reviewed by the task force at large. The panel multinodular goiter (TMNG), and toxic adenoma (TA) (1). agreed recommendations would be based on consensus of the Scientific advances relevant to this topic are reported in a panel and that voting would be used if agreement could not be wide range of literature, including subspecialty publications reached. Task force deliberations took place between 2014 and in endocrinology, pediatrics, nuclear medicine, and surgery, 2016 during several lengthy committee meetings and through making it challenging for clinicians to keep abreast of new electronic communication. developments. Although guidelines for the diagnosis and management of patients with thyrotoxicosis were published Rating of the recommendations previously by the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists These guidelines were developed to combine the best (AACE) in 2011, the ATA determined that thyrotoxicosis scientific evidence with the experience of seasoned clini- represents a priority area in need of updated evidence-based cians and the pragmatic realities inherent in implementa- practice guidelines. tion. The task force elected to rate the recommendations The target audience for these guidelines includes general according to the system developed by the Grading of Re- and subspecialty physicians and others providing care for commendations, Assessment, Development, and Evalua- patients with thyrotoxicosis. In this document, we outline tion Group (3–6). The balance between benefits and risks, what we believe is current, rational, and optimal medical quality of evidence, applicability, and certainty of the practice. These guidelines are not intended to replace clin- baseline risk are all considered in judgments about the ical judgment, individual decision making, or the wishes strength of recommendations (7). Grading the quality of of the patient or family. Rather, each recommendation the evidence takes into account study design, study quality, should be evaluated in light of these elements so that opti- consistency of results, and directness of the evidence. The mal patient care is delivered. In some circumstances, the strength of a recommendation is indicated as a strong rec- level of care required may be best provided in centers with ommendation (for or against) that applies to most patients specific expertise, and referral to such centers should be in most circumstances with benefits of action clearly out- considered. weighing the risks and burdens (or vice versa), or a weak recommendation or a suggestion that may not be appro- METHODS OF DEVELOPMENT priate for every patient, depending on context, patient OF EVIDENCE-BASED GUIDELINES values, and preferences. The quality of the evidence is in- dicated as low-quality evidence, moderate-quality evi- Administration dence, or high-quality evidence, based on consistency of The ATA Executive Council selected a chairperson to results between studies and study design, limitations, and lead the task force and this individual (D.S.R.) identified the directness of the evidence. In several instances, the the other 10 members of the panel in consultation with the evidence was insufficient to recommend for or against a test ATA board of directors. Membership on the panel was or a treatment, and the task force made a statement labeled based on clinical expertise, scholarly approach, and rep- ‘‘no recommendation.’’ Table 1 describes the criteria to be resentation of adult and pediatric endocrinology, nuclear met for each rating category. Each recommendation is medicine, and surgery. The task force included individuals preceded by a description of the evidence and, is followed in from North America, South America, and Europe. Panel some cases by a remarks section including technical sug- members declared whether they had any potential conflict gestions on issues such as dosing and monitoring. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1345 Table 1. Grading of Recommendations, Assessment, Development, and Evaluation System Type of grading Definition of grades Strength of the recommendation Strong recommendation (for or against) Applies to most patients in most circumstances Benefits clearly outweigh the risk (or vice versa) Weak recommendation (for or against) Best action may differ depending on circumstances or patient values Benefits and risks or burdens are closely balanced, or uncertain No recommendation (insufficient evidence for or against) Quality of the evidence High quality; evidence at low risk of bias, such as high quality randomized trials showing consistent results directly applicable to the recommendation Moderate quality; studies with methodological flaws, showing inconsistent or indirect evidence Low quality; case series or unsystematic clinical observations Insufficient evidence Presentation of recommendations the main body of the text. Location keys can be copied into Downloaded by 5.2.156.233 from online.liebertpub.com at 01/28/18. For personal use only. the Find or Search function in a file or Web page to rap- The organization of the task force’s recommendations is idly navigate to a particular section. A listing of the recom- presented in Table 2. The page numbers and the location key mendations without text is provided as Supplementary can be used to locate specific topics and recommendations. Appendix A (Supplementary Data are available online at Specific recommendations are presented within boxes in www.liebertpub.com/thy). Table 2. Organization of the Task Force’s Recommendations Location key Description Page [A] Background 1347 [A1] Causes of thyrotoxicosis 1347 [A2] Clinical consequences of thyrotoxicosis 1347 [B] How should clinically or incidentally discovered thyrotoxicosis be evaluated and 1348 initially managed? [B1] Assessment of disease severity 1348 [B2] Biochemical evaluation 1348 [B3] Determination of etiology 1349 [B4] Symptomatic management 1350 [C] How should overt hyperthyroidism due to GD be managed? 1350 [D] If RAI therapy is chosen, how should it be accomplished? 1352 [D1] Preparation of patients with GD for RAI therapy 1352 [D2] Administration of RAI in the treatment of GD 1353 [D3] Patient follow-up after RAI therapy for GD 1354 [D4] Treatment of persistent Graves’ hyperthyroidism following RAI therapy 1355 [E] If ATDs are chosen as initial management of GD, how should the therapy be 1355 managed? [E1] Initiation of ATD therapy for the treatment of GD 1355 [E2] Adverse effects of ATDs 1356 [E3] Agranulocytosis 1356 [E4] Hepatotoxicity 1356 [E5] Vasculitis 1356 [E6] Monitoring of patients taking ATDs 1357 [E7] Management of allergic reactions 1358 [E8] Duration of ATD therapy for GD 1358 [E9] Persistently elevated TRAb 1358 [E10] Negative TRAb 1358 [F] If thyroidectomy is chosen for treatment of GD, how should it be accomplished? 1359 [F1] Preparation of patients with GD for thyroidectomy 1359 [F2] The surgical procedure and choice of surgeon 1359 [F3] Postoperative care 1360 [G] How should thyroid nodules be managed in patients with GD? 1361 [H] How should thyroid storm be managed? 1361 [I] Is there a role for iodine as primary therapy in the treatment of GD? 1363 (continued) [N1] Ethanol ablation 1369 [N2] Radiofrequency ablation 1369 [O] How should GD be managed in children and adolescents? 1369 [O1] General approach 1369 [P] If ATDs are chosen as initial management of GD in children.liebertpub. Table 2.com at 01/28/18.2. how should it be 1372 accomplished? [Q1] Preparation of pediatric patients with GD for RAI therapy 1372 [Q2] Administration of RAI in the treatment of GD in children 1373 [Q3] Side effects of RAI therapy in children 1373 [R] If thyroidectomy is chosen as treatment for GD in children.156. how should it be accomplished? 1367 [L1] Preparation of patients with TMNG or TA for surgery 1367 [L2] The surgical procedure and choice of surgeon 1367 [L3] Postoperative care 1368 [L4] Treatment of persistent or recurrent disease following surgery for 1368 TMNG or TA [M] If ATDs are chosen as treatment of TMNG or TA. For personal use only.233 from online. (Continued) Location key Description Page [J] How should overt hyperthyroidism due to TMNG or TA be treated? 1363 [K] If RAI therapy is chosen as treatment for TMNG or TA. 1346 ROSS ET AL. how should the therapy be managed? 1368 [N] Is there a role for ethanol or radiofrequency ablation in the management of TA or 1369 TMNG? Downloaded by 5. how should the therapy be 1370 managed? [P1] Initiation of ATD therapy for the treatment of GD in children 1370 [P2] Symptomatic management of Graves’ hyperthyroidism in children 1371 [P3] Monitoring of children taking MMI 1371 [P4] Monitoring of children taking PTU 1371 [P5] Management of allergic reactions in children taking MMI 1371 [P6] Duration of MMI therapy in children with GD 1372 [Q] If radioactive iodine is chosen as treatment for GD in children. how should it be 1374 accomplished? [R1] Preparation of children with GD for thyroidectomy 1374 [S] How should subclinical hyperthyroidism be managed? 1375 [S1] Prevalence and causes of SH 1375 [S2] Clinical significance of SH 1375 [S3] When to treat SH 1376 [S4] How to treat SH 1377 [S5] End points to be assessed to determine effective therapy of SH 1378 [T] How should hyperthyroidism in pregnancy be managed? 1378 [T1] Diagnosis of hyperthyroidism in pregnancy 1378 [T2] Management of hyperthyroidism in pregnancy 1379 [T3] The role of TRAb level measurement in pregnancy 1384 [T4] Postpartum thyroiditis 1385 [U] How should hyperthyroidism be managed in patients with GO? 1386 [U1] Assessment of disease activity and severity 1386 [U2] Prevention of GO 1387 [U3] Treatment of hyperthyroidism in patients with no apparent GO 1389 [U4] Treatment of hyperthyroidism in patients with active GO of mild severity 1389 [U5] Treatment of hyperthyroidism in patients with active and moderate-to-severe or 1390 sight-threatening GO [U6] Treatment of GD in patients with inactive GO 1390 [V] How should iodine-induced and amiodarone-induced thyrotoxicosis be managed? 1390 [V1] Iodine-induced thyrotoxicosis 1390 [V2] Amiodarone-induced thyrotoxicosis 1391 (continued) . how should it be 1365 accomplished? [K1] Preparation of patients with TMNG or TA for RAI therapy 1365 [K2] Evaluation of thyroid nodules prior to RAI therapy 1366 [K3] Administration of RAI in the treatment of TMNG or TA 1366 [K4] Patient follow-up after RAI therapy for TMNG or TA 1366 [K5] Treatment of persistent or recurrent hyperthyroidism following RAI therapy for 1367 TMNG or TA [L] If surgery is chosen. MMI. or tyrosine kinase inhibitor toms. subclinical hyperthyroidism. It increases tissue thermogenesis and basal meta- receptor can cause sporadic or familial nonautoimmune hyper. PTU. GD. toxic adenoma. but it was 6% of fined as a low or undetectable serum TSH with values within the patients in Toronto and 22% of patients in Wisconsin (16–18).12). Although activation of thyroid hormone synthesis and secretion occurs. TSH. that regulate the expression of many genes. accounted for only 0. radioactive iodine. TA.156. Germline mutations in the gene encoding the TSH system. increasing thyroid hormone production and re. Therefore. Both overt and Painless thyroiditis may occur during lithium (19). deficiency. which occur due to although in reality the disease represents a continuum of over. and de. Nongenomic velopment of autonomy over time (8). In TAs. although subclinical hyperthyroidism is usually considered therapy (21).. tations of genes regulating thyroid growth and hormone syn. especially in regions of tious. metastatic differentiated mission of mild GD has been reported in up to 30% of patients thyroid cancer) or exogenous (factitious thyrotoxicosis). important physiologic functions. Thyroid hormone influences almost every tissue and organ thesis. bolic rate and reduces serum cholesterol levels and systemic . Endogenous overt or subclinical thy. ties of painless and subacute thyroiditis. thyrotropin. particularly (not usually lymphocytic) occurs in 5%–10% of amiodarone- subclinical thyrotoxicosis. propylthiouracil. inflammation of thyroid tissue with release of preformed active thyroid function.5% of thyrotoxic patients. interferon-a) (20). Downloaded by 5. chemical. GD is an autoimmune disorder in [A2] Clinical consequences of thyrotoxicosis which thyrotropin receptor antibodies (TRAb) stimulate the The cellular actions of thyroid hormone are mediated by TSH receptor. normal reference range for both T3 and free T4. or (iv) there is exposure iodine deficiency (13. without treatment (15). Overt hyperthyroidism is defined as a hormone into the circulation. toxic nodular goiter may actually be more leased in excessive amounts owing to autoimmune. Less common causes of thyrotoxicosis include the enti- depending on the biochemical severity of the hyperthyroidism. Subclinical hyperthyroidism is de. GO.liebertpub. new nodule formation. Subacute thyroiditis is thought to be rotoxicosis is caused by excess thyroid hormone production and caused by viral infection and is characterized by fever and release or by inflammation and release of hormone by the gland. re- either endogenous (struma ovarii.2. which is to extrathyroidal sources of thyroid hormone. its prevalence leading to autonomous release of excess thyroid hormone. RAI. autonomous actions of thyroid hormone include regulation of numerous hormone production can be caused by somatic activating mu. T3 binds to two lease. SH. (Continued) Location key Description Page [W] How should thyrotoxicosis due to destructive thyroiditis be managed? 1394 [W1] Subacute thyroiditis 1394 [W2] Painless thyroiditis 1395 [W3] Acute thyroiditis 1395 [W4] Palpation thyroiditis 1395 [X] How should other causes of thyrotoxicosis be managed? 1395 [X1] Interferon-a and interleukin-2 1395 [X2] Tyrosine kinase inhibitors 1396 [X3] Lithium 1396 [X4] TSH-secreting pituitary tumors 1397 [X5] Struma ovarii 1397 [X6] Choriocarcinoma 1398 [X7] Thyrotoxicosis factitia 1398 [X8] Functional thyroid cancer metastases 1398 ATD. Unlike toxic nodular goiter. GD is the most common excessively stimulated by trophic factors.233 from online. cyto- subclinical disease may lead to characteristic signs and symp. TRAb. and the administration of [A1] Causes of thyrotoxicosis pharmacologic amounts of iodine to such patients may result in In general. Painless thyroiditis caused by subnormal (usually undetectable) serum thyrotropin (TSH) with lymphocytic inflammation appears to occur with a different elevated serum levels of triiodothyronine (T3) and/or free thy. RESULTS thyroidism associated with a diffuse enlargement of the thyroid [A] Background gland (9). For personal use only. common than GD in older patients. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1347 Table 2.com at 01/28/18. Overzealous or suppressive thyroid hormone adminis. Graves’ orbitopathy. Autonomous hormone production may progress from subclinical to overt hyperthyroidism. A painless destructive thyroiditis tration may cause either type of thyrotoxicosis. which may be progressive (unless triggered by excessive iodine intake). Graves’ disease. (ii) constitutive cause of hyperthyroidism in the United States (11. TMNG. kine (e. the active form of thyroid hormone. or mechanical insult. increases with age and in the presence of dietary iodine (iii) thyroid stores of preformed hormone are passively re. thyrotropin receptor antibody. postpartum thyroiditis (22). and in the postpartum period it is referred to as milder. antithyroid drug. infec. frequency depending on the population studied: in Denmark it roxine estimates (free T4). T3. The development of nodular thyroid disease includes specific nuclear receptors (thyroid hormone receptor a and b) growth of established nodules. thyrotoxicosis can occur if (i) the thyroid is iodine-induced hyperthyroidism (10). toxic nodular goiter is less common than GD. Endogenous hyperthyroidism is most commonly due to GD or nodular thyroid disease. thyroid pain (24). Hyperthyroidism is generally considered overt or subclinical. treated patients (23).g.14). toxic multinodular goiter. methimazole. com at 01/28/18.liebertpub. TBG excess may occur as a hereditary X-linked trait. and the presence or absence of peripheral edema. These laboratory younger patients and those with larger goiters (28). measurement of TSH in serial dilution. Holter monitor. Al. In immunometric assays. and may require an echocardiogram. ious free T4 elevations may occur from heterophilic respiratory rate. therefore. Cardiac evaluation may be necessary. binding protein disorders. In addition to the administra. immunoglobulins that directly bind T4 tion of b-blockers (31). perphenazine. and free T4 can be normal. excess biotin displaces biotinylated anti- strongly suspected. For personal use only. measurement of total T3 is fre- quently preferred over free T3 in clinical practice. Symptoms a third-generation assay).233 from online. only serum T3 may be elevated. and especially trations are low avoid the need for subsequent blood draws. rarely. neuropsychiatric measurements for assessing thyroid hormone excess (35). which cause elevated total serum The importance of age as a determinant of the prevalence and T4 concentrations (and frequently elevated total serum T3 severity of hyperthyroid symptoms has recently been con. The relationship between free T4 and TSH when biotin competes with biotinylated analogue and results in . or subclinical. technique (41. Serum TSH levels are associated with weight loss. (TBG) or transthyretin (37). frequently used to measure free T4. atrial fibrillation. acute psychosis the degree of hyperthyroidism or hyperthyroid symptoms. Serum TSH measurement has the highest sensitivity and Ingestion of high doses of biotin may cause spurious re- specificity of any single blood test used in the evaluation sults in assays that utilize a streptavidin–biotin separation of suspected thyrotoxicosis and should be used as an ini. measurements are affected by protein binding. and clude tachycardia and anxiety and may be more pronounced in serum TSH will be low or undetectable. extreme high altitude (39). serum free T4. a normal serum symptoms is proportional to the elevation in the serum levels TSH level precludes the diagnosis of thyrotoxicosis. and nodularity should also be assessed along with activation of lipoprotein lipase and release of free fatty acids pulmonary. concentrations) in the absence of hyperthyroidism (36). Estimates of free thyroid hormone concentrations fre- should undergo a comprehensive history and physical exam. and this should be ruled out by repeating the TSH in another assay. the presence of an abnormal electrocardiogram. or Heterophilic antibodies can also cause spurious high TSH pretibial myxedema. free T4. and initially managed? centration. the narcotics. Mea. obstructive ing treatment with 5-fluorouracil. Assays for es- dynamics. tremor. hepatitis. excess evaluation. congestive heart failure. vascular resistance. in one small study of 25 patients with GD. antibodies or in the setting of heparin therapy. The signs findings have been called ‘‘T3-toxicosis’’ and may represent the and symptoms of mild. However.31.33) that displace T4 from its binding proteins. muscle weakness. or [B2] Biochemical evaluation direct measurement of human anti-mouse antibodies.2. and rarely cardiovascular collapse and death (26. quently also give erroneous results in these disorders. the pituitary–thyroid axis is intact is an inverse log-linear creased thyroid hormone levels occur within the cardiovascular relationship. term ‘‘euthyroid hyperthyroxinemia’’ has been used to de- the Hyperthyroid Symptom Scale did not strongly correlate scribe a number of entities. tenderness. treatment may be needed for con. The need for evaluation should not postpone buminemic hyperthyroxinemia). Goiter size. considerably more sensitive than direct thyroid hormone embolic events. primarily thyroid hormone– with free T4 or T3 and was inversely correlated with age (28). thyroid hormone resistance. osteoporosis. and serum TSH is subnormal (usually <0. In overt hyperthyroidism. The of free T4 and T3. especially These conditions include elevations in T4 binding globulin in the older patient. is In the absence of a TSH-producing pituitary adenoma or essential in formulating an appropriate treatment plan. and body weight. a similarly abnormal trans- therapy of the thyrotoxicosis. and the severity of Graves’ orbitopathy (GO). or it may be acquired as a result of pregnancy or estrogen ad- atrial arrhythmias (25). acute intermittent porphyuria or dur- patients in atrial fibrillation (32).01 mU/L in hormone elevation and clinical signs and symptoms.156. omously functioning thyroid nodule. and amphetamine abuse All patients with known or suspected hyperthyroidism (40). frequently used tial screening test (34). and total T3 are assessed at the initial binding assays. thyrotoxicosis are similar earliest stages of hyperthyroidism caused by GD or an auton- to those of overt thyrotoxicosis but differ in magnitude. small changes in free T4 result in large system (25).27). T3.42). and psychiatric and neuropsychological function can timating free T3 are less widely validated and less robust than be present in mild thyrotoxicosis (29). can be discordant with darone (23) or high-dose propranolol (31). or T3. with subnormal serum TSH con- Downloaded by 5. In mild hyperthyroidism. Laboratory protocols that store sera and automati- cally retrieve the sample and add on free T4 and total T3 [B1] Assessment of disease severity measurements when the initial screening serum TSH concen- Assessment of thyrotoxic manifestations. symptoms. Subclinical [B] How should clinically or incidentally hyperthyroidism is defined as a normal serum free T4 and discovered thyrotoxicosis be evaluated normal total T3 or free T3. due to in vitro symmetry. while in competitive serum TSH. cardiovascular hemo. 1348 ROSS ET AL. Therefore. cardiac. or both are Only moderate correlation exists between the degree of thyroid elevated. or some symptoms. Other causes of euthyroid hyperthyroxinemia in- inflammatory disease that develops in the orbit in association clude drugs that inhibit T4 to T3 conversion. or myocardial perfusion albumin which binds T4 with high capacity (familial dysal- studies (31). eye signs. or in the presence of spurious though it might be anticipated that the severity of thyrotoxic assay results due to interfering antibodies. including measurement of pulse rate. and. firmed (30). Thyroid size. Anticoagulation may be necessary in ministration. diagnostic accuracy improves when a bodies and causes spuriously low results. when thyrotoxicosis is to measure TSH. values. (38). total T3 surable changes in basal metabolic rate. or comitant myocardial ischemia. potential cardiovascular and neuromuscular complications. those for free T4. such as amio- with autoimmune thyroid disorders. As with T4. serum T4 and signs that result from increased adrenergic stimulation in. Some of the most profound effects of in. Spur- ination. and neuromuscular function (29. Untreated or partially treated thyrotoxicosis is changes in serum TSH concentrations. blood pressure. thyretin. total body ra- nosis (45). While technetium scans result in a low range of reduced costs by 47% and resulted in a 46% quicker diag. recent adjusted for urine creatinine concentration or a 24-hour urine onset of orbitopathy.233 from online. This test may . Causes of Thyrotoxicosis supplements containing biotin.000 enrollees in a managed care scans may be obtained coincident with the RAIU and tech- organization in the United States. resulting in usually elevated in patients with GD and normal or high in positive TRAb levels and a nodular ultrasound or heteroge- toxic nodular goiter. RAIU is rarely <1% unless the iodine expo- when the clinical presentation suggests a TA or TMNG. should stop taking biotin and have repeat uptake over the necka measurements at least 2 days later. (1) measurement of TRAb. mination of the radioactive iodine uptake (RAIU). Patients taking high doses of biotin or Table 3. indicated and can include. gland from those with near-absent uptake (Table 3). Technetium uptake measurements utilize pertech. diagnosis is not apparent based on the clinical presentation a and initial biochemical evaluation. For personal use only. evaluation requires careful adjustments to prevent artifacts ated contrast in the preceding 1–2 months or with ingestion of and measures the peak systolic velocity from intrathyroidal a diet unusually rich in iodine such as seaweed soup or arteries or the inferior thyroidal artery (49). the image may rotoxicosis having elevated or normal uptake over the thyroid be difficult to distinguish from that of GD (46). triiodo- tise and resources. If the Extensive metastases from follicular thyroid cancer Downloaded by 5. T3. Additionally. patient with a nonnodular thyroid and no definite orbitopathy.. flow Doppler can distinguish thyroid hyperactivity (increased factitious ingestion of thyroid hormone. In a study using a model of a concentration of the radioisotope within thyroid tissue. TSH-mediated TA or TMNG hyperthyroidism should be considered when thyroid hormone Trophoblastic disease concentrations are elevated and TSH is normal or elevated. the uptake may be low. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1349 falsely high results. The ministered technetium that is trapped by the thyroid after a pattern of uptake in a patient with a single TA generally fixed interval. Uptake is GD and nontoxic nodular goiter may coincide. If autonomy is extensive. ultrasonography with color patients with painless. In a thyrotoxic the abnormal thyroid tissue is located in an ovarian teratoma. to iodine (e.liebertpub. b Patients are not uniformly clinically hyperthyroid.com at 01/28/18. radiocontrast). The image in in question (except during pregnancy and usually during TMNG demonstrates multiple areas of focal increased and lactation (see Section [T4]) and distinguishes causes of thy. usually in the presence of thyroid nodularity. Thyroid scans provide a planar image of the thyroid gland measurement of TRAb or RAIU can be used to distinguish using a gamma camera to assess potential variability in the GD from other etiologies. When exposure to excess iodine is suspected (e. usually 20 minutes.g. either type of scan RAIU measures the percentage of administered RAI that is can be useful in determining the etiology of hyperthyroidism concentrated into thyroid tissue after a fixed interval. diffuse unless coexistent nodules or fibrosis is present. when Strong recommendation. Subacute (granulomatous. the diagnosis of GD is likely and further evaluation of neck will also be absent in a patient with struma ovarii. moderate-quality evidence. the RAIU is lower than expected from the clinical history). RAI theoretical population of 100. thyronine. where hyperthyroidism causation is unnecessary. The pattern of RAIU in GD is technetium (TcO4) uptake measures the percentage of ad. or subacute thyroiditis. postpartum. assessment of urinary iodine concentration (spot urine iodine In a patient with a symmetrically enlarged thyroid. normal uptake and high background activity. A 123I or 99mTc pertechnetate scan should be obtained kelp. diagnostic testing is In iodine-induced or iodine-exposed hyperthyroidism (including amiodarone type 1). depending on available exper. or recent excess io.156. 24 hours.g.. the use of TRAb mea. unless there has been a recent exposure neous uptake images (47). iodine concentration) may be helpful. Thyrotoxicosis associated with a near-absent RAI uptake agnosis of a TSH-producing pituitary adenoma (43). The RAIU may be low after exposure to iodin. A thyroid scan should be obtained if the clinical presen- netate that is trapped by the thyroid. suppressed uptake. GD After excluding euthyroid hyperthyroxinemia. A family over the neck history and genetic testing for mutations in the thyroid hormone Painless (silent) thyroiditis receptor b (THRB) gene supports the diagnosis of resistance to Amiodarone-induced thyroiditis thyroid hormone (44). netium scans may be obtained coincident with the technetium surements to diagnose GD compared to RAIU measurements uptake. shows focal uptake in the adenoma with suppressed uptake in Uptake measurements are indicated when the diagnosis is the surrounding and contralateral thyroid tissue. but not organified. A TSH-producing pituitary adenomas pituitary lesion on magnetic resonance imaging (MRI) and a Resistance to thyroid hormone (T3 receptor b mutation. sure is reoccurring. A tation suggests a TA or TMNG.2. However. diation exposure is less than for 123I scans. The RAIU will be near zero in Where expertise is available. or (3) measurement of thyroidal blood flow on ultrasonography. de Quervain’s) thyroiditis Palpation thyroiditis Iatrogenic thyrotoxicosis [B3] Determination of etiology Factitious ingestion of thyroid hormone Struma ovarii & RECOMMENDATION 1 Acute thyroiditis The etiology of thyrotoxicosis should be determined. such as during treatment with amiodar- one. and moderate to severe hyperthyroid. who have elevated T4 and Thyrotoxicosis associated with a normal or elevated RAI suppressed TSH. disproportionately high ratio of the serum level of the a-subunit THRB)b of the pituitary glycoprotein hormones to TSH supports the di. Quantitative Doppler dine intake. The uptake over the ism. flow) from destructive thyroiditis (48). (2) deter. and <20 in painless or postpartum thyroiditis (51). A labeled TSH to a recombinant TSH-R. were 1.233 from online. 1350 ROSS ET AL. traindicated. its release is suppressed in the setting of exogenous thyroid hormone administration. distinction between subacute and painless chospastic asthma in whom heart rate control is essential. and a T3 to T4 ratio (ng/lg) Patients with overt Graves’ hyperthyroidism should be <20 if due to exogenous levothyroxine (53). ATDs. be particularly useful when radioactive iodine (RAI) is con. these drugs are generally contraindicated in patients dose (see Section [D2]). and it can be negative in very mild GD. cause if it is positive it confirms the diagnosis of the most disease. In patients with treated with any of the following modalities: RAI therapy. with symptomatic thyrotoxicosis. measuring TRAb in a taking b-adrenergic blockers had lower heart rates. from engineered [V2]) and between GD and destructive thyroiditis (see Sec. moderate-quality evidence. tinguish among other etiologies. especially elderly pa- The choice of initial diagnostic testing depends on cost. in one study the ratio of total [B4] Symptomatic management T3 to total T4 (ng/lg) was >20 in GD and toxic nodular goiter. tients and thyrotoxic patients with resting heart rates in availability. patients therapy (see Section [C]). roid and the cause is GD. an alternative but not widely avail- able approach is measurement of fecal T4 (54). Chinese Hamster Ovary (CHO) cells transfected with tion [W2]). a relative b-1 selective agent can be erythrocyte sedimentation rate is usually >50 mm/h and used cautiously. after 4 weeks. less patient with GD who plans on taking methimazole (MMI) shortness of breath and fatigue. If third-generation TRAb assays are not readily available.7% . and improved ‘‘physical with the hope of achieving a remission will provide a baseline functioning’’ on the SF-36 health questionnaire (58). tom relief. These TRAb or TBII 2011 survey of clinical endocrinologists showed that 59. with careful monitoring of pulmonary status sometimes over 100 mm/h. Because a hyperactive gland produces more the setting of overt thyrotoxicosis. RAI has been the therapy most competition assays which measure inhibition of binding of preferred by physicians. Thyroglobulin is released along with thyroid hormone both verapamil and diltiazem. such as during pregnancy or breastfeeding. a near-zero RAIU. For personal use only. Obtaining a RAIU in a Technical remarks: Since there is not sufficient b-1 se- patient who prefers RAI treatment will provide both diag. Bioassays for the Thyroid Stimulating Immunoglobulin Doppler flow has also been used to distinguish between (TSI) measure the ability of TSI to increase the intracellular subtypes of amiodarone-induced thyrotoxicosis (see Section level of cAMP directly or indirectly. antithyroglobulin antibodies. For example. with bronchospastic asthma. In the United States. the heart rate to near the upper limit of normal (31).57). If negative it does not dis- Strong recommendation. but most immune thyroid disease and typically have measurable serum often low to moderate doses (Table 4) give sufficient symp- concentrations of anti–thyroid peroxidase antibodies (52).g. or thyroidectomy. In contraindicated. common cause of thyrotoxicosis. but a trend has been present in recent either a labeled monoclonal anti-human TSH-R antibody or years to increase use of ATDs and reduce the use of RAI. have been shown to affect rate in subacute. painless. Subacute thyroiditis is generally patients with mild obstructive airway disease or symptomatic painful. In a randomized controlled trial of MMI alone versus MMI Diagnostic testing may be influenced by the choice of and a b-adrenergic blocking agent. Such assays specifically detect simulating antibodies (TSI) sessing the etiology of thyrotoxicosis when scintigraphy is and can differentiate between the TSH-R antibody types. however. 1. [C] How should overt hyperthyroidism factitious ingestion of thyroid hormone can be distinguished due to GD be managed? from other causes of thyrotoxicosis by a low serum thyro. e. whereas b-adrenergic blocking agents. and the Raynaud’s phenomenon.93 nmol/g in Graves’ hyperthyroidism. hTSH-R reported through increased luciferase production. & RECOMMENDATION 3 globulin level. A high & RECOMMENDATION 2 T4 to T3 ratio may be seen in thyrotoxicosis factitia (from Beta-adrenergic blockade is recommended in all patients exogenous levothyroxine). TRAb is cost effective be. and 12–24 nmol/g in factitious Once it has been established that the patient is hyperthy- thyrotoxicosis. excess of 90 beats per minute or coexistent cardiovascular Downloaded by 5. In patients with quiescent bron- In most patients. and local expertise. the gland is firm to hard on palpation. Oral administration of calcium channel blockers.com at 01/28/18. roidism.156. very high doses of b-blockers are presenting within the first year after childbirth (postpartum required to manage symptoms of thyrotoxicosis and to reduce thyroiditis) often have a personal or family history of auto. and palpation thyroiditis (following control in patients who do not tolerate or are not candidates for manipulation of the thyroid gland during surgery). measurement for disease activity. 99% for GD (56. globulin measurement. mean values Strong recommendation. RAIU is preferred for initial testing. lectivity of the available b-blockers at the recommended nostic information and facilitate the calculation of the RAI doses. ATDs. or thyroidectomy TSH Binding Inhibition Immunoglobulin (TBII) assays are (59). whereas T4 is elevated more than T3 in thyrotoxi- cosis caused by thyroiditis (50). The ratio of total T3 to total T4 can also be useful in as. newer TRAb binding and T3 than T4. Third generation treatment options: RAI therapy. assays are unable to distinguish the TSH-R antibody types. Patients with painless thyroiditis (Table 4). moderate-quality evidence. the patient and physician must Technical remarks: There are two methods for measuring choose between three effective and relatively safe initial Thyroid Receptor Antibodies (TRAb) (55).2. T3 will be elevated above the upper limit of bioassays have a sensitivity of 96–97% and a specificity of normal more than T4 in thyrotoxicosis caused by hyperthy. Occasionally.03 nmol/g in euthyroid patients. which interfere with thyro. or in thyroiditis is not difficult.liebertpub. If not elucidated by the history. small goi- physician preference for ATDs (61). ATDs: Definite contraindications to ATD therapy in- hypokalemic paralysis. patients with moderate treatment options. especially women. relatively low uptake of costs. benefits. right heart failure pulmonary clude previous known major adverse reactions to ATDs.156. expected to severe active GO.e. patients with previously operated Technical remarks: Once the diagnosis has been made. coexisting hyperparathyroid- with ATDs may be considered in selected cases (65. b. safety regulations. The treatment selection should RAI were chosen as therapy).g. no scientific evidence ex.66). a. patients with lack of access to a treating physician and patient should discuss each of the high-volume thyroid surgeon. costs (64). there has been a greater tients. including the logistics.2. and negative or low-titer TRAb). potential side effects. lack of that expertise large thyroid nodules especially if greater than 4 cm or should be considered against the known risk of alternative if nonfunctioning. and Japan. RAI therapy: Women planning a pregnancy in the fu- ment for Graves’ hyperthyroidism: ture (in more than 6 months following RAI adminis- tration. For personal use only.233 from online. Downloaded by 5. the life (QoL) following treatment for GD was found to be the elderly or others with comorbidities increasing surgi- same in patients randomly allocated to one of the three cal risk or with limited life expectancy.com at 01/28/18. Latin America. The long-term quality of ters. pos- the final decision to incorporate the personal values and sibly before thyroid hormone levels would be normal if preferences of the patient. especially if TRAb levels are particularly high. thyroxine. drawbacks. when thyroid malignancy is documented or sus- consider the use of expert high-volume thyroid surgeons with pected (e. individuals in treatment options (62).liebertpub. with 69% in a similar survey performed 20 years earlier (60). T4. Long-term continuous treatment of hyperthyroidism pertechnetate scanning. and biochemical disease control. on average lower risk of complications. nancy. coexisting thyroid cancer.. or congestive heart failure should also be mary therapy for an uncomplicated case of GD. bAlso available in once daily preparations. or suspi- and patients with previously operated or externally ir. and patients who need more rapid speed of recovery. compared considered good candidates for RAI therapy. This sets the stage for the physician to make c. ism requiring surgery. Whenever surgery is selected as treatment one should RAI. treatment for Graves’ hyperthyroidism (Table 5): Contraindications to a particular modality as treat- a. of respondents from the United States selected RAI as pri. with mild disease. Patients with periodic thyrotoxic b. individuals unable to comply radiated necks. Currently. but to date none has been approved for the treatment of thyrotoxicosis. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1351 Table 4. ATDs: Patients with high likelihood of remission (pa- In Europe. the or irradiated necks. RAI therapy: Definite contraindications include preg- individuals with comorbidities increasing surgical risk. lactation. and patients with moderate to severe Clinical situations that favor a particular modality as active GO. Surgery: Women planning a pregnancy in <6 months recommendations based on best clinical judgment and allows provided thyroid hormone levels are normal (i. symptomatic compres- also take into account the local availability and the associated sion or large goiters (‡80 g). hypertension. or lack of access to a high-volume with radiation safety guidelines and used with informed thyroid surgeon. nursing homes or other care facilities who may have ists to support the recommendation of alternative therapies limited longevity and are unable to follow radiation for the treatment of hyperthyroidism (63). and patients with contraindications to caution in women planning a pregnancy within 4–6 ATD use or failure to achieve euthyroidism during months. Beta-Adrenergic Receptor Blockade in the Treatment of Thyrotoxicosis Druga Dosage Frequency Considerations b Propanolol 10–40 mg 3–4 times per day Nonselective b-adrenergic receptor blockade Longest experience May block T4 to T3 conversion at high doses Preferred agent for nursing and pregnant mothers Atenolol 25–100 mg 1–2 times per day Relative b-1 selectivity Increased compliance Avoid during pregnancy Metoprololb 25–50 mg 2–3 times per day Relative b-1 selectivity Nadolol 40–160 mg 1 time per day Nonselective b-adrenergic receptor blockade Once daily Least experience to date May block T4 to T3 conversion at high doses Esmolol IV pump 50–100 lg/kg/min In intensive care unit setting of severe thyrotoxicosis or storm a Each of these drugs has been approved for treatment of cardiovascular diseases.. suspicious or indeterminate cytology). or hypofunctioning on 123I or 99mTc choices. provided thyroid hormone levels are normal). . treatment with ATDs. cion of thyroid cancer. pregnancy. Clinical Situations That Favor a Particular Modality as Treatment for Graves’ Hyperthyroidism Clinical situations RAI ATD Surgery Pregnancya x OO / ! O/! Comorbidities with increased surgical risk and/or limited OO O x life expectancy Inactive GO O O O Active GO b OO OO Liver disease OO ! O Major adverse reactions to ATDs OO x O Patients with previously operated or externally irradiated necks OO O ! Lack of access to a high-volume thyroid surgeon OO O ! Patients with high likelihood of remission (especially women. MMI should be discontinued 2–3 days remission and the avoidance of lifelong thyroid hor- prior to RAI. a For women considering a pregnancy within 6 months.2. how should Optimally. thyroidectomy is performed in the second it be accomplished? trimester. for GD should be considered in patients who are at in- b. severity. and and definitive control of hyperthyroidism. the possibility of disease recurrence. as well as a relatively lower value on the need for lifelong & RECOMMENDATION 5 thyroid hormone replacement. rapid resolution of hy- In addition to b-adrenergic blockade (see Recommenda- perthyroidism. O = acceptable therapy. mone treatment. and potential worsening or development tions 2 and 4). and negative or low-titer TRAb) Patients with periodic paralysis OO O OO Patients with right pulmonary hypertension. and other risk factors for GO progression. Thyroid surgery in pregnancy is also associated with a & RECOMMENDATION 4 higher rate of complications. or other debilitat.5%–5. . Surgery: Patients choosing surgery as treatment for GD ing disorders. of ATDs and a relatively lower value on potential thyroid medications cannot be used. and need for lifelong thyroid hormone best avoided in the first and third trimesters of pregnancy replacement. elderly patients and patients with ment for GD would likely place relatively higher value comorbidities). including hypoparathy. ! = cautious use. Thyroid malignancy confirmed or suspected x - One of more large thyroid nodules . and the potential side effects of ATDs. it is not [D1] Preparation of patients with GD for RAI therapy without risk (4. and the potential side effects rapid control of hyperthyroidism is required and anti. small goiters. X = contraindication. acerbation of hyperthyroidism.68).. ATDs: Patients choosing ATD as treatment for GD creased risk for complications due to worsening of hy- would place relatively higher value on the possibility of perthyroidism.e. O OO Coexisting primary hyperparathyroidism requiring surgery . pretreatment with MMI prior to RAI therapy of GO (69). Because RAI treatment of GD can cause a transient ex- roidism and recurrent laryngeal nerve (RLN) injury (68). Table 5. Pregnancy is a relative contraindication.com at 01/28/18. O OO O with mild disease.= not first-line therapy but may be acceptable depending on the clinical circumstances. although it is the safest time. RAI therapy: Patients choosing RAI therapy as treat. c. OO OO = preferred therapy. considering disease activity. For personal use only. b-adrenergic blockade should be considered even in asymptomatic patients who Patient values that may impact choice of therapy: are at increased risk for complications due to worsening of a. on definitive control of hyperthyroidism. or congestive heart failure OO O ! Elderly with comorbidities O O ! OO Downloaded by 5. because of teratogenic effects associated with anesthetic agents and increased risk of fetal loss in the first tri- mester and increased risk of preterm labor in the third. pulmonary disease. c. or lack of access to a high-volume thyroid would likely place a relatively higher value on prompt surgeon. however. the avoidance of surgery. b Table 14 describes the use of RAI in GO in detail.233 from online. [D] If RAI therapy is chosen. Thyroidectomy is surgical risks.liebertpub. low-quality evidence. . moderate-quality evidence.5% risk of preterm labor) (67.156. . 1352 ROSS ET AL. Surgery: Factors that may mitigate against the choice of avoidance of ATD side effects (see Section [E]). of surgery. avoidance of surgery should only be used in the circumstance when exposure to radioactivity. and surgery include substantial comorbidity such as cardio. see discussion in Section [T2]. end-stage cancer. and exposure to radioactivity and a relatively lower value on the Weak recommendation. the avoidance Weak recommendation. hyperthyroidism (i. roid. The clinically well compensated despite significant biochemical most frequently used uptake is calculated at 24 hours. hyperthyroidism and may prevent the thyroid hormone in- crease seen upon ATD withdrawal (81–83). and propylthiouracil (PTU) reduce the success rate if is very effective. and indi. the duration of cardiac disease treated with RAI as the sole modality.156. to recommend the practice. activity [lCi] = gland weight [g] · 50–200 lCi/ hyperthyroid symptoms poorly.g.. this RAI has been used to treat hyperthyroidism for more than approach is not used widely.g. rotoxicosis was seen (73). calculating the activity based on the size of the thyroid and its A special diet is not required before RAI therapy. MMI (75) and carbimazole (78) have shown to re. Over several decades. a recent meta-analysis of The goal of RAI therapy in GD is to control hyperthy- randomized controlled trials also found that MMI. If possible iodinated radiocontrast should be avoi- obtain this test and verify a negative result prior to ad- ded. Young activity in microcuries or becquerels is converted to milli- and middle-aged patients who are otherwise healthy and curies or megabecquerel by dividing the result by 1000. and if MMI was not restarted & RECOMMENDATION 7 after RAI.. provided a sufficient radiation dose is de- given in the week before or after RAI treatment (71).com at 01/28/18. hyperthyroidism who would have been candidates for pre- Thyroid storm occurs only rarely following the administra. tritional supplements that may contain excess iodine and The first method is simple.233 from online. treatment. low-quality evidence. term increase of thyroid hormone levels (74. roidism by rendering the patient hypothyroid.76). ning 1 week after RAI administration (84). then be calculated using these two factors and the quantity of Technical remarks: Patients that might benefit from ad. RAI can induce a short. MMI and carbimazole One study found that this estimate by experienced physicians should be discontinued before the administration of RAI. Such patients frequently g · [1/24 hour uptake in % of administered activity]). the use of MMI or [D2] Administration of RAI in the treatment of GD carbimazole. optimized prior to RAI therapy. the elderly. infection. saturated solution of potassium iodide [SSKI]) begin- Downloaded by 5. This outcome can be accomplished higher activities of RAI may offset the reduced effectiveness equally well by either administering a fixed activity or by of RAI therapy following antithyroid medication (75. but who are allergic to ATDs. there have been reports that pretreatment with lithium reduces the activity of RAI necessary for cure of Graves’ Strong recommendation. before and after RAI treatment may be considered in & RECOMMENDATION 8 patients with severe hyperthyroidism. but nu. For personal use only. and insufficient evidence exists seven decades. (370–555 MBq). In selected patients with Graves’ except for those related to orbitopathy (see Section [U]). which is found after Alternately. if MMI was restarted 7 days after RAI. (e.liebertpub. no hyperthyroidism may be shortened by administering iodine clinical worsening in any of the cardinal symptoms of thy. In one after RAI administration should be considered. a more detailed calculation can be made to 6 days (75. the free T4 Weak recommendation. low-quality evidence. However. A low-iodine quires two unknowns to be determined: the uptake of RAI diet may be useful for those with relatively low RAIU to and the size of the thyroid. this treatment zole. is accurate compared with anatomic imaging (86). moderate-quality evidence. b-adrenergic blocking drugs should be used ministering RAI. resuming MMI or carbimazole 3– In patients who are at increased risk for complications due 7 days after RAI administration should be considered and to worsening of hyperthyroidism. However. If given as pretreatment. size of the thyroid is determined by palpation or ultrasound. heart failure. Discontinuation of ATDs for 2–3 days prevents a short-term other investigators have not confirmed this observation (87). and cerebrovascular or & RECOMMENDATION 9 pulmonary disease (70). while the second method re- seaweeds should be avoided for at least 7 days. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1353 & RECOMMENDATION 6 cardiovascular disease. It is well tolerated and complications are rare. Use of posited in the thyroid. judiciously in these patients in preparation for RAI therapy (25. the latter of which is not marketed in the United States. duce thyroid hormone levels after RAI treatment in ran- domized controlled trials. low-quality evidence. ability to trap RAI (85). the free T4 values were 36% higher than the values Medical therapy of any comorbid conditions should be at the time of RAI administration (80). radiation (lCi or Bq) to be deposited per gram (or cc) of junctive MMI or carbimazole may be those who tolerate thyroid (e. poorly controlled diabetes mellitus. . However.76). Strong recommendation. These comorbid conditions should A pregnancy test should be obtained within 48 hours prior be addressed with standard medical care and the patient to treatment in any woman with childbearing potential who rendered medically stable before the administration of RAI if is to be treated with RAI. Sufficient activity of RAI should be administered in a viduals with substantial comorbidity that puts them at greater single application.75). treatment with ATDs because of comorbidities or excessive tion of RAI (70–72).76). however. The therapeutic RAI activity can increase the proportion of RAI trapped. increase of thyroid hormone levels (79). or pulmonary Strong recommendation. study. The treating physician should possible. measured 3 weeks after RAI was 6% lower than the values at the time of RAI administration. In addition. The have free T4 at 2–3 times the upper limit of normal.77). trauma. To prevent a clinical exacerbation of hyperthyroidism. In elderly patients or in those with underlying deposit a specific radiation dose (in rad or Gy) to the thyroid. to render the patient with GD hypothy- The latter includes patients with cardiovascular complica. typically a mean dose of 10–15 mCi risk for complications of worsening thyrotoxicosis (75. resuming MMI 3–7 days generally tapered as thyroid function normalizes. In one study of patients with thyrotoxic symptoms. and the hyperthyroidism can generally receive RAI without pre. tions such as atrial fibrillation. hypertension and those with renal failure.2. carbima. 33 mCi (1. clinical longer. In patients without adjunctive ATD.2. including a The success of RAI therapy in GD strongly depends on the request for therapy from the former and a statement from the administered activities. and TSH.4 mCi (200 MBq) (92).156. In some men.102) and are also at a theoretical in. As free T4 and total T3 improve.22 GBq) or greater. Conception should be delayed 3–4 months in men to symptoms.7 mCi (580 MBq) (95) RAI. however. and careful ti- tration is necessary owing to nonsuppressible residual & RECOMMENDATION 10 thyroid function. Breastfeeding based on an assessment of free T4. therapy on mortality (96.5 mSv (500 milli-roentgen equivalent in man [mrem]) better. Transient hypothy- allow for turnover of sperm production. This typically takes 4–6 months or determined by results of thyroid function tests. in hypothyroidism as opposed to unchanged mortality in becomes hypothyroid and is stable on thyroid hormone RAI-treated patients on levothyroxine therapy. timing of thyroid hormone replacement therapy should be cessful thyroid ablation). When thyroid hor- lactation-associated increase in breast sodium iodide sym. However. In the with free T4 and total T3.2 mCi (302 MBq) (93). advice concerning radiation safety precautions following Once euthyroidism is achieved.105). Overt hypothyroidism should be avoided. and kidney cancer was seen. when the patient is discharged with a retained activity of Evidence shows that to achieve a hypothyroid state. Fetuses ex. Conception and >80% by 16 weeks (106). This transition can occur should be delayed in women until stable euthyroidism is es.97). A delay of 3 months will more reliably ensure that determine the need for levothyroxine. or if tive therapy should be selected. In lowing RAI.55 MBq/g) needs to be delivered (88–90). the levels should be interpreted cautiously and only in concert garding RAI treatment should be followed (104. The physician administering RAI should provide written especially in patients with active GO (see Section [U2]). Patients who are on dialysis or who have jejunostomy or Technical remarks: Continuity of follow-up should be gastric feeding tubes require special care and management provided and can be facilitated by communication between when being administered RAI treatment (91).233 from online. the dose should be adjusted porter activity has returned to normal (103). once the roidism following RAI therapy can rarely occur. In such patients the thyroid gland anomalies compared to the population at large (100). levothyroxine should be instituted. and because the outcome has not shown to be 0. of thyroid function tests and improvement of clinical symp- ther research (98). function testing is recommended at least annually.com at 01/28/18. at 1 m. If the precautions cannot be followed. A long-term increase in cardiovascular and cerebrovas. 69% with 8. with sub- patient (either sex) is euthyroid. the referring physician and the treating physician. Technical remarks: Rendering the patient hypothyroid can Beta-blockers that were instituted prior to RAI treatment be accomplished equally well by administering either a suf. this method is seldom used in the United States. A recent meta-analysis found no increase in the overall cancer risk after RAI treatment for hyperthyroidism. and offspring of treated patients show no congenital hyperthyroidism (107). for GD should include an assessment of free T4. 81% with 15 mCi (555 MBq) (94). there is no evidence of reduced sequent complete recovery of thyroid function or recurrent fertility. stomach. should be tapered when free T4 and total T3 have returned to ficient fixed activity or calculating an activity based on the the reference range. a trend towards increased risk of Most patients respond to RAI therapy with a normalization thyroid. the patient experiences symptoms of hypothyroidism or hyperthyroidism. 1354 ROSS ET AL. with 40% of patients being hypothyroid by 8 weeks therapy that is subclinical and reversible (99). requiring fur. All national and regional radiation protection rules re. which allows an assessment of the posed to RAI after the 10th to 11th week of gestation may be response to RAI. which is indicated by a free T4 below normal breastfeeding women. it is also necessary to know the effective United States. alterna. be less than the typical full replacement. Strong recommendation. rapidly but more commonly between 2 and 6 months. At this point.liebertpub. randomized controlled trials found 61% success with 5. and physical examination. or emits ‡7 mrem/h (70 lSv/h) >150 lCi/g (5. Biochemical monitoring should be continued at cular deaths has been reported after RAI therapy not resulting 4. Because & RECOMMENDATION 11 of the high proportion of patients requiring retreatment. role of persistent hyperthyroidism as opposed to that of RAI Strong recommendation. Technical remarks: Since TSH levels may remain sup- pressed for a month or longer after hyperthyroidism resolves. a modest fall in the testos. can usually be tapered. the treating physician must ensure and docu- half-life of RAI (88). low-quality evidence. range. toms within 4–8 weeks. latter that the treatment has been administered. This requires additional time and ment that no adult member of the public is exposed to computation. total T3. or until the patient Downloaded by 5. lifelong annual thyroid treatment. MMI size of the thyroid and its ability to trap iodine. RAI Follow-up within the first 1–2 months after RAI therapy therapy with low activities is generally not recommended. Most patients eventually develop hypothyroidism fol- creased risk for reduced intelligence and/or cancer. low-quality evidence. reflecting the replacement. often remains palpable. Hypothyroidism may occur from 4 terone to luteinizing hormone (LH) ratio occurs after RAI weeks on. RAI therapy should not be adminis.to 6-week intervals for 6 months. . Using this approach. born athyreotic (101. For personal use only. The required dose may should not be resumed after RAI therapy. and the tablished (on thyroid hormone replacement following suc. 74% [D3] Patient follow-up after RAI therapy for GD with 10 mCi (370 MBq) (94). tered for at least 6 weeks after lactation stops to ensure that TSH levels may not rise immediately with the develop- RAI will no longer be actively concentrated in the breast ment of hypothyroidism and should not be used initially to tissues. and 86% with 15. mone replacement is initiated. except during the first trimester of times daily is usually possible. . arthralgias. low-quality evidence. fatigue. it is important to use an MMI dose that will of GD. gland size.114). and in some countries. The treatment itself tailored to the individual patient. low-quality evidence. when given in the upper limit of normal. fever.2. MMI should be used in virtually every patient who chooses reduction to a maintenance PTU dose of 50 mg two or three ATD therapy for GD.119). reduced risk of major side effects compared to PTU. The goal of retreatment is to referred to as MMI in this text. incorporating additional might have a beneficial immunosuppressive role. and a liver When hyperthyroidism due to GD persists after 6 months profile including bilirubin and transaminases. thyroid function. MMI and PTU are available. Preferably. perthyroidism and fewer adverse reactions compared to Strong recommendation. goal of the therapy is to render the patient euthyroid as The task force suggests the following as a rough guide to quickly and safely as possible. studies (120). In selected patients with minimal response 3 months after therapy additional RAI may be considered. either to information on symptoms.com at 01/28/18. in the treatment of control is needed in patients with severe thyrotoxicosis. moderate-quality evidence. however. this information should be in ATD therapy for GD has been investigated in previous writing. acolic stools or dark side effects (109.. and in patients with minor reactions to MMI initial split dose of MMI (e. where relevant.5–2 times adequate doses.5 times cure Graves’ hyperthyroidism. the rate of remission with ATD therapy is continuing thyrotoxicosis (117). HYPERTHYROIDISM MANAGEMENT GUIDELINES 1355 [D4] Treatment of persistent Graves’ hyperthyroidism & RECOMMENDATION 15 following RAI therapy Prior to initiating ATD therapy for GD. pothyroidism in patients with mild disease (116). adverse drug reactions are more frequent with higher MMI [E] If ATDs are chosen as initial management doses. In addition. and total T3 levels primarily decrease thyroid specific autoimmunity. will not restore a euthyroid state in patients with severe dis- several applications of RAI. In the United States. how should the therapy be managed? achieve the clinical goal of normalization of thyroid function ATDs have been employed for seven decades (109). Weak recommendation. Patients who have persistent.liebertpub. depending on the severity of the hyperthyroidism.g. The dose of MMI should be targeted ther relapse or development of hypothyroidism. nausea. At the start of MMI therapy.156. Indeed. The use of potassium iodide (KI) as a beneficial adjunct to or pharyngitis. However. starting with 50–150 mg three times daily. much higher (112) than the historical rates of spontaneous MMI has the benefit of once-a-day administration and a remission (113). or sec. which resulted in better control of hy- suggestive of agranulocytosis or hepatic injury. Both are effective as a single control hyperthyroidism with certainty by rendering the pa- daily dose. PTU has a shorter duration of action and is usually administered two or [E1] Initiation of ATD therapy for the treatment of GD three times daily. These rough guidelines should be the usual cause is nonadherence (110). As the & RECOMMENDATION 13 clinical findings and thyroid function tests return to normal. jaundice. the upper limit of normal. we suggest that patients have a baseline complete blood count. Thus. The reasonably rapidly. this approach is not generally recommended the necessity of informing the physician promptly if they because it has been shown to result in a higher rate of ATD should develop pruritic rash. they are very effective in controlling the the upper limit of normal. For personal use only. 10–20 mg for free T4 1.233 from online. including & RECOMMENDATION 12 white blood cell (WBC) count with differential. 15 or 20 mg twice a day) may who refuse RAI therapy or surgery. urine. Higher Strong recommendation. They work in an identical fashion and both will be and clinical signs and symptoms. carbimazole. low-quality evidence. and the dose can TSH with normal total T3 and free T4 may not require im- then be titrated down to a maintenance level (generally 5– mediate retreatment but should be monitored closely for ei- 10 mg daily) (109. These medications do not initial MMI daily dosing: 5–10 mg if free T4 is 1–1. while minimizing adverse drug effects. by ameliorating the hyperthyroid state. of MMI). an thyroid storm. Before starting ATDs and at each subsequent visit. a recent randomized controlled trial the patient should be alerted to stop the medication im- described the administration of 38 mg of KI together with mediately and call their physician if there are symptoms 15 mg of MMI daily. Weak recommendation. 30 mg of MMI given alone (121). When they fail to achieve euthyroidism. surgery should be considered ease (115) and an excessive dose can cause iatrogenic hy- (108). following RAI therapy. In the small to the degree of thyroid dysfunction because too low a dose percentage of patients with hyperthyroidism refractory to Downloaded by 5. a precursor of MMI. initial doses of 10– tient hypothyroid. which may initially because some patients normalize their free T4 levels restore the dysregulated immune system back to normal with MMI but have persistently elevated serum T3. In fact. Serum T3 levels are important to monitor ondarily. doses of antithyroid medication are sometimes administered & continuously and combined with L-thyroxine in doses to RECOMMENDATION 14 maintain euthyroid levels (so-called block and replace ther- Patients should be informed of side effects of ATDs and apy). Carbimazole is rapidly converted to MMI in the serum Technical remarks: Response to RAI therapy can be as- (10 mg of carbimazole is metabolized to approximately 6 mg sessed by monitoring the size of the gland. indicating (111). is widely used. and 30–40 mg for free T4 2–3 times hyperthyroidism. abdominal pain. be more effective than a single daily dose because the dura- tion of action of MMI may be less than 24 hours (118). suppressed 30 mg daily are used to restore euthyroidism. retreatment with RAI is suggested. When more rapid biochemical pregnancy when PTU is preferred. while PTU hepatotoxicity is most often hepatocellular group (123). PTU and successfully treated with granulocyte colony stimulating rarely MMI can cause antineutrophil cytoplasmic antibody factor. tions (median 28 days). hepatotoxic reactions were not classified as limited for PTU-associated agranulocytosis.27% with PTU and 0. significantly earlier than transaminase eleva- Downloaded by 5. In 7% of patients. but the frequency of ‘‘liver study. or supportive care.141). (134).7% devel. liver transplantation has been nec- oped agranulocytosis (absolute neutrophil count <500) essary in some patients taking PTU (132). In a recent systematic review of eight studies MMI (129).147). No predictive risk factors for the as drug-induced lupus (139). but one of five patients (pANCA)-positive small vessel vasculitis (137. Three recent reports of large tients).com at 01/28/18.026% in MMI-treated pa- doses of MMI (124–126). an observa. 24% de. In the first cholestatic or hepatocellular. but hepatocellular disease may be seen veloped a cutaneous reaction. Two studies were from gest that prior data on MMI-related hepatotoxicity from small Japan and one was from Denmark. crosis that may be fatal. 0. culitis (133). 725 patients received MMI. Cutaneous reactions were more common with PTU or that the Food and Drug Administration (FDA) issued a safety higher dose MMI (30 mg/d) compared with lower dose MMI alert in 2010 regarding the use of PTU. The percentage of patients dis. adverse effects of ATDs can be divided into second or subsequent exposure. be more likely to develop PTU-related ANCA-positive vas- locytosis was slightly older (45 vs.25% vs.019% vs. The average age of patients developing agranu. A recent pharmacoepidemiologic study from Taiwan chal- continuing ATD therapy was 17% in the low-dose MMI lenges the concept that MMI hepatotoxicity is usually chole- group. sug- treatment.11% with hepatic damage.136). and an analysis of (15 mg/d). the majority of reports come from Asia (143). MMI hepatotoxicity has been described as typi- study of 449 GD patients receiving MMI or PTU. In the third study from Denmark. granulocyte myeloperox- reported in the first study (128). be necessary (145). the median duration of that included 667 GD patients receiving MMI or PTU. As in prior studies.8% developed transaminase (130. China (135). agranulocytosis Rare cases of insulin autoimmune syndrome with symp- occurred later than 4 months after starting ATD. which are in logic complications provide information on risk factors. PTU at any dose appears to be (0. a retrospective cohort analysis of over 50. In a separate therapy. The risk appears to increase development of agranulocytosis could be identified. vasculitis is more common in patients of Asian ethnicity. 3.03%). 29% in the high-dose MMI group. Although ATD-associated agranulocytosis is uncom. and 11% developed pancytopenia or vast majority of such individuals do not develop clinical aplastic anemia. . 40% of patients taking PTU develop ANCA positivity.03%) and PTU (0. and 0.016%). Seventy-two percent discontinuation. Typically. but some tomatic hypoglycemia have been reported in patients treated of these patients had discontinued the medication for long with MMI (146. respectively. contrast to other data from the United States (133.liebertpub. the aver. patients. These surprising results from Asia.08%. 1356 ROSS ET AL. It is for this reason (123). All 50 patients with agranulocytosis alone were other rare side effects are associated with ATDs. 55 developed agranulocytosis.2. In the study from majority of patients are treated with MMI.233 from online. Eighty-nine percent devel. for an estimated incidence of 0. lergic reactions included pruritus or a limited. 13% therapy prior to the development of agranulocytosis was 36 of patients experienced adverse events (122). the ANCA age MMI dose was 25 mg/d and the average PTU dose was slowly disappear in most individuals (144). it is life-threatening. In both countries the case series may need to be reconsidered. 0. FDA Medwatch data (133) concluded that children are more Cutaneous reactions appeared after a median of 18–22 days susceptible to hepatotoxic reactions from PTU than are of treatment. minor allergic side effects and rare but serious were fatal. respectively). and Of them. The minor al. which may have included some patients of treatment (140. vasculitis. 69 days. MMI was associated with a higher rate [E3] Agranulocytosis of a diagnosis of noninfectious hepatitis than PTU (0.000 GD failure’’ was similar for MMI (0. the oped agranulocytosis. A total of 754 GD patients idase is the targeted antigen of the ANCA. PTU can cause fulminant hepatic ne- elevations more than 3-fold above normal. the vasculitis resolves with drug tion that has been made by others. with a median interval to onset of Aside from hematologic and hepatic adverse effects. Children seem to 217 mg/d. [E2] Adverse effects of ATDs periods of time and developed agranulocytosis after a In general. Among 71.156. minor rash in 6% of patients taking MMI and 3% of patients taking PTU [E4] Hepatotoxicity (122). for an estimated cumulative incidence of [E5] Vasculitis 0. but antibodies to who developed ATD-induced hematologic complications many other proteins are seen as well (142). and 34% in the PTU static. Hepatocellular injury occurred in 2. ANCA-positive were reported. of whom five had pancytopenia. adults. Hepatotoxicity was more common with PTU.4% of patients taking MMI. although immunosuppressive therapy may developed agranulocytosis within 60 days of starting ATD. whereas cholestasis was not different mon. the frequency allergic/toxic events such as agranulocytosis. and 38 days for MMI and PTU. Similar findings were also recently reported from numbers of ATD-treated patients who developed hemato. For personal use only. A diagnosis of liver failure was more more likely to cause agranulocytosis compared with low common after PTU (0. In most cases. Thirty of the events (4%) common. steroids.138) as well with pancytopenia died.131). 40 years).1%–0. or of agranulocytosis was 0. 0. The with duration of therapy as opposed to other adverse effects second study was based on a national database for adverse seen with ATDs that typically occur early in the course drug reactions.7% of patients Hepatotoxicity is another major adverse effect of ATD taking PTU and 0. 28 received PTU.15%. vasculitis (144). While up to and one received both drugs. and outcomes (127–129). At the onset of agranulocytosis. and 85% within 90 days. so data are more Denmark (129).048% vs. In contrast.379 new users of ATDs with a median follow-up of 196 days.3% in 100 days (127). cally cholestatic. When the drug is discontinued. Although routine monitoring of WBC counts may indicated) reach >3 times the upper limit of normal or if detect early agranulocytosis. If not recognized. If a patient the suggestion by some that patients taking this ATD have is receiving long-term MMI (>18 months). Technical remarks: PTU should be discontinued if trans- dicting early onset of adverse reaction to the medication aminase levels (found incidentally or measured as clinically (152). the serum free T4 levels may normalize despite persistent elevation of serum total T3. who has developed agranulocytosis.2%– discontinuing the drug. weeks after initiation of therapy. In a recent tored weekly until there is evidence of resolution. the first 6 months of therapy. before initiating ATD therapy. monitoring of WBC counts and liver function tests in pre. liver function tests should be moni- 0. low-quality evidence. An assessment of sessed in patients taking MMI or PTU who experience serum free T4 and total T3 should be obtained about 2–6 pruritic rash. or the thyrotoxicosis. the maximum benefit would be for the first the task force is that a baseline absolute neutrophil count 90 days of therapy.233 from online. However. 21% hepatologist for specialty care is warranted. the opinion of is employed. this practice is not likely to levels elevated at the onset of therapy increase further. a rising alkaline phosphatase with normalization of other liver function does not indicate Strong recommendation. thyroid storm) in a MMI-treated patient This information can be found online (150. difficult to ap- There is insufficient evidence to recommend for or against preciate clinically. ing is employed. and it is essential Liver function and hepatocellular integrity should be as- that patients understand its importance.. and document that it has been done. Serum TSH may remain sup- pressed for several months after starting therapy. Routine ATDs.151). measuring WBC are frequently seen in patients with thyrotoxicosis (149). the dose of MMI can usually of patients. Once euthyroid levels are achieved with the (155). Periodic clinical and biochemical evaluation of thyroid & RECOMMENDATION 18 status in patients taking ATDs is necessary. Except in cases . with improving thyrotoxicosis. trophil count under 2000 (148)]. when the vast majority of agranulocytosis <1000/mm3 or liver transaminase enzyme levels elevated occurs. the maximum benefit would be for the first 120 days of therapy. and abnormal liver enzymes Because patients are typically symptomatic. If monitoring increases the risk of complications from ATDs. abdominal pain or bloating. adjusted accordingly. a prevalence higher than with MMI. The onset of RECOMMENDATION 17 PTU-induced hepatotoxicity may be acute. clinical and laboratory evalua. For personal use only. If resolu- analysis of 211 patients with ATD-induced agranulocytosis tion is not evident. noted. nausea. insufficient evidence to assess not been found to prevent severe hepatotoxicity. Serum T3 should be monitored because Strong recommendation. had a normal WBC count within a week and 53% within 2 terpretation of future laboratory values should be considered weeks before developing agranulocytosis (128). PTU may cause in the course. and the dose of medication should be fatigue. when the vast majority of instances of No consensus exists concerning the utility of periodic hepatotoxicity occur. [E6] Monitoring of patients taking ATDs Downloaded by 5.156. leading to tion can be undertaken at intervals of 2–3 months. and it is Hyperthyroidism can itself cause mildly abnormal liver therefore not a good parameter for monitoring therapy early function tests in up to 30% of patients (149).e. this interval can routine monitoring of their liver function. and biochemical testing repeated limit of normal are seen in up to 4% of patients taking PTU in 4–6 weeks. A 2009 review of the literature (136) found that PTU hepatotoxicity occurred after a median & RECOMMENDATION 16 of 120 days after initiation of therapy. depending on the severity of joint pain. suggesting that moni- GD and in African Americans [10% of whom have a neu. In patients taking antithyroid medication. toring might have been useful in some affected patients (152).157–159). not liver. and rapidly progressive. anorexia. transient elevations of serum transaminases in up to one-third Once the patient is euthyroid. counts during febrile illnesses and at the onset of pharyngitis While there is no evidence that neutropenia or liver disease has been the standard approach to monitoring. Distinguishing these A differential WBC count should be obtained during fe. especially if the duration of therapy is brief (154). In a patient developing agranulocytosis or other seri- more than 5-fold above the upper limit of normal should ous side effects while taking either MMI or PTU. low-quality evidence. abnormalities from the effect of persistent thyrotoxicosis is brile illness and at the onset of pharyngitis in all patients difficult unless they are followed prospectively. jaundice.com at 01/28/18. worsening hepatic toxicity (156) because the origin of the & alkaline phosphatase is from bone. As previously minimal dose of medication.2. If monitor- benefits and risks. light-colored stool or dark urine. It other medication is contraindicated owing to risk of cross- is advisable to provide information concerning side effects of reactivity between the two medications (153). especially during be increased to 6 months (see below). Significant elevations to 3-fold above the upper be decreased by 30%–50%. routine monitoring of WBC counts in patients taking it can lead to liver failure and death (115. The contrain- ATDs to the patient both verbally and in writing to ensure dication to use PTU might be reconsidered in life-threatening their comprehension. This suggestion is made in other patients did display a gradual decline in WBC count part because low WBC counts are common in patients with prior to developing agranulocytosis.liebertpub. prompt referral to a gastroenterologist or who had at least one prior granulocyte count measured. use of the prompt serious reconsideration of initiating ATD therapy. thyrotoxicosis (i. After identify cases because the frequency is quite low (0. monitoring of liver function in all patients taking ATDs has No recommendation. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1357 Technical remarks: Baseline blood tests to aid in the in. PTU can also cause fatal hepatic necrosis.5%) and the condition is usually sudden in onset. sonable alternative approach (65. Those patients treated with RAI (n = 114) more often levels indicating greater chance for remission.161). For personal use only. insufficient evidence to assess normal serum TSH. smokers (espe- native drug is not recommended. months. about 20%–30% of patients were reported & to have a lasting remission after 12–18 months of medication RECOMMENDATION 20 (59). event from either MMI or PTU switched to the other ATD. 1358 ROSS ET AL. MMI can be used to treatment with RAI or thyroidectomy.e. Median dose of the have a higher probability of permanent remission (171.172).5–10 mg/d for a mean of 14 years [E8] Duration of ATD therapy for GD were safe and effective for the control of GD in 59 patients (174). and experienced more weight gain compared with Strong recommendation. moderate-quality evidence. and a study in Japan reported a 68% medication should be managed by cessation of the medi- remission rate after 2 years of treatment (164). pruritis. & If continued MMI therapy is chosen. A lower case of a serious allergic reaction. able. & RECOMMENDATION 23 [E10] Negative TRAb If a patient with GD becomes hyperthyroid after com. with consideration of MMI dis- If MMI is chosen as the primary therapy for GD. that was successfully managed with antihistamine therapy.173). MMI developed side effects. with normal (175).156. In selected patients (i. high-quality evidence. Higher initial doses of MMI (60–80 mg/d) do not improve remission rates. For patients choosing long-term MMI therapy. relapse rates approach 300 mg/d for PTU (range 150–450). against routine monitoring of liver function tests in pa- tients taking ATDs. a long-term Euro- rent antihistamine therapy without stopping the ATD. A meta- cation and changing to RAI or surgery. low-quality evidence. TRAb assessment at the end of the course of ATD therapy although patients may develop similar side effects with the is a useful method of dividing patients into two groups: one second ATD (123). 71 patients with an adverse with persistent elevations who are unlikely to be in remission. Continued low-dose control the thyrotoxicosis without ill effect (160. while the remaining patients [E9] Persistently elevated TRAb tolerated the second ATD without complications (123). and those with large goiters (‡80 g) (165–169). who were treated therapy is suggested because it aids in predicting which with either RAI and levothyroxine or long-term ATD therapy patients can be weaned from the medication. continuing thyroid dys- function. Strong recommendation. low-quality evidence. In this study. while in the latter group. There is insufficient information to recommend for or Weak recommendation. prescribing the alter- remission rate has been described in men. One Patients with persistently high TRAb could continue ATD recent case report described a more severe reaction to MMI therapy (and repeat TRAb after an additional 12–18 months) consisting of rash. consideration should be given to end of 12–18 months of MMI therapy.liebertpub. In the Downloaded by 5. of severe PTU-induced hepatotoxicity. The remission Minor cutaneous reactions may be managed with concur- rate may be higher in Europe and Japan. discontinuation of ATD therapy.com at 01/28/18. then discontinued if the TSH and TRAb levels are monitoring of thyroid function every 4–6 months is reason- normal at that time. Another study re- ported that MMI doses of 2. free T4.2. long-term MMI is a rea- anaphylaxis (162). and another group with low or undetectable TRAb. who with doses individually determined. relapse rates are in the patients switched to PTU and 30% of patients switched to 20%–30% range (171. it is reasonable to . cially men). they increase the risk of side effects and are A recent study provided evidence that switching from one not recommended (170). In earlier studies in [E7] Management of allergic reactions the United States. a course of ATDs longer than 18 months (119). but more recent data are not available. If TRAb is negative and thyroid function is normal at the pleting a course of MMI. ATD to the other is safe in the case of minor side effects. TRAb levels might be RECOMMENDATION 22 monitored every 1–2 years. or switching to the analysis shows the remission rate in adults is not improved by other ATD when RAI or surgery are not options. and patients can be seen for follow-up visits every 6–12 Strong recommendation. The remission rate varies considerably between geographical areas. A patient is considered to be in remission if they have had a No recommendation. and tongue and throat swelling or opt for alternate definitive therapy with RAI or surgery. months.172).233 from online.. had persistent thyroid eye disease. Thirty-four percent of 80%–100%. second ATD was 15 mg/d for MMI (range 10–30) and In the group with elevated TRAb. the continuation if TRAb levels become negative over long-term medication should be continued for approximately 12–18 follow-up. MMI treatment for longer than 12–18 months may be considered in patients not in remission who prefer this & RECOMMENDATION 19 approach. younger patients with mild stable but this is not generally recommended because of the risk of disease on a low dose of MMI). patients receiving long-term ATD treatment (n = 124). pean study indicated a 50%–60% remission rate after 5–6 Persistent symptomatic minor side effects of antithyroid years of treatment (163). and total T3 for 1 year after benefits and risks. generally the same type as oc- curred on the original ATD. A recent retrospective analysis compared long-term & RECOMMENDATION 21 outcomes (mean follow-up period of 6–7 years) of patients Measurement of TRAb levels prior to stopping ATD who had relapsed after a course of ATDs. patients should be 45 Graves’ patients treated with 1 g oral calcium carbonate rendered euthyroid prior to the procedure with ATD pre- three times a day for 2 weeks prior to surgery to 38 Graves’ treatment. Recent data suggest that supplementing oral calcium. low-quality evidence. hypothyroid (179). whereas subtotal thyroidectomy may have an 8% patients who are undergoing thyroidectomy should be ren.. patients should be aware that adequately powered to detect a significant difference. Therefore. In addition. KI.05–0. It is also unclear whether it was ATD therapy is chosen. when it is not possible to thyroidectomy hypocalcemia (191–193). and intraoperative blood loss during thyroidectomy patients whose MMI is stopped when TRAb is still positive (181. before surgery in most patients with GD. or postoperative complications the first 6 months. rapid preparation for emergent surgery should be monitored at least annually because relapses can can be facilitated by the use of corticosteroids (184) and occur years later (171). single high-volume institution. Should a relapse occur. glucocorticoids. For personal use only. serum 25-hydroxy vitamin D levels >20 ng/mL (> 8 nmol/L) sidered preoperatively in patients at increased risk for prior to the operating room (190). HYPERTHYROIDISM MANAGEMENT GUIDELINES 1359 discontinue the drug. then at 4. in nontreated Graves’ patients compared to the two other treatment groups. although 5% occurred within the first 2 months in patients with TMNG. existed.to 3-month intervals for tive times. or patient in- Downloaded by 5. none of whom received SSKI preop- one study (167). In a recent series of 162 patients with GD and 102 (171. hypocalcemia. and some patients eventually become potentially cholestyramine (185–187). factors for postoperative hypocalcemia identified preopera- tive vitamin D deficiency as a risk factor for postoperative Strong recommendation. low-quality evidence. scheduling issues. years (194–197). the patient should be adequately treated with b-adrenergic blockade. or thyroid manipulation and may be prevented by ism of GD. A meta-analysis of risk transient or permanent hypoparathyroidism. and there was no comparison group of patients would include another course of MMI.182). in this population. the need for thyroidectomy is urgent. low-quality evidence. Strong recommendation. its findings may not be gen- roidism are recognized. chance of persistence or recurrence of hyperthyroidism at 5 dered euthyroid by MMI before undergoing surgery (180).25– 0. this study mitigates concern when thy- even many years later. supplementing calcitriol for RECOMMENDATION 26 a brief period preoperatively helped reduce transient post- In exceptional circumstances. Total thyroidectomy has a nearly 0% risk of pretreatment with ATDs. If with GD who received SSKI. symptomatic hypocalcemia when patients have preoperative phylactically. thyroid func. In two studies in- & cluded in another meta-analysis.35 mL) of Lugol’s solution (8 mg iodide/drop) or 1–2 drops [F] If thyroidectomy is chosen for treatment of GD.176).liebertpub.com at 01/28/18. If the patient remains euthyroid for more shortages. comparison was made between two different pa- should be counseled about alternatives for therapy.1 mL) of SSKI (50 mg iodide/drop) three times daily how should it be accomplished? mixed in water or juice for 10 days before surgery. The surgeon and anesthesiologist should have ex- total or total thyroidectomy is the procedure of choice. Given that this study was performed at a to contact the treating physician if symptoms of hyperthy. Oltmann et al. However. RAI therapy or surgery can be considered. The most common complications following . & RECOMMENDATION 27 tentially cholestyramine in the immediate preoperative If surgery is chosen as the primary therapy for GD. beneficial because it decreases thyroid blood flow. or when the patient is [F2] The surgical procedure and choice of surgeon allergic to ATDs. Calcitriol supplementation should be con.e. or surgery. as well as GD itself (188). RAI. vi- [F1] Preparation of patients with GD for thyroidectomy tamin D. they are in remission). (0. Technical remarks: KI can be given as 5–7 drops (0. and then every 6–12 months in order to detect preoperative SSKI for GD patients does not impair patient relapses as early as possible. if one agranulocytosis can occur with a second exposure to a drug. near- period. with or without b-adrenergic blockade. than 1 year (i. perience in this situation. patient allergy.178). blood loss. A KI- patients who underwent thyroidectomy without treatment containing preparation should be given in the immediate as well as to 38 euthyroid controls. SSKI.to 6-month intervals for the next between the two groups. thyroid function tolerance. despite an earlier uneventful course of roidectomy is scheduled and SSKI is not given because of therapy (177. patients eralizable. or Lugol’s solution should be used follow-up. (189) compared If surgery is chosen as treatment for GD. This treatment is Technical remarks: In patients with negative TRAb. Thyroid storm may be precipitated by the stress of surgery. and symptomatic hypocalcemia were significantly higher Strong recommendation. thyrotoxic recurrence. or both preoperatively may reduce the risk of & postoperative hypocalcemia due to parathyroid injury or in- RECOMMENDATION 24 creased bone turnover (188).2. rates of biochemical preoperative period. or given pro. no significant differences were observed in opera- tion testing should be monitored at 2.156. which thologies. Thyroidectomy has a high cure rate for the hyperthyroid- anesthesia.233 from online. Strong recommendation. moderate-quality evidence. eratively. The patient should be counseled outcomes (183). and po. Another study that focused on postopera- & RECOMMENDATION 25 tive hypocalcemia after thyroid surgery for thyroid cancer. identified a reduction in postoperative preoperatively and repleted if necessary. re. Whenever possible. vascu- lapses tend to occur relatively later than those that develop in larity. If a patient experiences a relapse in Preoperative KI. Calcium and 25-hydroxy vitamin D should be assessed not hyperthyroidism. the authors concluded that omitting 6 months. render a patient with GD euthyroid prior to thyroidectomy. but more data are needed volume. insufficiency may serve as an underlying cause. For personal use only. A significant association is seen between in. reduced serum phosphate and increased outcome. average complication rates.com at 01/28/18. (0. Vitamin D hypoparathyroidism (which can be transient or permanent).200).000 and 5 in 1.3%– calcium levels. . In patients with se- vere hypocalcemia. Per- of hospital stay. The appropriate dosing of L-thyroxine will Low iPTH levels (<10–15 pg/mL) in the immediate postop. or prophylactic calcium with or without calcitriol started at a daily dose appropriate for the patient’s weight prescribed empirically. The discharged if they are asymptomatic and have stable serum frequency of bleeding necessitating reoperation is 0. tapered by 500 mg of elemental ducted a significant number of thyroidectomies with a low calcium every 2 days. and b-adrenergic blockers should be weaned follow- Following thyroidectomy for GD. Following thyroidectomy for addition.156. calcium and calcitriol therapy can be tapered.000. and com. recurrent or superior laryngeal nerve injury (which can be Patients can be discharged if they are asymptomatic and temporary or permanent).25 vitamin D) supple. complication rates are 51% higher on average eucalcemia. postoperative bleeding. or 1000 mg every 4 days as tolerated. somewhat less. and oral calcium and & RECOMMENDATION 31 calcitriol supplementation administered based on these Following thyroidectomy for GD. Strong recommendation. vary with patient body mass index (219). Once stable and and need for calcium and calcitriol (1. since recovery of the pituitary–thyroid axis is occa- calcium requirement. magnesium repletion (216. alternative strategies ing surgery. and have con. normal levels of serum iPTH quently if clinically indicated. sionally delayed. low-quality evidence. L-thyroxine should be results. 1360 ROSS ET AL.199). may be undertaken for management of calcium levels: Strong recommendation. and the percentage erative setting appear to predict symptomatic hypocalcemia of levothyroxine absorbed from the gut. and permanent RLN injury occurs in <1% (201). serum iPTH levels should be Data show that surgeons who perform more than 25 thy. low-quality evidence.6 lg/kg). The use of ionized calcium measurements are pre- & RECOMMENDATION 28 ferred by some and are helpful if the patient has abnormal If surgery is chosen as the primary therapy for GD. dL (2. ectomy can be achieved using the slope of 6. length before it can be considered for clinical practice (215). However. Patients can be <2%. Intravenous calcium gluconate the patient should be referred to a high-volume thyroid should be readily available and may be administered if pa- surgeon. 1250–2500 mg. when surgery is performed by low-volume surgeons Technical remarks: Calcium supplementation can be ac- (62. measured in the setting of persistent hypocalcemia to deter- roid surgeries per year have superior patient clinical mine if permanent hypoparathyroidism is truly present or and economic outcomes compared to those who perform whether ‘‘bone hunger’’ is ongoing. syndrome. calcium) four times daily. moderate-quality evidence.2. creasing thyroidectomy volume and improved patient serum calcium levels. As the patient reaches fewer. In addition to reduced Downloaded by 5. The surgeon should be thoroughly trained in the procedure. their serum calcium levels corrected for albumin are 8. Postoperative evaluation is generally con- 0. equivalent to 500–1000 mg of elemental have an active practice in thyroid surgery. supplementation based on clinical parameters. specifically. with elderly patients needing Weak recommendation. allowing for safer early discharge (211). near-total or total thyroidectomy are hypocalcemia due to may not predict eucalcemia for GD patients (214).213).5 lg daily and GD in the hands of high-volume thyroid surgeons. levels are falling despite oral repletion. the association is robust and is more pronounced serum potassium levels may be observed in hungry bone with an increasing number of thyroidectomies (198.and 12-hour postoperative calcium levels (204–210). encouraging preliminary results (elimination of symptoms pendently associated with high thyroidectomy surgeon and earlier hospital discharge). Postoperative routine Technical remarks: If TSH was suppressed preoperatively. and cost are reduced when the operation sistent hypocalcemia in the postoperative period should is performed by a surgeon who conducts many thyroid. prompt measurement of serum magnesium and possible ectomies.7% (202).217). TSH should be measured annually or more fre- mentation (212. tients have worsening hypocalcemic symptoms despite oral supplementation and/or their concomitant serum calcium Strong recommendation. levels of serum proteins. supplementation with oral calcium and calcitriol decreases free T4 and TSH should be measured 6–8 weeks postopera- development of hypocalcemic symptoms and intravenous tively. and serum TSH measured 6–8 weeks postoperatively. low-quality evidence. serum calcium with or without intact parathyroid hormone (iPTH) levels can be measured. Following discharge. [F3] Postoperative care & RECOMMENDATION 30 ATD should be stopped at the time of thyroidectomy for & RECOMMENDATION 29 GD. Mortality following thyroidectomy is between 1 ducted 1–2 weeks following discharge with continuation of in 10. complished with oral calcium (usually calcium carbonate.0 mg/ plications related to general anesthesia. teriparatide administration has yielded Improved patient outcome has been shown to be inde.233 from online.8 lg/lb or 1.199. normal. In frequency of complications.liebertpub. Successful prediction of calcium status after total thyroid. calcitriol may be started at a dose of 0.000 (203). the rate of continued for 1–2 weeks (218) and increased or tapered ac- permanent hypoparathyroidism has been determined to be cording to the calcium and/or iPTH level.0 mmol/L) or above and are not falling over a 24-hour period. For personal use only. clinical features to assign patients to the diagnostic cate- Surgery should also be considered for indeterminate cytol. and <25 points mak- considered for fine-needle aspiration because they may have ing thyroid storm unlikely. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1361 & RECOMMENDATION 32 or thyroid storm 2 (TS2) with evidence of systemic de- Communication among different members of the multi. diarrhea. should be communi. Di- RECOMMENDATION 33 agnostic criteria for thyroid storm in patients with severe If a thyroid nodule is discovered in a patient with GD. the thyrotoxicosis were first proposed in 1993 and subsequently nodule should be evaluated and managed according to widely adopted as the BWPS for thyroid storm (26. The decision to disciplinary team is essential. nutritional support. but a tendency toward underdiagnosis coexisting thyroid cancers (222). cated by the surgeon to the patient and the other physicians who will be important in the patient’s postoperative care Life-threatening thyrotoxicosis or thyroid storm is a rare (220). A BWPS ‡45 appears more sensitive than a JTA classifica- roid Association ( JTA) categories of thyroid storm 1 (TS1) tion of TS1 or TS2 in detecting patients with a clinical . Recently. A high index of suspicion for thyroid storm in patients with GD? should be maintained in patients with thyrotoxicosis asso- & ciated with any evidence of systemic decompensation.226. if the patient is noted to have signif. ogy.228). in addition. an additional empiri- a higher probability of being malignant (62). low-quality evidence. roid storm should be used. point total of ‡45 consistent with thyroid storm. disorder characterized by multisystem involvement and Downloaded by 5. inorganic iodide. and coma. as appropriate for an care. agement of surgical hypothyroidism. Strong recommendation.8%) had a diagnosis category of either TS1 or differentiated thyroid cancer (225). If a RAI scan is performed.186. low-quality evidence. & RECOMMENDATION 35 It is important to ensure that adequate communication occurs between the medical team and the treating surgeon to A multimodality treatment approach to patients with thy- ensure that euthyroidism is achievable prior to surgical in. surgery JTA (72). These criteria (Table 6) include hyperpyrexia. If the cyto. the BWPS does palpation and 123I scintigraphy. moderate-quality evidence. Strong recommendation. recently published guidelines regarding thyroid nodules in 226. preoperative vitamin D repletion cooling with acetaminophen and cooling blankets. cally defined diagnostic system has been proposed by the pathology is suspicious or diagnostic of malignancy. should be based on clinical judgment. Wartofsky Point Scale (BWPS) of ‡45 or Japanese Thy. use aggressive therapy in patients with a BWPS of 25–44 tions of care in the pre. ATD therapy. Disease-free survival at 20 years is reported to be 99% Data comparing these two diagnostic systems suggest an after thyroidectomy for GD in patients with small (£1 cm) overall agreement. decompensation. management guidelines for patients with thyroid nodules and and 21 (16. However.224). using the JTA categories of TS1 and TS2. arrhythmias. in the same series.72.6%) had a BWPS ‡45. including calcium supplementation needs and man. Strong recommendation.2. vomiting. euthyroid individuals. Adjunctive use of a sensitive diagnostic In summary.liebertpub. among 125 patients hos- (223. and the presence of an Thyroid cancer occurs in GD with a frequency of 2% or identified precipitant (26).72. tachycardia. pitalized with a clinical diagnosis of compensated thyrotox- Technical remarks: The ATA recently published updated icosis but not in thyroid storm.186. JTA system (226). trasound (which may lead to surgery) can be recommended Importantly. compared to a The use of thyroid ultrasonography in all patients with GD BWPS ‡45 (72.233 from online. TS2. particularly during transi.5 cm should be based on the severity of individual manifestations. moderate-quality evidence. 27 (21. compensation require aggressive therapy. congestive heart failure. individual patient. resuscitation.226. including b-adrenergic block- tervention. and respiratory care and portant intraoperative findings and details of postoperative monitoring in an intensive care unit. delirium. an additional 50 patients (40%) hospi- [H] How should thyroid storm be managed? talized with a clinical diagnosis of thyrotoxicosis without thyroid storm would have been diagnosed as having im- & RECOMMENDATION 34 pending thyroid storm by the BWPS. gories TS1 or TS2.227). which reinforces that a The diagnosis of thyroid storm should be made clinically BWPS in the 25–44 range does not supplant clinical judg- in a severely thyrotoxic patient with evidence of systemic ment in the selection of patients for aggressive therapy. with a evaluated before RAI therapy. agitation. psychosis. as well as nausea. the diagnosis of thyroid storm remains a system should be considered. suggesting similar rates of overdiagnosis with these two systems.156. but these cancers are papillary microcarcinomas with minimal these latter five patients (20%) were not identified using the clinical impact. since most of was ‡45 in 20 patients and 25–44 in the remaining five. ade. Points in the BWPS system are less (221).and postoperative settings. Strong recommendation.227). 25–44 points any nonfunctioning or hypofunctioning nodules should be classified as impending thyroid storm. volume could be performed and surgery scheduled to permit it. mortality rates in the range of 8%–25% in modern series [G] How should thyroid nodules be managed (25. The JTA system uses combinations of similar is advised after normalization of thyroid function with ATDs. hepatic failure. corticosteroid therapy. stupor.com at 01/28/18. In a recent study including 25 has been shown to identify more nodules and cancer than patients with a clinical diagnosis of thyroid storm. further study is required before routine ul. Thyroid nodules larger than 1–1. However. icant vitamin D deficiency. Patients with a Burch– clinical one that is augmented by current diagnostic systems. Im. nausea/vomiting) 101. thyroidectomy.4–39.230). decrease T4-to-T3 conversion.9 10 Moderate (diarrhea.233 from online.9 15 Severe (jaundice) 20 102. For without severe thyrotoxicosis because each of the manifes. ‡40 (30 points). diagnosis of thyroid storm. targeting of each pharmacologically accessible step in thy. Care should be taken with the use of b-adrenergic blocking agents such as propranolol. 38.2. abdominal 10 pain. Printed with permission. ensuring that patients are euthyroid prior to elective surgery. or nonthyroidal surgery in a patient tional therapeutic measures (233. educating patients (72. A based solely on diagnostic category in order to avoid over.9 (25).com at 01/28/18. an early article comparing acute changes in thyroid tations of thyroid storm. Technical remarks: Treatment with inorganic iodine roid hormone production and action (Table 7). glucocorticoid therapy (231). Both plasmapheresis/ Precipitants of thyroid storm in a patient with previously plasma exchange and emergency surgery have been used to compensated thyrotoxicosis include abrupt cessation of treat thyroid storm in patients who respond poorly to tradi- ATDs. coma) 30 ‡140 25 Downloaded by 5. Prevention of thyroid storm involves recognizing and ac- and a number of acute illnesses unrelated to thyroid disease tively avoiding common precipitants. example.2–37. Thyroid storm occasionally occurs following about avoiding abrupt discontinuation of ATD therapy. and observed closely for deterioration. therapy directed against thyroid hormone secretion and Combined with ATDs in patients with severe thyrotoxi- synthesis. with the possible exception of severe hormone level after initiation of PTU or MMI found that T3 hyperpyrexia.0–101.9 20 103.0–103. number of therapeutic measures are specifically intended to treatment and the resultant risk of drug toxicity.9–39. or other acute stressors. may also be seen in the presence of any major levels dropped by approximately 45% in the first 24 hours illness.228). 37.liebertpub.3–38. many of which are also known precipitants of thyroid of PTU therapy compared to an approximately 10%–15% storm (186). Aggressive treatment for thyroid storm involves the early labor and delivery.186. Atrial fibrillation Absent 0 Present 10 Congestive heart failure Precipitant history Absent 0 Status Mild 5 Positive 0 Moderate 10 Negative 10 Severe 20 Scores totaled >45 Thyroid storm Impending storm <25 Storm unlikely a Source: Burch and Wartofsky (26).3 (10).9 5 Absent 0 100. Table 6. patients in this intermediate category should be PTU over MMI (229.9 25 ‡104. 39. decrease after starting MMI (229). At a mini. 1362 ROSS ET AL.0 30 Cardiovascular Central nervous system disturbance Tachycardia (beats per minute) Manifestation 100–109 5 Absent 0 110–119 10 Mild (agitation) 10 120–129 15 Moderate (delirium. and (v) definitive therapy (26). (ii) measures directed against the peripheral action cosis.7 (5).234). these agents result in rapid clinical improvement . 20 extreme lethargy) 130–139 20 Severe (seizure. either system to avoid inappropriate application to patients with selective ability to inhibit type 1 deiodinase (232).8 (15). such as the preferential use of mum.156. but patients with a BWPS of 25– of thyroid hormone at the tissue level.0–99. with unrecognized or inadequately treated thyrotoxicosis. and RAI therapy.0–102. b Celsius 37. psychosis. For personal use only. 38.4 (20).8–38.0–100. (iv) treatment of the precipitating therapy should be based on sound clinical judgment and not event or intercurrent illness. Point Scale for the Diagnosis of Thyroid Storma Criteria Points Criteria Points Thermoregulatory dysfunction Gastrointestinal–hepatic dysfunction Temperature (F)b Manifestation 99. The treatment (SSKI/Lugol’s solution) or oral cholecystographic agents strategy for thyroid storm can be broadly divided into (i) (235) leads to rapid decreases in both T4 and T3 levels. (iii) reversal of sys- 44 represent a group in whom the decision to use aggressive temic decompensation. appropriate. a May be given intravenously. well as patient preference. Most patients were treated with 50 mg centrations by reducing hormone secretion (238. None of the patients had many countries. 11 (25% of all and durable elimination of the hyperthyroid state. and tions exist for TMNG and TA: RAI therapy and thyroid 39% achieved a remission after 7 years (range 2–23 years) surgery.156. Weak recommendation. Among the responders.liebertpub.2. comparable to that of the matched controls treated GD (236. Among 44 Japanese patients who had adverse reactions to ATD and who were treated with KI alone. those who have adverse re- [J] How should overt hyperthyroidism due actions to ATDs. and KI daily. 85% of the patients treated Prior to the introduction of ATDs. side effects. Among 15 nonresponders.237). and the use of KI & in hyperthyroidism complicating pregnancy is discussed in RECOMMENDATION 36 Section [T]. long-term.233 from online. insufficient evidence to assess sion. inhibits its own organification (the Wolff–Chaikoff effect) The inhibitory effects of iodine are greater in patients with (240). Recent studies have sug- thyroidectomy for GD is discussed in Section [F1]. The use of KI prior to couraged the use of iodine in GD. the use gested a potential role for iodine in patients who have had of KI as adjunctive therapy following RAI is discussed in adverse reactions to ATD and who also have a contraindi- Section [D1]. then Blocks new hormone synthesis 250 mg every 4 hours Blocks T4-to-T3 conversion Methimazole 60–80 mg/d Blocks new hormone synthesis Propranolol 60–80 mg every 4 hours Consider invasive monitoring in congestive heart failure patients Blocks T4-to-T3 conversion in high doses Alternate drug: esmolol infusion Iodine (saturated solution 5 drops (0. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1363 Table 7. . However. treating GD is discussed in Section [E1]. the oral radiographic contrast agents patients) escaped the inhibitory effects of iodine and four ipodate and iopanoic acid are not currently available in patients did not respond at all to KI.244). On occa- No recommendation. The decision regarding treatment should take into (243). be treated with RAI therapy or thyroidectomy. Potassium iodide may be of benefit in select patients with hyperthyroidism due to GD. the doses used were between consideration several clinical and demographic factors as 13 and 100 mg and were adjusted depending upon bio. and those who have a contraindication to TMNG or TA be managed? or aversion to RAI therapy (or aversion to repeat RAI therapy) or surgery. Thyroid Storm: Drugs and Doses Drug Dosing Comment a Propylthiouracil 500–1000 mg load. 66% were well Two effective and relatively safe definitive treatment op- controlled for an average of 18 years (range 9–28 years).239). (120). Unfortunately. May block T4-to-T3 conversion then 100 mg every 8 hours Prophylaxis against relative adrenal insufficiency Alternative drug: dexamethasone Downloaded by 5. The goal of therapy is the rapid chemical response. Iodine acutely lowers thyroid hormone con- with MMI (244). For personal use only. iodine was commonly with KI alone had normal thyroid function at 6 months and 1 reported to ameliorate the hyperthyroidism associated with year. Among 20 Japanese pa- [I] Is there a role for iodine as primary therapy tients with mild hyperthyroidism initially treated with KI in the treatment of GD? alone and matched using propensity score analysis with patients treated with MMI alone.com at 01/28/18. Initial free T4 concentration and goiter size did not predict a response to therapy. reports of escape from these beneficial ef- a prior history of RAI exposure (245) suggesting a role for KI fects of iodine (241) as well as reports of iodine-induced in patients who remain hyperthyroid after one dose of RAI hyperthyroidism in patients with nodular goiter (242) dis- and prefer to avoid a second dose. Treatment may be more suitable for & RECOMMENDATION 37 patients with mild hyperthyroidism or a prior history of We suggest that patients with overtly TMNG or TA RAI therapy. the use of KI in combination with MMI for cation or aversion to RAI or surgery (243. moderate-quality evidence. low-dose treatment with MMI may be benefits or risks.25 mL or 250 mg) Do not start until 1 hour after antithyroid drugs of potassium iodide) orally every 6 hours Blocks new hormone synthesis Blocks thyroid hormone release Alternative drug: Lugol’s solution Hydrocortisone 300 mg intravenous load. comorbidities with increased surgical risk and/or OO O x limited life expectancy Patients with previously operated or externally irradiated necks OO O ! Lack of access to a high-volume thyroid surgeon OO O ! Symptoms or signs of compression within the neck O . .com at 01/28/18. OO Large goiter/nodule O . 46% at 10 years.1% in TMNG patients (266).liebertpub. euthyroidism is achieved within pregnancy and there is a lack of studies in this setting. The panel agreed that TMNG and TA with high nodular perthyroidism and a 3%– 5.7% in In a large retrospective series of patients with TMNG pre. . X = contraindication. extranodular parenchymal suppression) due to prior therapy Euthyroidism is achieved within days after surgery (246. the response is 50%–60% by 3 months and 80% by 6 ectomy include the risk of permanent hypoparathyroidism months (246.264. with ATDs. all patients undergoing Technical remarks: Once the diagnosis has been made.257. compared with a 20% risk of incomplete TSH suppression (correlating with only partial the need for retreatment following RAI therapy (246. and costs. Overall. TA and 81. the risk of hypothyroidism and the requirement for undergoing RAI therapy. drawbacks. and 89% rate by 1 year following RAI therapy for TA there are insufficient data to make a recommendation based (225. upon best clinical judgment and for the final decision to incor- For patients with TA. RAI therapy: Advanced patient age. the optimal therapy might be been reported to be as high as 20% (254–256). whereas only 46% of patients undergoing RAI had ment options. the stage for the physician to make a recommendation based activity RAI only decrease in size by 30%–50% (253). after surgical resection (ipsilateral thyroid lobectomy or isth.258). days after surgery. side effects. This discussion sets due in part to the fact that very large goiters treated with high.247).5% risk of recurrent hyperthy. expected speed of improvement in such symptoms (252). OO Thyroid malignancy confirmed or suspected x . The prevalence of hypothyroidism varies considering the theoretical risks associated with surgery or ATD from 2% to 3% following lobectomy for TA.248). For patients with TA who months of a pregnancy. it should be used with caution if at all. progressive and hastened by the presence of antithyroid anti- bodies or a nonsuppressed TSH at the time of treatment Factors that favor a particular modality as treatment (257.249). the success rate of RAI year and 16% at 5 years (251). In a large study of patients with TMNG (<2. with 28% at 5 years. . benefits. ! = cautious use.259. and lower after definitive therapy with RAI or surgery in advance of a planned isthmusectomy in the unique circumstance in which the TA is pregnancy. total thyroidectomy.2.257. The prevalence of hypothyroidism after RAI is on these findings. For patients with TMNG. They observed a faster progression to need for repeat treatment is <1% following near-total and/ hypothyroidism among patients who were older and who had total thyroidectomy (246. the risk of treatment failure is <1% porate the personal values and preferences of the patient.= not usually first line therapy but may be acceptable depending on the clinical circumstances. A small risk of treated with RAI. there have been reports of new-onset GD common among patients under 50 years of age. OO Coexisting hyperparathyroidism requiring surgery . the prevalence of hypothyroidism was 3% at permanent RLN injury exists with surgery for TA (254).257). Most experts prefer to avoid the use of RAI within 6 confined to the thyroid isthmus. significant co- noted a 7. O = acceptable therapy.248. the total thyroidectomy had resolution of these symptoms after treating physician and patient should discuss each of the treat- Downloaded by 5. although rates of therapy (has to be used throughout pregnancy and there is a hypothyroidism after lobectomy for nontoxic nodules have tendency to overtreat the fetus).260). senting with compressive symptoms. TMNG and TA are an uncommon cause of hyperthyroidism in musectomy) (254).233 from online. OO Goiter/nodule with substernal or retrosternal extension O . A study following 684 patients with TA treated for TMNG or TA (Table 8): with RAI reported a progressive increase in overt and sub- clinical hypothyroidism (259). Typically. For personal use only. Clinical Situations That Favor a Particular Modality as Treatment for Toxic Multinodular Goiter or Toxic Adenoma Clinical situations RAI ATD Surgery TMNG Pregnancya x OO / ! O/! Advanced age. The nodule is rarely eradicated in patients with TA However. compared with (up to 4% prevalence) (263) as well as concern for thyroid those over 70 years (61% vs. RAIU and widely suppressed RAIU in the perinodular thy- roidism (254. For patients with TMNG who receive RAI Potential complications following near-total/total thyroid- therapy. Hypothyroidism was more lowing RAI therapy. (definitive hypothyroidism or euthyroidism) is high: 93.156. In a more malignancy (254. OO OO = preferred therapy. which can lead to the need for con- exogenous thyroid hormone therapy is 100% after near-total/ tinued surveillance (225. including the logistics. the risk of treatment failure or and 60% at 20 years. a For women considering a pregnancy within 6 months. There is a 75% response rate by 3 months roid tissue are especially suitable for RAI therapy. Fol- 1 year and 64% at 24 years (250). treatment.0%) or RLN injury (<2. see discussion in Section [T2]. 36% after 16 years).260). However. the prevalence of hypothyroidism was 4% at 1 nonthyroid malignancy (265).247). receive RAI therapy there is a 6%–18% risk of persistent hy.6% prevalence.262). At 1 year. the investigators a. However. prior surgery or scarring in the anterior neck. Table 8. 1364 ROSS ET AL.265) and a very minimal increase in late recent study. morbidity.0%) (261. This outcome may be recovery. RAI therapy: Patients with either TMNG or TA Weak recommendation. allowing the TSH to rise thyroid ATD therapy. but may benefit from b-blockade if symptoms would place a lower value on the certain need for warrant and contraindications do not exist. a. worsening of hyperthyroidism (i.2. Pregnancy is a relative contraindication. low-quality evidence. patients with TMNG choosing surgery receiving RAI. relatively higher value on definitive control of hyper- thyroid symptoms. Surgery: Patients choosing surgery would likely place a Weak recommendation. Weak recommendation. Worsened chemical safety guidelines and used with caution in women hyperthyroidism with increased heart rate and rare cases of Downloaded by 5. slightly prior to RAI administration. which increases the risk relatively higher value on avoidance of exposure to of developing hypothyroidism. how should it be accomplished? latter factor is more important for TMNG than for TA). thyroid after RAI treatment. ATDs: Definite contraindications to ATD therapy in. low-quality evidence.. Therefore. Surgery: Factors weighing against the choice of surgery atrial flutter. b. the third. ment for TMNG or TA: Medical management before RAI therapy should be tai- a.68). the use of b- surgery should only be used in this circumstance when blockers to prevent posttreatment tachyarrhythmias should rapid control of hyperthyroidism is required and ATDs be considered in all patients with TMNG or TA who are older cannot be used. substernal or retrosternal extension. ATDs: Patients choosing ATDs would likely place a contralateral normal thyroid tissue. comorbidities with increased sur. Because RAI treatment of TMNG or TA can cause a RAIU insufficient for therapy. vated to prevent direct RAI treatment of perinodular and c. ATDs: Advanced age. RAI therapy: Definite contraindications to the use of lored to the patient’s risk for complications if hyperthyroid- RAI include pregnancy. supraventricular tachycardia. if volume reduc- radioactivity and on potential surgical and anesthetic tion is a goal. or other debilitating (267–269). patients with TMNG would due to worsening of hyperthyroidism. or lack of access to a high-volume thyroid disease or in the elderly. tions 2 and 38) pretreatment with MMI prior to RAI c. blockade should be considered even in asymptomatic pa- c. planning a pregnancy within 4–6 months. based on the severity of the hyperthyroidism. cancer.5% risk of In addition to b-adrenergic blockade (see Recommenda- preterm labor) (67. elderly patients and and poor candidates for ablative therapy. thyroidectomy should be performed in the latter portion of the second trimester. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1365 small goiter size. it is not without risk (4. therapy for TMNG or TA should be considered in patients clude previous known major adverse reactions to ATDs. and nificant clinical worsening (268). Surgery: Presence of symptoms or signs of compression therapy within the neck. Contraindications to a particular modality as treat. b-adrenergic rection of the thyrotoxic state (252). lactation. also. Young and middle-aged patients with TMNG or TA gen- tivity and a lower value on potential surgical and erally do not require pretreatment with ATDs (MMI) before anesthetic risks. Thyroidectomy is best avoided in the first than 60 years of age and those with cardiovascular disease and third trimesters of pregnancy because of teratogenic or severe hyperthyroidism (31). Although it is & RECOMMENDATION 39 the safest time. such as cardiopulmo. or need for rapid cor. large & RECOMMENDATION 38 goiter size (>80 g). including the elderly and those Factors that may impact patient preference: with cardiovascular disease or severe hyperthyroidism. and comorbid conditions. In susceptible patients with pre-existing cardiac disorders. avoidance of exposure to radioac. choosing RAI therapy would likely place relatively higher value on the avoidance of surgery and attendant & RECOMMENDATION 40 hospitalization or complications arising from either In patients who are at increased risk for complications surgery or anesthesia. lifelong thyroid hormone replacement.233 from online.liebertpub. who are at increased risk for complications due to wors- ening of hyperthyroidism.156. patients with comorbidities). concern for coexisting thyroid cancer. including atrial fibrillation and b.com at 01/28/18. pretreatment with MMI. Optimally. However.5%–5. and [K] If RAI therapy is chosen as treatment for TMNG lack of access to a high-volume thyroid surgeon (the or TA. have been observed in patients treated with RAI include significant comorbidity. RAI treatment may produce sig- surgeon. low-quality evidence. caution should be on the possibility of achieving euthyroidism without taken to avoid RAI therapy when the TSH is normal or ele- hormone replacement.e. [K1] Preparation of patients with TMNG or TA for RAI b. The decision regarding the effects associated with anesthetic agents and increased use of MMI pretreatment is more complex and is discussed risk of fetal loss in the first trimester and preterm labor in below. for either TMNG or nontoxic multinodular goiter (MNG) nary disease. at the expense of an increased risk of hypo- risks and a lower value on the certain need for lifelong thyroidism. For personal use only. resuming ATDs place greater value on the possibility of remaining eu- 3–7 days after RAI administration should be considered. end-stage cancer. individuals unable to comply with radiation patient age. RAIU sufficient to allow therapy. coexisting thyroid ism worsens. tients who are at increased risk for complications due to gical risk or associated with decreased life-expectancy. results in greater volume . transient exacerbation of hyperthyroidism. whereas patients Technical remarks: If an ATD is used in preparation for with TA who choose surgery would place greater value RAI therapy in patients with TMNG or TA. coexisting hyperparathyroidism requiring surgery. Use of a calculated activity allowed for a lower RAI activity to be administered for a The goal of RAI therapy. difficulty ism (272). Both pretreatment with MMI allowing the TSH to human TSH (rhTSH) before RAI therapy in nontoxic MNG rise slightly (270) and the off-label use of rhTSH (271) may or TMNG results in greater thyroid volume reduction but reduce the total activity of RAI needed. Downloaded by 5.com at 01/28/18. it represents an off-label use. and TSH.3– single application to alleviate hyperthyroidism in patients 3.4 MBq) RAI per gram corrected for 24-hour (275). Higher activities of RAI.277). should be carefully assessed and monitored. Similarly. single application to alleviate hyperthyroidism in patients with TA. is the similar efficacy in the cure of hyperthyroidism. & RECOMMENDATION 43 Sufficient activity of RAI should be administered in a Strong recommendation. Radiation safety precautions may with further reduction observed over 24 months.7 Bq) and corrected for 24-hour RAIU (279). confirmed previous reports showing an earlier disappear- ance of hyperthyroidism and earlier appearance of hypothy- Strong recommendation. moderate-quality evidence. is usually roidism in approximately 55% of patients at 3 months and higher than that needed to treat GD. reduction after fixed doses of RAI (270). Strong recommendation. The prevalence continued at 4. the latter in TA. RAI administered to treat TA can be given either as a fixed torically has been estimated to be about 3% (247). roidism with higher RAI activity. However. therapy for TMNG. Technical remarks: Enlargement of the thyroid is very rare ministration before RAI therapy of TMNG is not generally after RAI treatment. and if clinically necessary. which is activity calculated on the basis of nodule size using 150– similar to the 10.2. but they increase the higher hypothyroidism rates than RAI therapy alone (271). result in more rapid resolution of hyperthyroidism and less need for retreatment. patients should be advised recommended as it could possibly exacerbate hyperthyroid. and mainly stimu. More activity of approximately 10–20 mCi (370–740 MBq) or an recently. rhTSH ad. in which patients with nodules <4 cm were administered conjunction with the European Thyroid Association and an average of 13 mCi (481 MBq) and those with larger nod- Associazione Medici Endocrinologi. be managed according to published guidelines regarding thyroid nodules in euthyroid individuals. Thorough assessment of suspicious nodules within a TMNG. In addition. necessitating an increase in 15% (246–248).to 6-week intervals for 6 months. swelling. 1366 ROSS ET AL. The activity of RAI used to treat TMNG. with a higher prevalence among patients total T3. One study showed Follow-up within the first 1–2 months after RAI therapy a 64% prevalence of hypothyroidism 24 years after RAI for TMNG or TA should include an assessment of free T4.156. RAIU (278). or stridor following the administration of RAI. and the Latin American ules an average of 17 mCi (629 MBq). calculated on the basis of goiter size to deliver 150–200 lCi (5. to immediately report any tightening of the neck. such as discomfort. Any compressive symptoms. which develop following RAI [K2] Evaluation of thyroid nodules before RAI therapy therapy. especially in older patients.233 from online. gesting that hypothyroidism develops over time regardless of activity adjustment for nodule size (259). the RAIU 80% of patients at 6 months.274). corticosteroids can be administered.55–7. sug- patients with thyroid nodules (225.5–7. moderate-quality evidence.4 MBq) RAI therapy for TMNG results in resolution of hyperthy- per gram of tissue corrected for 24-hour RAIU. low-quality evidence. the applied activity of RAI.274.5 mCi or 833 MBq) or low (13 mCi or 481 MBq) fixed & RECOMMENDATION 42 activity RAI. risk of hypothyroidism (see prior discussion Section [K1]). or until of hypothyroidism following RAI therapy is increased by the patient becomes hypothyroid and is stable on thyroid normalization or elevation of TSH at the time of treatment hormone replacement. breathing. The prevalence of thyroid cancer in TMNG his. Unless volume reduction is an important goal. with an average failure rate of values for TMNG may be lower. a recent be onerous if high activities of RAI are needed for large meta-analysis indicated that the application of recombinant goiters.276. Biochemical monitoring should be who required more than one treatment (250). This study with TMNG.6% prevalence noted in nontoxic MNG 200 lCi (5. with a calculated activity that was either high Sufficient activity of RAI should be administered in a (180–200 lCi/g or 6. Strong recommendation.7–7. for a total . A randomized [K3] Administration of RAI in the treatment of TMNG or TA trial of 97 patients with TA compared the effects of high (22. & RECOMMENDATION 41 Respiratory compromise in this setting is extremely rare and Nonfunctioning nodules on radionuclide scintigraphy or requires management as any other cause of acute tracheal nodules with suspicious ultrasound characteristics should compression. & RECOMMENDATION 44 but a higher risk for early hypothyroidism. elimination of the hyperthyroid state. showed a progressive Thyroid Society have published management guidelines for increase in hypothyroidism over time in both groups. should be completed before selection of RAI as the treatment of choice.liebertpub. A long-term follow-up study of patients with Technical remarks: Both the ATA and AACE. Goiter volume is decreased by 3 months. For personal use only. lates RAIU in TSH-sensitive perinodular tissues (273).4 Bq) or low (90–100 lCi/g or 3. even when appropriately calculated for the specific [K4] Patient follow-up after RAI therapy for TMNG or TA volume or mass of hyperthyroid tissue. it has been estimated to be as high as 9%. resulting from ATD pretreatment or use of rhTSH and by the presence of antithyroid antibodies (278). or hoarseness. moderate-quality evidence. dysphagia. according to the published guidelines (225. Such patients develop worsening hyperthy. with nodule volume de- & RECOMMENDATION 47 creased by 35% at 3 months and by 45% at 2 years (257). moderate-quality evidence. or isthmusectomy & RECOMMENDATION 46 if the adenoma is in the thyroid isthmus.2. suspicious in appearance or that will necessitate future surveillance. hyperthermia.e. without b-adrenergic blockade. Thyrotoxic crisis during or after the operation. sistent hyperthyroidism due to TMNG or TA. . both circumstances in which a total thyroid- Risks of surgery are increased in the presence of thyro. prevention with large clinical series for TA demonstrated no surgical deaths careful preparation of the patient is of paramount importance and low complication rates (254). low-quality evidence. Because tomies is an independent predictor of patient clinical and some patients with mild hyperthyroidism following RAI economic outcomes (i. normal thyroid function in the majority of patients. hypothyroidism (256. Overall. ment because of underlying persistent autonomous thyroid & function. Long-term total thyroidectomy should be performed. Downloaded by 5. the risk of anesthesia can be lowered further Preoperative iodine therapy is not indicated because of the when cervical block analgesia with sedation is employed by risk of exacerbating the hyperthyroidism (284). moderate-quality evidence. Therefore. For TA. with b-blockers alone. when necessary. In patients who wish (281. studies con- suggested. use of stay. RECOMMENDATION 48 Surgery for TMNG should be performed by a high-volume [K5] Treatment of persistent or recurrent hyperthyroidism thyroid surgeon. how should & RECOMMENDATION 49 it be accomplished? If surgery is chosen as the treatment for TA.283). should be per- If surgery is chosen as treatment for TMNG or TA.282). the risk of permanent vocal cord paralysis or hypoparathy- sary. allowing residual result in extreme hypermetabolism. and an average of 3% by 1 year and 64% by 24 years for TMNG (250). Risk of persistent or recurrent hyperthyroidism ranged from 0% to If surgery is chosen as treatment for TMNG. length of administration will continue to improve over time. volume surgeon is essentially the same as that described in Section [F2] for the choice of surgeon in GD. and total hospital charges) following thyroid surgery MMI with close monitoring may be considered to allow (198. with overt hyperthyroidism should be rendered euthyroid prior to the procedure with MMI pretreatment. retreatment with RAI is shown conflicting results. Preoperative iodine should not be used in this setting.257).291). 75% of patients were no [L2] The surgical procedure and choice of surgeon longer hyperthyroid at 3 months. morbidities. patients with allergy to ATDs can be prepared for bodies preoperatively have a higher risk of postoperative surgery.liebertpub. tachycar. thyroid surgeons and anesthesiologists experienced in this perthyroidism is less severe in patients with TMNG. near-total or 30%. [L] If surgery is chosen. The recommendation for referral to a high- control of the hyperthyroidism until the RAI is effective. following Robust data demonstrate that surgeon volume of thyroidec- treatment with RAI. hypertension. rent or persistent goiter results in a 3. ectomy may be more appropriate. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1367 size reduction of 40% (248).278). so that in approach (294). & RECOMMENDATION 45 TMNG is more common in older patients. coma. a thyroid [L1] Preparation of patients with TMNG or TA for surgery ultrasound should be done to evaluate the entire thyroid gland. Patients with positive antithyroid anti- most cases. with or Strong recommendation. The literature reports a very low risk of anesthesia. Treatment with a subtotal thyroidectomy (286–289). Strong recommendation. or death.233 from online. can be performed with the same low rate of complications as roidism within a few months of RAI therapy.to 10-fold increase in Technical remarks: If thyroid hormone therapy is neces. Data regarding If hyperthyroidism persists beyond 6 months following outcomes following thyroidectomy in elderly patients have RAI therapy for TMNG or TA. following RAI therapy for TMNG or TA Strong recommendation. and higher costs among elderly pa- tients (198). longer Weak recommendation. follow-up studies show a progressive risk of clinical or sub.293). roidism (290. For personal use only. low-quality evidence.com at 01/28/18. can TA while leaving normal thyroid tissue. however. to avoid general anesthesia or who have significant co- related mortality associated with thyroidectomy (254. Data showing equivalent outcomes among the Technical remarks: In severe or refractory cases of per. in-hospital complications. Recurrence can be avoided in TMNG if a near-total or total GD might develop after RAI for TMNG in up to 4% of thyroidectomy is performed initially (285). surgery may be considered.156. One dia. A preoperative thyroid ultrasound is useful because it will detect the presence of contralateral nodularity that is Strong recommendation. Usually hy. elderly usually have come from high-volume centers (292). Reoperation for recur- additional RAI is effective.199.. An ipsilateral thyroid lobectomy. In selected patients with minimal response 3 ducted at the population level have demonstrated signifi- months after therapy additional RAI may be considered. moderate-quality evidence. clinical hypothyroidism of about 8% by 1 year and 60% by 20 years for TA (259). This procedure patients (280). patients formed for isolated TAs. depending on the series (246–248. the dose required may be less than full replace. cantly higher rates of postoperative complications. Lobectomy removes the toxicosis. length of hospital stay. recurrent hyperthyroidism following inadequate surgery ment in GD. (every 3 months) monitoring is recommended initially.156. Additionally. and calcium and ing lobectomy than low-volume surgeons. [L4] Treatment of persistent or recurrent disease following Weak recommendation. it remains a factor to consider in deciding between surgery and RAI therapy. For personal use only. and then Long-term MMI treatment of TMNG or TA might be in- annually. prolonged (lifelong) ATD therapy may be the best choice for some individuals with & RECOMMENDATION 53 limited life expectancy and increased surgical risk. remains following thyroidec. cium levels do not need to be obtained. low-quality evidence. the results. low-quality evidence. . the patient’s weight (0.291). & RECOMMENDATION 56 with elderly patients needing somewhat less. the heart rate. hypocalcemia. While surgeon experience in the setting of TA is of some.8 lg/lb or 1. and RLN injury. Technical remarks: After lobectomy for TA.com at 01/28/18. However. low-dose ATD treatment in doses and subsequently adjusted based on thyroid function nodular hyperthyroidism can be difficult to regulate. how should the therapy be managed? blockade should be tapered should take into account the preoperative free T4 concentration. TSH and estimated free T4 volume surgeon. and the ATDs do not induce remission in patients with nodular week-long half-life of T4. in patients who are not good Strong recommendation. low-quality evidence. Thy- are not statistically significant (198). but the differences calcitriol supplements do not need to be administered. 1368 ROSS ET AL. it is essential that the surgery be performed by a high-volume thyroid surgeon. [M] If ATDs are chosen as treatment of TMNG Technical remarks: The duration over which b-adrenergic or TA. patients following thyroid lobectomy (295).liebertpub. moderate-quality evidence. High. Strong recommendation. continued RECOMMENDATION 51 monitoring in an asymptomatic patient for 4–6 months Following thyroidectomy for TMNG. TSH levels may remain in the high normal range & for 3–6 months following lobectomy. which may demonstrate autonomous pro- duction of thyroid hormone. As remedial thyroid surgery MMI should be stopped at the time of surgery for TMNG comes at significantly increased risk of hypoparathyroidism or TA. what less importance than in TMNG. patients taking thyroid disease. in relapse (262. thyroid remnant. thyroid hormone residents of nursing homes or other care facilities where replacement should be started at a dose appropriate for compliance with radiation safety regulations may be difficult. Severe or prolonged preoperative hyperthy. and oral cal- recovery of normal thyroid function (296). Therefore. it should be avoided. depending on the degree of preoperative preparation [L3] Postoperative care with ATDs. low-quality evidence. therefore. Following lobectomy for TA. roidism and larger size and greater vascularity of the goiter (more typically seen in GD) increase the risk of postoperative Strong recommendation. TSH should be measured every 1–2 months until stable. High-volume surgeons roid hormone replacement is required in about 15%–20% of may be more comfortable with performing the thyroid lobec. and in patients who prefer this option. Technical remarks: The appropriate dosing of L-thyroxine will vary with patient body mass index (219). serum cal- volume thyroid surgeons tend to have better outcomes follow.233 from online. low-quality evidence. in favor of continued following surgery. Strong recommendation. If a significant Weak recommendation. Persistent or recurrent hyperthyroidism following surgery is & RECOMMENDATION 52 indicative of inadequate surgery.6 lg/kg) and age. including Following thyroidectomy for TMNG. immediate postoperative doses of thyroid hormone the euthyroid state in TMNG or TA patients is usually low should be initiated at somewhat less than full replacement (5–10 mg/d). Beta-adrenergic blockade should be slowly dis.2. low-quality evidence. surgery for TMNG or TA Technical remarks: The management of hypocalcemia & RECOMMENDATION 55 following thyroidectomy for TMNG is essentially the same RAI therapy should be used for retreatment of persistent or as that described in Section [F3] for postoperative manage. If this is not an option. & RECOMMENDATION 50 & RECOMMENDATION 54 We suggest that surgery for TA be performed by a high. dicated in some elderly or otherwise ill patients with limited life expectancy. cium and calcitriol supplementation administered based on Downloaded by 5. candidates for surgery or ablative therapy. levels may have been suppressed or normal prior to lobec- tomy.297). Because long-term. Technical remarks: The required dose of MMI to restore tomy. frequent testing. Serum TSH tomy under cervical block analgesia with sedation. levels should be obtained 4–6 weeks after surgery and thyroid hormone supplementation started if there is a Weak recommendation. persistent rise in TSH above the reference range. discontinuation of treatment results higher doses of b-blockers will require a longer taper. serum calcium with postoperatively is reasonable. RAI therapy (290. for TMNG or TA. if possible. since there may be eventual or without iPTH levels should be measured. moderate-quality evidence. but 20% of nodules re.liebertpub. and they decline nontoxic nodules (306). cure. A retro. clinical of both TA and TMNG. MMI. Ninety-three percent of patients achieved a in only a minority of pediatric patients with GD. RFA was associated with an 85% with advancing age (314. depending on size of and surgery can be performed by a high-volume thyroid the area to be ablated) into the TA or autonomous area of a surgeon.2% had siderably among institutions and practitioners. In determining had a >50% reduction in nodule size (299). its use has been limited due to pain Because some children will go into remission. If remission is not achieved after a Both radiofrequency ablation (RFA) and laser therapy course of therapy with ATDs. The use of RFA should be limited [N] Is there a role for ethanol or radiofrequency to centers where clinicians have received adequate training in ablation in the management of TA or TMNG? the technique. or refused. In one study. after which testing frequency can be decreased. All patients complained of pain children with GD and subsequent thyroid cancer (313). . only MMI should be used. RAI. & RECOMMENDATION 57 Alternative therapies such as ethanol or radiofrequency [O] How should GD be managed in children ablation of TA and TMNG can be considered in select and adolescents? patients in whom RAI. finitive therapy is required. contraindicated. with GD will eventually require either RAI or surgery. size (301). 78% of cases achieved a functional status. A meta-analysis considered. United States is limited. the child is too young for RAI. all nodules regressed. Advocates of RFA neoplasm in children. Al- mained autonomous on scintigraphy. and 92% children treated with ATDs for many years. and likelihood of remission should be considered.312). paranodular fibrosis interfering with subsequent When ATDs are used in children. were fewer complications (RLN injury or hypoparathyroid. it is during the procedure. and for children between 5 and 10 years of injection under sonographic guidance to treat TA and TMNG age if the calculated RAI administered activity is <10 mCi come largely from Europe (299–301). and there was no recurrent hy. but there were no complications (305). there apy and cancer risk in Section [P3] below. or surgery may [N2] Radiofrequency ablation be considered initially. However. RAI benefits and risks. surgery (302). sions at 2-week intervals (299). MMI associated with extravasation of the ethanol to extranodular therapy for 1 year is still considered first-line treatment for locations. RAI or surgery should be have been used to treat thyroid nodules. and toxic necrosis of the larynx and adjacent except in exceptional circumstances. In another study the initial treatment approach. and expertise in these procedures is available. and 3. The treatment of pediatric patients with GD varies con- 2. additional data are needed to determine the success at correcting hyperthyroidism in pa- tients with TA and TMNG. esthesia. jection of ethanol (average dose 10 mL. surgery or RAI. the average patient required four ses.com at 01/28/18. owing primarily to concern over cancer risks (311. Alternatively. RAI therapy in children [N1] Ethanol ablation is acceptable if the activity is >150 lCi/g (5. and other adverse effects. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1369 especially in the elderly (298). If clinical character- skin (303). For personal use only. spective multicenter report of RFA for TA in 44 patients Properly administered. known that risks of thyroid cancer after external irradiation A Korean study compared the use of RFA to surgery for are highest in children <5 years of age. see discussion of RAI ther- reduction in nodule size. In comparison. the patient’s age. surgery.55 MBq/g) of Reports that support the efficacy of percutaneous ethanol thyroid tissue. Strong recommendation. RAI is widely used in with a mean follow-up of 20 months (305). and 18% of patients though there are sparse clinical data relating to RAI use in remained hyperthyroid. TMNG. surgery or RAI (307).2. However. MMI therapy may be continued demonstrated that RFA resulted in larger reductions in nodule long term or until the child is considered old enough for size with fewer sessions than laser therapy (304). It is important complications including transient RLN palsy. including functional cure (no uptake on RAI scintigraphy). insufficient evidence to assess Children with GD should be treated with MMI. abscess. Patient and parent values and preferences should also be perthyroidism during 5 years of follow-up (300). An 82% reduction children but still viewed as controversial by some practitioners in nodule volume was achieved. Ethanol strongly considered when choosing one of the three treatment ablation also has been used following RAI to reduce nodule modalities. until stability has been argue that it preserves normal thyroid function compared to documented. therapy. A typical protocol involves the in. RAI is an effective treatment for GD utilized an 18-gauge electrode under ultrasound guidance in the pediatric population (308–310). or thyroidectomy.4% refused further treatment because of pain. or to recognize that lasting remission after ATD therapy occurs hematoma (299). One hundred twenty-five patients with TA were followed for an average of 5 years. Thyroidectomy should be chosen when de- Downloaded by 5. activities of RAI used with contemporary therapy are not ism: 6% for surgery and 1% for RFA). the majority of pediatric patients transient thyrotoxicosis.156. Experience in the (<370 MBq). However.315). the cost was similar to surgery. istics suggest a low chance of remission at initial presen- tation (see Section [P6] below). permanent ipsilateral facial dys. which have included most children. and long-term ATD are [O1] General approach inappropriate. & RECOMMENDATION 58 No recommendation.233 from online. and no patient who known to be associated with an increased risk of thyroid received RFA became hypothyroid (306). RAI therapy should be avoided in very young children (<5 years). MMI doses can 0. doses that function tests and transaminase levels has not been shown to are 50%–100% higher than the above can be used. rather than hepatocellular (326). after addressing compliance. toxicity in children. because meta-analyses suggest a higher prevalence be administered with the child closely monitored clinically of adverse events using block-and-replace regimens than for signs of hepatic dysfunction including nausea. blockade and SSKI (50 mg iodide/drop) 3–7 drops (0. but it is counseled about this possibility and nutrition consultation associated with a higher complication rate in children than in considered if excessive weight gain occurs. At least one case of chole- who are inadequately controlled on one dose of MMI. low-quality evidence.com at 01/28/18.0 mg/d. associated with PTU use (326. even in patients with severe hy. how should the therapy be managed? patients have. For personal use only.5–5.323). RAI therapy is indicated in young children. arthralgias. Weak recommendation. as a baseline. be considered. Patients of Asian origin seem to be more susceptible to . Prior to surgery it is desirable to have the (112). transplantation has been necessary in some patients taking perthyroidism. PTU is associated with an unacceptable risk of hepato- Strong recommendation. or pharyngitis. and the ne- children. complete blood cell count.2. Pediatric patients and their caretakers should be informed preferably with experience in conducting thyroidectomies in of side effects of ATD preferably in writing. 10–20 mg/d. noting that 32 (22 and show that compliance with once-daily MMI therapy is adult and 10 pediatric) cases of serious liver injury have been superior to multiple daily doses of PTU (83% vs. 5–10 mg/d.liebertpub.5 mg/kg daily. biochemical monitoring of liver severe clinical or biochemical hyperthyroidism. and abdominal pain. we suggest that pediatric in children. nal pain.’’ performed within a few weeks. liver can be given once daily. become hypothyroid after a minimal dose increase.2–0. MMI should be used in children who are treated with ATD therapy. Alternatively. 5– Because PTU-induced liver injury is of rapid onset and can 10 years.233 from online. if the patient is not too within the first 3 months of treatment (128). failure (327). a short course of PTU use can rotoxicosis (free T4 > 7 ng/dL [0. and alkaline phosphatase. although this occurs far less frequently than with weight can persist (325). cessity of stopping the medication immediately and in- Technical remarks: There may be circumstances in which forming their physician if they develop pruritic rash.15– When thyroid hormone levels normalize. then static jaundice has been reported in a child (326). adults (316–318). with a recommendation to avoid PTU use in children was issued. and a liver pro- in children file including bilirubin. the FDA issued a black box divided doses. data in adults show ATD therapy is necessary in a patient who has developed a only modest benefit of higher doses and only in severe thy. treated with ATDs.g. it dren. minor toxic reaction to MMI. However. likely due to higher doses of MMI malaise. PTU can Technical remarks: MMI comes in 5. Excessive weight gain within 6 months of MMI may also be associated with ANCA-positive vascu- treatment is seen in children treated for GD.328). the MMI (e. 53%) (319). tablet doses: infants.1–1. Parents and patients should be PTU. Although many practitioners give MMI in PTU (326).327). fatigue. transaminases. One approach is are unaware of any published cases of PTU-related liver to prescribe the following whole tablet or quarter to half. & RECOMMENDATION 59 Downloaded by 5. [P1] Initiation of ATD therapy for the treatment of GD including WBC count with differential. low-quality evidence. a short course of PTU may However. we range from 0. anorexia. nausea. candidate.156. Alternatively. Thyroidectomy should be performed in those children who are too young for RAI. with a risk of liver failure of 1 in 2000– 4000 children taking the medication (326.35 mL) by mouth. moderate-quality evidence. abdomi- child has developed a reaction to ATDs. However.0 mg/kg daily (320–322). provided that & RECOMMENDATION 60 surgery can be performed by a high-volume thyroid surgeon. proper surgical ex. acolic stools or dark urine. and lower doses of MMI at treatment onset. we suggest that this practice be avoided. some physicians elect not to reduce free T4 level or total T4 and total T3 levels in the normal or the MMI dose and add levothyroxine to make the patient subnormal range. and 10–18 years. dose titration (119. pertise is not available.554 pmol/L]) (115). such as when a jaundice. high doses of thyrotoxic (and the hyperthyroidism is due to GD). and the gain in litis (329). Be. & RECOMMENDATION 61 [P] If ATDs are chosen as initial management of GD Prior to initiating ATD therapy. there have been reports of hepatocellular toxicity with MMI Practitioners should also monitor the weight of children in adults (134). When surgery is the planned therapy and cause most side effects of MMI are dose-related and occur MMI cannot be administered. For this reason. or the patient is not a suitable surgical Strong recommendation. 1–5 years. a practice referred to as ‘‘block and replace. >30 mg for an adolescent or adult) should rarely hyperthyroid state can be controlled before surgery with b- be used initially. fever. With be rapidly progressive. but this tends to be milder and is typically cholestatic may have utility in rare patients.. 2. When Although there may be a tendency to use higher rather than neither prompt surgery nor RAI therapy are options. Furthermore. given three times a day for 10 days be reduced by 50% or more to maintain a euthyroid state before surgery. 1. be useful in surveillance for PTU-related liver injury.or 10-mg tablets and cause fulminant hepatic necrosis that may be fatal. and the dose-related complications associated with MMI MMI may also be associated with hepatotoxicity in chil- (324).25 mg/d. since the The MMI dose typically used is 0. Thyroidectomy is an effective treatment for GD. if the surgery cannot be euthyroid. 1370 ROSS ET AL. data in adults do not support a need for such warning regarding the use of PTU (328). In the case of a serious ad- ATDs should be stopped immediately and WBC counts verse reaction to an ATD. but monary and/or renal involvement. with the patient monitored for aminase levels (obtained in symptomatic patients or found exacerbation of asthma. Discontinuation of the it is estimated to be very low. the risks of MMI-related cholestasis and hepato. pharyngitis. mouth recommended. low-quality evidence. Agranulocytosis has been reported in about 0. 5–10 mg/d) (128.g. nausea. In general. After discontinuing the drug. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1371 this adverse reaction. and transaminases) should be moni- After initiation of MMI therapy. PTU may be considered for of starting therapy. and who are dren who experience anorexia. 95% of the time it occurs in the first 100 days of Technical remarks: It is advisable to provide information therapy (128. But if it is used.335). muscle weakness.337). liver function tests (i.2.324. rashes. purpuric skin lesions. incidentally) reach 2–3 times the upper limit of normal. Depending on the severity of hyperthyroidism [P5] Management of allergic reactions in children taking and the MMI dose. In special include allergic reactions. or neuropsychologi- pain or abdominal bloating. counts may occasionally detect early agranulocytosis. and then every 2–3 months once the dose is stabilized. For this rea- ism in children son.336. Data on the polyarthritis. cardio-selective b-blockers such as atenolol or metoprolol Technical remarks: PTU should be discontinued if trans- can be used cautiously (331). again at 4–6 weeks. arthralgias. (e. and occasionally pul. . which is generally symptomatic.e. discussion regarding the utility of obtaining complete blood Technical remarks: While routine monitoring of WBC count and liver profile before initiating MMI therapy. or malaise.com at 01/28/18. When agranulocytosis de- pressive therapy may be needed.3% of adult Typical manifestations of ANCA-positive vasculitis are patients taking MMI or PTU (128. bilirubin. RAI MMI is associated with minor adverse events that may affect or surgery should be considered because the risks of PTU are up to 20% of children (332). and it can develop after months to years cellular injury appear to be much less than those observed in of therapy.324. propranolol. thyroid function tests tored weekly until there is evidence of resolution. sudden onset. thyroid storm and ATD therapy is needed in a child with a Side effects from MMI usually occur within the first 3 months serious adverse reaction to MMI. In those with reactive airway disease. the dose is no evidence of resolution. measuring WBC counts during febrile illnesses and at the onset of pharyngitis has become the standard approach for & RECOMMENDATION 62 monitoring. In this setting. In short-term therapy to control hyperthyroidism.156. MMI-related adverse events considered greater than the risks of RAI or surgery. Downloaded by 5. it is not recommended because of the rarity of the condition and its [P2] Symptomatic management of Graves’ hyperthyroid.. Strong recommendation. myalgias. low-quality evidence. but adverse events can occur later. tremor. sores.334). velops. Although MMI has a better overall safety profile than PTU. agranulocytosis is drug generally results in resolution of the symptoms. positivity on treatment but remain asymptomatic (330).335). but not limited to. but in dose dependent with MMI and rarely occurs at low doses more severe cases. light- showing significant symptoms. referral to a gastroenterologist or adjusted if indicated. TSH) are obtained at 2–6 weeks. jaundice. If children develop serious adverse reactions to MMI. cal changes. joint pain. and arthralgias circumstances.liebertpub. low-quality evidence. The overall rate of side effects from concerning side effects of ATDs to the patient or caretaker in ATDs (both major and minor) in children has been reported writing. or malaise. low-quality evidence. colored stool or dark urine. it can take several months for elevated MMI thyroid hormone levels to fall into the normal range. metopro- lol. glucocorticoids or other immunosup.334. & RECOMMENDATION 64 Strong recommendation. as well as hypothyroidism from overtreatment. the medication should be stopped immediately and In children in whom the diagnosis of Graves’ hyperthy- liver function and hepatocellular integrity assessed in chil- roidism is strongly suspected or confirmed. children should be managed by concurrent antihistamine & treatment or cessation of the medication and changing to RECOMMENDATION 63 therapy with RAI or surgery. or other b-blockers leads to a decrease in heart rate and Strong recommendation.324. rash..233 from online. including. symptoms of GD. especially [P4] Monitoring of children taking PTU those with heart rates in excess of 100 beats per minute. Many PTU-treated patients also develop ANCA adults (326). PTU should not be used in children. families should be informed of the risks of PTU. and thyroid function tests are measured hepatologist is warranted. For personal use only. If there is (free T4.335). right upper quadrant tachycardia. prescribing the other ATD is not measured in children who develop fever. Beta-adrenergic blockade is recommended for children experiencing symptoms of hyperthyroidism. See Recommendation 14 Technical remarks for a to be 6%–35% (332. total T3. children. treatment with atenolol. in which the patient appears to be at risk for (333. pruritus. In adults. Strong recommendation. [P3] Monitoring of children taking MMI alkaline phosphatase. prevalence of agranulocytosis in children are unavailable. Serum TSH may remain suppressed for several months after starting & RECOMMENDATION 65 therapy and is therefore not a good parameter for monitoring Persistent minor cutaneous reactions to MMI therapy in therapy early in the course. respectively (343).8 years). depending on the age of the child. in cohorts from Germany therapy (344) and Denmark (345). whereas the time mission has occurred. these data suggest that treatment for longer dren and those with high initial thyroid hormone levels were periods is also reasonable. Prospective studies in longer in children than in adults (346).4% [Q] If RAI is chosen as treatment for GD in children. 46. a recent pro- years of ATDs is low if the thyroid gland is large (more than spective report from France shows that with prolonged ATD 2. Therefore. 1138 children. if prepubertal children (median age. show that the vast majority of patients treated studies have suggested that the chance of remission after 2 for GD with ATDs do not go into remission. >20 lg/dL (260 nmol/L) or free T4 >5 ng/dL (60 pmol/L) . 20%–30%. serum TRAb levels are above normal on ther. this approach ATDs are used for 1–2 years. In another report. Persistence of GD in children is correlated with the persis- Strong recommendation. 23% (339. remission oc. 15%. In another Strong recommendation. after 2 years. study reported remission rates of 20%.1 years (340). suggesting higher likelihood. Remission was achieved in 10 patients (28%) doses after 1–2 years to determine if a spontaneous re. in a retrospective analysis from Japan of sidered. [P6] Duration of MMI therapy in children with GD curred in only 17% of prepubertal children treated 5.8 years. The use of MMI in this group of children that likelihood of remission could best be predicted by the was associated with a very low rate of medication side effects initial response to ATDs. years with MMI. Importantly. Alternatively. Whereas monitoring of adults show that if remission does not occur after 12–18 TRAb levels while on ATDs has been shown to be useful in months of therapy. of larger cohorts of pediatric patients with GD treated with if children are tolerating ATD therapy. least 1 or 2 years of therapy. with achievement of euthyroid state (337). 37%.2% relapsed. remission rates of up to 49% could be achieved. or it may be continued until the child to remission tended to be longer in the small proportion of and caretakers are ready to consider definitive therapy.3 to 24. adverse reactions typi- after a mean of 3. large cohort of 184 medically treated children. 21 pubertal. adult patients for predicting the likelihood of remission or re- curring with prolonged therapy (338). and after 4 years. 45%. and 34. The prevalence of adverse events associated with MMI and PTU were 21. [Q1] Preparation of pediatric patients with GD for RAI especially with longer follow-up. 271 underwent surgery or RAI.2. with similar rates among the three groups. longer time. other studies ered for treatment with RAI or thyroidectomy. and 18. A recent study found that TRAb levels nor- malized after 24 months in only 18% of pediatric patients on ATDs (346). 8.2% cally occur within the first few months of therapy. Of 120 pediatric patients treated the child not considered to be a candidate for either surgery with ATDs at one center. This not Caucasian. should be reevaluated every 6–12 months and when transi- and after 4–10 years. after 1 year of therapy with ATDs. Of as adverse drug effects do not occur and the hyperthyroid the 639 patients of the 723 who discontinued ATD treatment state is controlled. there is a lower chance of remission oc.8%. including recent large database year after cessation of therapy (333. it appears that TRAb levels persist troversy and warrants further study. achieved remission.342).liebertpub. and 49% apy. & RECOMMENDATION 68 sponsiveness to ATDs.339. and 144 dropped out. moderate-quality evidence.337). Data also suggest that age-related differences exist in re. One prospective study suggested with ATDs (337). In children. in the prospective studies (334. it may be tapered in those children requiring low children (336). after 2 years. RAI or surgery should be con- More recently.5 times normal size for age). or free T4 levels are substantially elevated at diagnosis after 4. tence of TRAb. when lapse of GD after stopping the medication (172). as long as side effects to medi- also found to be less likely to achieve remission within 2 years cation do not occur. the child is young (<12 years) or use.8 – 1.340). extended periods. Individuals on prolonged ATD therapy (>2 years) 25% were in remission. ATDs may be used for ATDs for extended periods have not revealed similar remis. If remission is not achieved upon stopping MMI after at 14%. after 4 years. who went into remission eventually relapsed (333). 50 pmol/L) (339). compared with 30% of pubertal individuals treated & RECOMMENDATION 66 2. whereas many practitioners will treat for 1–2 within 3 months. For personal use only. 10% were in remission.156.8 years (range 0. remission rates are generally has yet to be validated in children.342). In one study that compared outcomes We suggest that children with GD having total T4 levels of of 32 prepubertal and 68 pubertal children. 6. needed. 1372 ROSS ET AL. as long ment. 6 years) (336).com at 01/28/18. 37%.9 – 2.339. other recent studies of long-term remission rates of pediatric GD treated with ATDs are very low (<20%). low-quality evidence. after 3 years. 723 were continued on long-term ATD treat- practitioners can continue MMI for extended periods. or RAI. Thus. Although two decades ago it Pediatric patients with GD who are not in remission fol- was suggested that 25% of children with GD go into remission lowing at least 1–2 years of MMI therapy should be consid- with every 2 years of continued treatment (341). Younger chil. 20%. with remission defined as being euthyroid for 1 Whereas most studies. Downloaded by 5. the course of GD was If MMI is chosen as the first-line treatment for GD in compared in 7 prepubertal.233 from online. how should it be accomplished? In comparison. 26%. As already noted. after 1 year of therapy with ATDs. There were no data showing that there was nor- The issue of how long ATDs should be used in children malization of TRAb levels when patients were on ATDs for a before considering either RAI or surgery is a topic of con. 30% of the children tioning to adulthood. Alternatively. and 10 years follow-up of 154 children treated (>4 ng/dL. This approach may be especially useful for sion rates (333. Retrospective reports (343). Remission rates in children treated with ATDs for longer & RECOMMENDATION 67 than 2 years have been reported. and 12 postpubertal children. be treated with RAI. Because of an increased risk of thyroid 1110 Bq/g) (314. rather than euthyroidism. ultrasonography is recommended In one study.96 MBq/g may be possible to use lower administered activities of RAI.09–30 lCi/g or 3. apart from the lifelong hypothyroidism that is the goal of therapy. point to the increased rates of thyroid cancer and thyroid Strong recommendation. T4. directly when assessing risks of RAI therapy. Therefore.315.33– development (351). Physicians at some centers administer a fixed dose of about While there are several studies of this issue in adults treated 15 mCi RAI to all children (350).357). Although the frequency of short-term worsening of hy- this is very infrequent. However. RAI treatment. particularly in in childhood or adolescence.352. Hypothyroidism typi- start ATDs after treatment with RAI (80). and a tendency exists to un. With large glands (50–80 g). and the mean administered activity of RAI to the tential advantage of calculated versus fixed dosing is that it thyroid was 88 Gy (approximately 80 lCi/g or 2. in adults. *0. Because TSH levels may remain placed on b-blockers (if not already taking) until total T4 and/ suppressed for several months after correction of the hyper- or free T4 levels normalize following RAI therapy. whereas others calculate the with RAI for GD (see Section [D2]). To assess thyroid size. ATDs can complicate assessment of posttreat- [Q3] Side effects of RAI therapy in children ment hypothyroidism since it could be the result of the MMI Side effects of RAI therapy in children are uncommon rather than the RAI therapy. 6000 children who received RAI for the purpose of diag- derestimate the size of the gland (and thereby administer nostic scanning (359). RECOMMENDATION 69 If residual thyroid tissue remains in young children after If RAI therapy is chosen as treatment for GD in children. tears. seldom required in children (309. Increased thyroid cancer rates also were not seen in with very large goiters is high. perthyroidism following pretreatment with ATD therapy is Technical remarks: RAI is excreted by saliva.348). Although some physicians re- setting for assessing hypothyroidism. normalize before proceeding with RAI treatment. similar outcomes populations (360). . nodules observed in young children exposed to radiation from nuclear fallout at Hiroshima or after the Chernobyl The goal of RAI therapy for GD is to induce hypothy.233 from online. equivalent). nuclear reactor explosion. thyroid cancer rates were hypothyroidism (312). partially irradiated thyroid neoplasia is greatest with exposure to low-level thyroid tissue that is at increased risk for thyroid neoplasm external radiation (0. years. which thyroid state. an activity known to be associated with thyroid especially when uptake is high and the thyroid is small. it can in children be treated effectively with acetaminophen or nonsteroidal & anti-inflammatory agents for 24–48 hours (310. the setting of a large gland.339. a theoretical risk of development of thyroid sufficient RAI should be administered in a single dose to cancer exists. the medication should be stopped 2– After RAI therapy. RAI not increased among 3000 children exposed to RAI from activities of 131I 200–300 lCi/g (7. Detractors of the use of RAI therapy in children render the patient hypothyroid. administered activities used to treat GD. It is also important ation in children (314. urine. and/or free T4 levels should be 3 days before treatment (349).liebertpub.com at 01/28/18. T3. and stool.350). not with the higher nodules and cancer associated with low-level thyroid irradi. One po. It is therefore important after receiving RAI (347.349). Weak recommendation.352–354) and poor remission rates to note that iodine deficiency and exposure to radionuclides with low-administered activities of RAI (88–90). TSH determinations may not be useful in this generally takes 2–4 months. While there are reports that hyperthyroidism can re- lapse in pediatric patients rendered hypothyroid with RAI.55 MBq/g) rather of thyroid cancer in young children after the Chernobyl than smaller activities of RAI be administered to achieve reactor explosion (315). that patients and families be informed of and adhere to local Technical remarks: When children receiving MMI are to radiation safety recommendations following RAI therapy. other than RAI may have contributed to the increased risk portant that RAI activities >150 lCi (>5.S.156. Significant radioactivity is retained severe hyperthyroidism who have developed thyroid storm within the thyroid for several days. because lower adminis. Thyroid hormone at which time levothyroxine should be prescribed. Notably.350).55 MBq/g) of RAI have an in- larger than 80 g. calculated activities in children. The administered activity of RAI to patients (358). per- not known. these data do not apply roidism.354. neoplasia and below that recommended for treatment of GD. There are no data comparing outcomes of fixed versus exposed to RAI below 20 years of age in Swedish and U. hypothyroidism rates are about 95% (88. At that time patients should be obtained every month. moderate-quality evidence. Fewer than 10% of children complain of mild ten- [Q2] Administration of RAI in the treatment of GD derness over the thyroid in the first week after therapy.1 MBq/g) may be the Hanford nuclear reactor site in an iodine-replete region needed (349).2.4–11. insufficient RAI activities to these patients) (90). No evidence suggests that children or adults treated for GD surgery may be preferable to RAI in children with goiters with more than 150 lCi/g (5.349. levels in children begin to fall within the first week following Downloaded by 5. The risk of tered activities of RAI result in residual. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1373 who are to receive RAI therapy be pretreated with MMI Calculated dosing also will help assure that an adequate ad- and b-adrenergic blockade until total T4 and/or free T4 ministered activity is given. this practice is cally develops by 2–3 months posttreatment (333. low-quality evidence. it is im. For personal use only. 349). RAI therapy.1–25 Gy.310.55 MBq/g) are ad- ministered. When RAI activities >150 lCi/g (>5. creased risk of thyroid cancer directly attributable to RAI. there are rare reports of pediatric patients with spiration. an analysis was carried out of 602 individuals (355). The average follow-up period was 10 have been reported with the two approaches (356). few studies have fo- activity from estimation or direct measurement of gland size cused on populations exposed to RAI for the treatment of GD and 123I uptake (349). total or quired activity for treatment is <10 mCi (<370 MBq). Using phantom modeling.02 a Using a gross average of dying from a spontaneous cancer of 25% data analysis by Dr.. year outcomes of 116 patients. low-quality evidence.000 per Per 100.com at 01/28/18. Two cases of thyroid cancer were reported compared to 0. 1374 ROSS ET AL.96 1 4.156. we recommend that RAI therapy be avoided in very young children (<5 years) and that RAI be considered in & RECOMMENDATION 71 those children between 5 and 10 years of age when the re- If surgery is chosen as therapy for GD in children.05–0. If a small risk exists. important to emphasize that these recommendations are based on theoretical concerns and further direct study of this issue is Strong recommendation.000 per Lifetime cancer Age at (rem or rad) 0.85 12. It is important to note that the sample size was small. A KI-containing estimated that at 0. Table 9. of RAI administered (361).0 852 1347 1100 85 135 110 3958 3. low-level radiation exposure as re- lated to age. Theoretical Projections of Cancer Incidence or Cancer Mortality Related to 131I Therapy for Hyperthyroidism as Related to Age Lifetime attributable risk of cancer mortality 131 Total-body I dose Per 100. 1. Based on cancer risk projections from Technical remarks: MMI is typically given for 1–2 months estimated whole-body. Patrick Zanzonico. Effects on the de.1 mL) three times daily for risk of malignancies in very young children treated with RAI.56 1. low-level radiation exposure (362). it has been rendered euthyroid with the use of MMI.90) and surgery lignancies.02 60 0. of Ionizing Radiation Committee VII analysis of acute.5 603 914 759 60 91 76 1024 1. quired. the statistical power was inadequate to address this issue fully.9 1.1 167 1099 1770 1435 110 177 143 23.0 1099 1770 1435 110 177 143 9898 9.884 23. and adult- preparation should be given in the immediate preoperative hood. period. At present.97 1.1 Gy or Sv rad or rem risk for 15 mCi 131I Relative lifetime exposure cancer risk for (year) Per mCi Per 15 mCi Males Females Average Males Females Average Cases per 100. KI (50 mg iodide/drop) can be given as 1–2 drops (i. No patient developed thyroid cancer or in young individuals.000 % 15 mCi 131I a 0 11.6 69.90. it is theoretically possible that there may be a low in preparation for thyroidectomy. Thyroidectomy is the preferred treatment for GD in mortality for a large population of treated children can be young children (<5 years) when definitive therapy is re- estimated (Table 9). 10. NY). 0. and in children. thyroid surgeon.2. moderate-quality evidence. likely exceeding the number of near-total or total thyroidectomy is the recommended pro- cedure (363).85 rem (1 rem = 0.8 712 1104 908 71 110 91 1975 1. and 0. weighed against the known risks inherent in thyroidectomy or velopment of nonthyroid cancers were not examined. 10 days before surgery. a sample size of more than also may be preferable for these patients. long-term studies of children treated with RAI for GD have not revealed an increased risk of nonthyroid ma. tional RAI therapy and radiation exposure. Thus.45 21.1 needed. the theoretical lifetime attributable risk of all-cancer incidence and all-cancer Surgery is an acceptable form of therapy for GD in chil- dren.9 1. how should it be accomplished? the same absolute activities of RAI will result in more radi- [R1] Preparation of children with GD for thyroidectomy ation exposure to a young child than to an adolescent or adult (361). we do not have dosimetry information & RECOMMENDATION 70 regarding RAI use in children with GD to assess total body Children with GD undergoing thyroidectomy should be exposure in children.03 40 0. such treated children. and 15 years of age. The patients ranged in age at treatment roid size and uptake and not arbitrarily reduced because of age from 3 to 19 years.85 12. prolonged ATD use when choosing among the three different The pediatric study with the longest follow-up reported 36.233 from online.e.9 13. It is near-total thyroidectomy should be performed.8 319 409 364 32 41 36 464 0. respective total-body radiation activities are 11. SSKI can be mixed in juice or milk. 0. In individuals with large thyroid glands (>80 g). Based on the Biological Effects Strong recommendation.46 1.liebertpub. the response to RAI may be poor (88.96 1. For personal use only. 1. When performed. . Attempts to minimize the RAI activity leukemia. 10.1. treated with RAI between The activity of RAI administered should be based on thy- 1953 and 1973 (100).45.16 10 1. [R] If thyroidectomy is chosen as treatment for GD Total-body radiation dose after RAI varies with age.04 20 0.6. 2. 4. thus.000 children who were treated at <10 years of age would be needed to identify the risk.1 Sv) per millicurie Downloaded by 5.8 511 762 637 51 76 64 812 0. treatment options for GD in the pediatric age group. and the surgery can be performed by a high-volume To date.85 12.08 15 0. Memorial Sloan Kettering Cancer Center (New York.81 1.4.4 36.8 377 507 442 38 51 44 564 0. 5.40 5 2.02 1. The theoretical risks of RAI use must therefore be cases expected over that period of time. There was no increase in the rate of spontaneous will result in undertreatment and the possible need for addi- abortion or in the number of congenital anomalies in offspring. A multidisciplinary health-care team that includes ranges. the need solitary autonomously functioning nodules and various forms for postoperative calcium infusions is markedly reduced. subjects without known thy. while others indicate no relation (384–387). the risk was greater in black non-Hispanic Americans. concluded that SH confers a [S] How should subclinical hyperthyroidism 24% increased risk of overall mortality (388).391). all of ratios of 1. older subjects (381. and pituitary/hypothalamic disease. some otherwise healthy older persons may have low serum Some of these studies. some of whom may have subjects with TSH levels <0. including the meta-analyses.370–377).379–383). Some other. younger children also appear to serum TSH at 3–6 months. Data from one center suggest that if calcitriol is started ously received ATD therapy. with and no evidence of thyroid or pituitary disease. and iodine intake. smaller studies representative sample of U. the latter of which would be more strictly leading to reduction in the length of stay (318). creased left ventricular mass and impaired left ventricular veloped a normal TSH when first checked at some time function in SH that improve with treatment (393–396).4 mU/L) (375–377).392). be managed? [S1] Prevalence and causes of SH Cardiovascular disease. with for the development of heart failure (381. A recent large study of 26. pooled from 10 cohorts and providing greater power.1–0.707 The prevalence of subclinical hyperthyroidism (SH) in an people followed for 12 years reported increased cardiovas- adult population depends on age.388.5 lg. although other roid disease. two studies have shown impaired glucose tolerance . also examined nonfatal cardiovascular events in SH.377). level data from 52. and 1. Mechanistic correlates of these findings include in- one study (372). In be at higher risk for transient hypoparathyroidism than ado- clinical series. length of follow-up. Lim- has pediatric experience is indicated. Since SH is a mild form of hyperthyroidism.392) and those with lower TSH levels thyroidism and 5%–12% reversion to normal TSH levels. with higher rates in younger than in older children document that SH is a persistent problem by repeating the (316. have TSH levels.com at 01/28/18. it is important to adults.liebertpub. In the individual-level which need to be ruled out before the diagnosis of SH can be meta-analysis. drug effects. suggesting an similar increased risks (383.383). Some studies report increased overall mor- thyroid surgery expertise is not available. especially annualized rates of 0. A large number of recent studies have (316). for GD in children should be performed by experienced thyroid surgeons comes from reports of institutional ex- Overall mortality. Further support for the notion that thyroidectomy elucidated these effects.674 ential diagnosis of an isolated low or suppressed TSH level participants (388).4 mU/L) (365). The most recent altered set point of the pituitary–thyroid axis (368.4 mU/L. 0. Both analyses concluded that SH confers includes exogenous thyroid hormone use. or the presence of car- TSH level.1 mU/L compared to those with slightly low TSH levels without thyroid disease (365).29 (388). Finally. age children.01–0. moderate-quality evidence. In within 5 years (mean time to repeat TSH. low-normal serum levels of free T4 and total T3.233 from online. In addition. rather than low volume thyroid surgeons. especially in older persons (367. one of study-level data of 17 co- levels in women and older subjects (366. established in a patient with an isolated low or suppressed pre-existing cardiovascular disease. In patients at high risk of complications from SH. 51. Postoperatively. rather than a TMNG as the cause of SH may be more likely to spontaneously remit (367. The calcitriol termed ‘‘subclinical thyrotoxicosis. it is not sur- who do not have extensive current experience in this proce- prising that deleterious effects seen in overt hyperthyroidism dure than when performed by high-volume thyroid surgeons might also occur in SH. especially for young itations of some of these studies include sample sizes.386). However. The differ. Similar 384.7% had suppressed TSH levels (<0.318). A recent meta-analysis of individual- geons and anesthesiologists is optimal. lescents or adults (316.674 participants. complication rates are 2-fold higher when [S2] Clinical significance of SH thyroidectomy is performed by pediatric or general surgeons Downloaded by 5. but detectable (0. TMNG is the most common cause of SH. In circumstances in which local pediatric variable results. with higher examined this question. prior to initiating therapy.S.25 or 0. addition. horts (390) and the other of individual-level data in 52.1 mU/L). especially older with GD to a high-volume thyroid surgery center that also subjects. For all other patients.318).388. twice daily). Other unusual causes include 3 days before surgery (0. Pro. TSH and free T4 should be repeated Surgical complication rates are higher in children than in within 2–6 weeks. There have been two recent meta-analyses that rates have been reported in studies from Europe.369). In (392). nonthyroidal ill.381.52 (390) and 1. relative risks did not differ based on age.01 mU/L).5%–7% progression to overt hyper.’’ is then weaned over the first two postoperative weeks (318).390. which is more prevalent in cium infusions appears to occur more frequently than in in younger persons and is also common in patients who previ- adults.376. Several longitudinal studies have ex- perience showing low complication rates at high-volume amined correlations between SH and overall mortality. The second most Postoperative hypocalcemia requiring intravenous cal- common cause of SH is GD. data indicate that SH subjects appear to be at particular risk The natural history of SH is variable (367. TSH levels 0. In a cular mortality with SH (389). have reached similar conclusions (374.364). 13 months). In addition. an increased risk of cardiovascular mortality.378). Patients with GD Strong recommendation. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1375 & RECOMMENDATION 72 gression from SH to overt hyperthyroidism appears more Thyroidectomy in children should be performed by high. with hazard ness.367). mean serum TSH levels are lower in diovascular risk factors. sex. smaller studies have failed to find a correlation (380.156. referral of a child tality rates in SH subjects (374.2% of patients had spontaneously de. likely if the TSH is suppressed (<0. sex. of thyroiditis. and diagnosis of SH by a single pediatric endocrinologists and experienced thyroid sur- TSH measurement.8% had low TSH levels (<0. with centers (318. For personal use only.2. decline [reviewed by Gan and Pearce (418). In 2004.2 frac- first reported a 2. (421–423). possibly trials that have shown improvement in bone mineral density because other causes predominate with age. heart disease or osteopo- SH patients is not clear.9 fractures per 1000 Arrhythmias are another concern in SH. or subjects who progress to overt hyperthyroidism over time (391). showed an increase in muscle mass and muscle strength in Taken together. Approximately equal numbers roid women). and in subjects with therapy of SH with ATDs or RAI (414–417). which improve with treatment of SH mance in men only (425). Risks were further in- SH subjects over age 60 years in 1994. were seen for men. while the fourth rate variability. and possible subsequent stroke. and in individuals with hyperthyroid symptoms. humerus.9% of with small uncontrolled studies that have shown improve- subjects with a normal TSH level (407).8-fold increased risk of atrial fibrillation in tures per 1000 person-years) (413). 0.384. as well as older. and muscle strength (393–396. In the largest study to date (586. Most studies of endogenous Strong recommendation. Additionally. but not in men or premenopausal women (406). 1376 ROSS ET AL. A further population-based study found no conclusions regarding this issue can be reached. nonrandomized for atrial fibrillation occurred in younger subjects. Whether younger patients should be treated for the same preventive indications is less [S3] When to treat SH clear. versus no associations.405.420)]. none of these 13. studies by others (419. Osteoporosis and fractures. When TSH is persistently <0. Thus.5% of subjects with a low TSH level had experienced at studies included a control arm. frequency of premature atrial and ventricular beats. compared to 6.405). Another uncontrolled study (393.44 mU/L. There that SH increased the risk for stroke in subjects over age appears to be no correlation between SH and depression 50 years with a hazard ratio of 3. the highest relative risk lower in younger subjects.1 mU/L compared to 0. ther than thyroid hormone administration. The most Weak recommendation. suggesting this may cluded that SH subjects had significantly elevated hazard contribute to increased cardiovascular risk (397. However. the absolute risks of these events are very low in recommended in all individuals ‡65 years of age. decreased heart 423–425).4 vs. treatment of creased fracture risk. the evidence rests only least one major osteoporotic fracture. heart rate and the not found increased fracture rates in SH subjects (410–412). especially for [confidence intervals 1. or bisphosphonates. median follow-up of 12. with more recent years (relative risk of 1.1 years) con.39 (402). A number of population-based studies SH should be considered in asymptomatic individuals have reported that certain groups of subjects with SH <65 years of age without the risk factors listed in Re- have increased fracture rates. moderate-quality evidence. postmenopausal women (408).5 years.com at 01/28/18. although a re. patients with SH. ra- larly atrial fibrillation. while women 65 years and older had incidence of studies report significant associations between SH and rates of 22. The most recent data provide evidence that relative risks of cardiovascular mortality and atrial fibrillation are & RECOMMENDATION 73 elevated in younger. ratios of 1. 11.3 events per 1000 person. Four studies have investigated Complementing these epidemiologic studies. Risk increased with du.5 years). 4.2.394. recent and by far the largest individual study to date (231. forearm. found a correlation between SH and lower physical perfor- tricular premature beats.7 per 1000 person-years (relative risk of 1. commendation 73. a panel of experts determined that the . There are smaller. in postmenopausal women who are not on estrogens these cases. Mood and cognition. since few intervention fractures combined (hip. and decreased insulin sensitivity in SH.233 from online.13 studies showing benefit have been performed.014–1. Clinical judgement should be used in rosis. at this time.156. and treatment decisions individualized.404. atrial fibrillation. and fractures. Three could find no correlation. it is not clear that this finding translates to in- When TSH is persistently <0.400.liebertpub. investigations whether SH is associated with self-reported functional ca- of smaller numbers of subjects with SH have revealed in. so the risk/benefit ratio of treating younger tients with cardiac risk factors. SH show decreased bone mineral density in postmenopausal women. Physical functioning. 417. clinically important endpoints such as cardiovascular events. Downloaded by 5.401). moderate-quality evidence. & RECOMMENDATION 74 However. and if SH was due to endogenous etiologies. although absolute fracture rates were followed for a median of 5. including all adults (407). Other studies have ments in cardiac structure and function. Risks did not differ 391. For personal use only. Therefore. cent meta-analysis of stroke risk in SH found insufficient number of events to draw definitive conclusions (403). and increased frequency of atrial and ven.398).1– studies have confirmed that the risk of arrhythmias.36 for hip fractures (6 vs.414– (70.28 for any fractures (14.1 mU/L. spine) of 1. such that after a median follow-up of 7.26].460 people when stratified by age.27 measures of cognitive decline and the development of de- compared to age-matched euthyroid women). treatment of SH is However.355 subjects) reported a hazard rate for all major osteoporotic Treatment of SH is controversial.1 mU/L. in pa- younger patients. for example. creased heart rate at rest and during exercise. A large body of literature has in- jects.388. Sawin et al. Similar trends mentia. with lower TSH levels (401). absolute incidence rates of atrial fibrillation were much lower in younger sub. women under the age of 65 years had atrial vestigated possible correlations between SH and cognitive fibrillation incidence rates of 2. (399) person-years) and 1. these data provide a strong argument for middle-aged women with SH after treatment with RAI or the treatment of SH in older subjects to avoid dysrhythmias thyroidectomy (426). particu. pacity or objective measures of physical functioning (420.426). is increased in SH (381. ration of SH.298 participants. men (409). and subsequent creased if TSH levels were <0. bone A recent participant-level meta-analysis of 13 cohorts mineral density.89 compared to age-matched euthy. drugs. Some of these studies re. For personal use only. but which are largely concordant with recommendations pre. is provided (Table 10). Strong recommendation.1 mU/L and risks for overall and cardiovascular-specific mortality. measurement over a 3.1 mU/L. pecially in older patients when TMNG is a frequent cause of normal TSH or treatment. younger subjects should be monitored at regular 6.429). treatment marized above.4 mU/L is the lower limit of the normal range. thyroid function before RAI therapy. moderate-quality evidence. effectively ruling out transient thyroiditis as a sider when deciding whether or not to treat a patient with SH cause. low-quality evidence. [S4] How to treat SH & RECOMMENDATION 75 When TSH is persistently below the lower limit of normal & RECOMMENDATION 77 but ‡0. Given the low risk of exacerbation (71). effectively ruling out transient thy- persistent TSH <0. The European Thyroid demiologic evidence and patient risk factors. and guidelines for the treatment of subclinical hyperthyroidism.1 mU/L on repeated transient. treatment decisions TSH persistently within this range should be diagnosed be- must be individualized. RAI in patients with GD and SH. GD. and vertebral fractures in older women (408). therefore treatment should be considered for older subjects. osteoporosis. Although this study did not include Technical remarks: A TSH level between 0. In roiditis as a cause. it is not recommended for subjects <65 years of age. or symptoms of hyperthyroidism. the treatment should be based on the individuals ‡65 years of age and in patients with cardiac etiology of the thyroid dysfunction and follow the same disease. and is most commonly TMNG. Subclinical Hyperthyroidism: When to Treat Factor TSH (<0. not on estrogens or bisphosphonates Yes Consider treating Hyperthyroid symptoms Yes Consider treating Age <65 years.to 6-month period is considered to be and other causes of low TSH. Therefore. The task force Association recently reviewed these data and published felt that the limited data are stronger for older subjects.com at 01/28/18.1 mU/L. One uncontrolled study of middle-aged hyperthyroidism.1 mU/L) TSH (0. the task force elected to recommend L on repeated measurement over a 3. treatment of SH patients younger than 65 years of age with considered persistent. & RECOMMENDATION 76 When TSH is persistently below the lower limit of nor- mal but ‡0.1–0. the risks of ATD therapy may outweigh A number of the epidemiologic studies listed above per. even in decisions must be individualized. The thyroid disorder underlying SH should be diag. treatment of SH should be considered in If SH is to be treated. However. heart failure (381).to 12-month There are insufficient data for or against treatment of SH in intervals.156. es- without further investigation of the etiology of the sub.1 and 0. Emerging epidemiologic data since then on of individuals with serum TSH levels between 0. nosed.233 from online. a trial of b-adrenergic blockers may be useful patients showed an improvement in hyperthyroid symptoms to determine whether symptomatic therapy might suffice. How- altered skeletal health with a suppressed level of TSH de.liebertpub. based on the limited epi- the absence of interventional data. Weak recommendation.1 mU/L (380. (427). RAI is appropriate for most patients. There are no data to inform whether elderly patients with SH would benefit from pretreatment with ATDs to normalize Weak recommendation.1 mU/L and hyperthyroid symptoms. any potential small benefit. and treatment should be considered if the TSH per- younger persons or premenopausal women with SH and serum sistently decreases to <0. low-quality evidence.4 mU/L)a Age >65 years Yes Consider treating Age <65 years with comorbidities Heart disease Yes Consider treating Osteoporosis Yes Consider treating Menopausal. This recommendation was based primarily on the and atrial fibrillation in all subjects (401) or in older subjects studies showing an increased rate of atrial fibrillation and (384). have strengthened this argument. sented here (428). sum. fore considering treatment to avoid treating patients with Technical remarks: A TSH level of <0.1 mU/L. A summary of factors to con- persistent. The thyroid disorder underlying SH with the absence of symptoms or risk factors.4 mU/L). In patients with symptoms of TSH <0. with therapy (393).1 mU/L. asymptomatic Consider treating Observe a Where 0.2.1–0. cardiovascular events (391). HYPERTHYROIDISM MANAGEMENT GUIDELINES 1377 evidence for benefit was sufficient to warrant therapy of SH ported increased risks of overall mortality in older subjects in older individuals whose serum TSH level was <0. especially in younger Table 10. asymptomatic patients under age 65 The treatment of SH is similar to the treatment of overt without cardiac disease or osteoporosis can be observed hyperthyroidism. SH. .4 mU/ younger individuals. or TA. functional disorders related to acute illness. principles as outlined for the treatment of overt hyper- thyroidism. formed analyses for SH subjects with low but detectable TSH A course of ATD therapy is a reasonable alternative to levels (generally 0. ever. there are no interventional data for or against treatment scribed above. the lower limit of the reference range.to 6-month period is Downloaded by 5. 233 from online. we T4’’ values may be useful for diagnosing hyperthyroidism in will address only the most common issues related to hyper- pregnancy.liebertpub. Based on the slightly higher (5%–10%) than nonpregnancy values. Since the rationale for therapy of SH Free T4 and T3 measured in an equilibrium dialysate or an is to a large degree preventive. In the vast majority of patients. given to utilizing total T4 and T3 levels and multiply the nonpregnancy reference range by 1. Technical remarks: Some patients with SH due to mild GD The decrease in TSH in early pregnancy is the result of may remit spontaneously and may be followed without stimulation of the normal thyroid by high levels of serum therapy with frequent (every 3–6 months) monitoring of human chorionic gonadotropin (hCG) (440). and the principal more than 25 years (445). so that continued obser. tive age range (432). with serum free T4 with mild disease (109). however. the lower therapy of SH limit of normal for TSH in the nonpregnant population can be The goal of therapy for SH is to render the patient euthy. patients. as pre- [T1] Diagnosis of hyperthyroidism in pregnancy viously discussed. and these with SH due to GD. In these patients.5%–1. However. GD is the most com- The diagnosis of hyperthyroidism in pregnancy should be mon cause of hyperthyroidism during pregnancy (431. made using serum TSH values. the disease is based assays for free T4 and free T3 has been questioned for caused by a primary thyroid abnormality. hyperthyroidism). 1378 ROSS ET AL. tectable in serum. and the cause can be identified by obstetrical investigation. surgery is also an option. and either total T4 and T3 nodular thyroid disease is less common.2% of them are treated with Total T4 and T3 values may be combined with a T3 uptake test ATD during pregnancy (433. few end points can be used to ultrafiltrate of serum around week 10 of pregnancy may be document that therapy has been successful.444). Hyperthyroidism with total T4 and T3 reference ranges increasing to 1. In one longitudinal study. For personal use only. especially that of atrial fibrillation gestational weeks 9–13. A small subset of elderly patients with changes may be assay dependent. decrease occurs during pregnancy. & Excluding patients with TSH suppression or gestational RECOMMENDATION 78 thyrotoxicosis during the first trimester. The diagnosis of hyperthyroidism in pregnancy can be Technical remarks: The reliability of automated analog- challenging. pending full guidelines on thyroid ranges should be established for each individual test and disease and pregnancy that are currently being updated by the assay used.5 caused by a hCG-producing molar pregnancy or a chorio- times above the nonpregnant range by the second and third carcinoma presents with a diffuse hyperactive thyroid similar trimester or free T4 and total T3 estimations with trimester- to GD. In these guidelines. total T4 and T3 values remain stable roidism that does not require therapy (431). of a normal-term pregnancy (435.5 after week 16. or within the reference range (SH). Serum TSH levels may half of the normal range. used (441).436). low-quality evidence.434). TSH. but these estimates are currently . below). roid with a normal TSH. the major end point is a TSH level within the age. than expected. During the second half of pregnancy. since remission rates are highest in persons finding will be a suppressed serum TSH. In select patients with SH due to TMNG ally the biochemical findings that develop may correspond to who have compressive symptoms. consideration should be ATA. An understanding of pregnancy-related variations in thy- function can be followed without intervention. women may develop a suppressed serum TSH (437–439). it is reasonable to follow sponding to the period of high serum hCG and low serum hyperthyroid symptoms or bone density (393. and 0.com at 01/28/18. or in whom there is con.156. and late third trimester adjusted reference range. but without eye signs and without TRAb being de- specific normal reference ranges. overt thyrotoxicosis (gestational hyperthyroidism discussed cern for malignancy. low serum TSH levels with normal free T4 Downloaded by 5. Treatment with b-adrenergic be below the nonpregnant reference range in the first half blockade may be sufficient to control the cardiovascular. Such ‘‘free T4 index’’ or ‘‘TBG-adjusted course and outcome of pregnancy. persistently low TSH and no evidence of true thyroid dys. serum hCG will be higher Strong recommendation. during which a subset of pregnant (430).2.0% of women in the reproduc- ranges over the remaining weeks of pregnancy (442. Both the thyrotoxicosis or measurements of TBG to adjust for pregnancy-associated and therapy of the disease may seriously complicate the variations in TBG. primarily due to increases in TBG. and especially so in related morbidity from SH. In early week over the 10-week period of gestation weeks 7–16 (443).414–416). the increase in T4 and T3 reference ranges were ob- Normal pregnancy leads to changes in thyroid physiology served to occur at a rate of 5% of nonpregnant values per that are reflected by altered thyroid function testing. corre- original indication for treatment. trimester-specific normal reference thyroidism in pregnancy. (or total T4) and/or T3 levels above the reference range (overt Some patients with SH due to GD may remit spontane. From normal or slightly elevated levels. reference values are 10%–30% below nonpregnancy values (442). In the absence of these.443). and occasion- thyroid function. point is that reference ranges for thyroid function tests are vation without therapy is reasonable for younger patients different during different stages of pregnancy. these changes can mimic biochemical hyperthy- After this 50% increase.1%–0. A key ously without therapy (375–377). pregnancy. a gradual otherwise. (or total T4) in early pregnancy do not indicate disease in need [S5] End points to be assessed to determine effective of therapy.5 times above nonpregnancy due to GD occurs in 0. [T] How should hyperthyroidism in pregnancy Serum total T4 and T3 increase in parallel in early preg- be managed? nancy. especially roid function tests is important in making the diagnosis when the serum free T4 and total T3 levels are in the lower of hyperthyroidism in pregnancy. Hyperthyroidism with reference range limits 1. is not associated with adverse pregnancy outcomes (449). See remarks to Recommendation 92. See remarks under Recommendations 89 and 93. samples for thyroid function is caused by the high serum hCG of early pregnancy (440). Gestational hyperthyroidism is a generally asymp- for each trimester of pregnancy should be used and provided tomatic. a trial of b-blocker therapy [propranolol or me- etiology and whether it warrants treatment. this indicates a risk of delayed neonatal hyperthyroidism (see remarks to Recommendations 87 and 94).448). and use Downloaded by 5. ure to gain weight. but not atenolol (450. In many clinics. Technical remarks: There is no evidence that treatment of nancy should not be treated with ATD therapy. again at 18–22 weeks of gestationd a See remarks under Recommendations 83. this may indicate a need to reduce or stop ATD therapy to avoid fetal hypothyroidism. excessive sweating. The disorder lacks the characteristics of GD (431) and assays are not locally available. if elevated. d If the mother has undergone some type of thyroid ablation (RAI or surgery) for GD and TRAb is high. If thyroidectomy is required. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1379 widely used because of their suitability for large-scale auto. it is optimally performed during the second trimester GD diagnosed and Currently taking Switch to PTU or withdraw ATD therapy as soon as treated prior to methimazole pregnancy is confirmed with early testinga pregnancy Measure TRAb initially and. and signs of hyperthyroidism.com at 01/28/18. Because The two most common types of biochemical hyperthy- pregnancy may influence results of these assays from different roidism that occur during pregnancy are gestational hyper- manufacturers in different ways. heat intolerance. again at 18–22 weeksb and 30–34 weeksc of gestation In remission after Perform thyroid function testing to confirm stopping antithyroid euthyroidism. . of ATD in early pregnancy has been associated with an in- Strong recommendation. Summary of Recommendations Concerning Management of Graves’ Disease Causing Overt Hyperthyroidism in Pregnancy Timing of diagnosis Specific circumstances Recommendations a GD diagnosed Diagnosed during Begin PTU during pregnancy first trimester Measure TRAb at diagnosis and. Transient hCG-mediated TSH suppression in early preg. they tachycardia beyond that normally associated with pregnancy.. crease in risk of birth defects. and 87 for discussion regarding switching from one ATD to the other during pregnancy or withdrawing from therapy. Complicated cases of gesta- tional hyperthyroidism should be referred to medical centers & RECOMMENDATION 79 with expertise in treating these patients. gestational hyperthyroidism with ATDs is beneficial. and self-limiting biochemical hyperthyroidism by the manufacturer (447. Table 11.liebertpub. attention should focus on determining the disease. are the standard of measurement in pregnancy. In these patients. mild.451)] for this transient dis- that indicate the presence of hyperthyroidism include fail. low-quality evidence. It testing in pregnancy should be sent to a reference laboratory. If trimester-specific references that may be observed in the first trimester of normal preg- for free T4 (and free T3) are not provided. c If the ATD-treated mother has high TRAb values in late pregnancy. repeat at 18–22 weeksb and again at 30–34 weeksc of gestation (all depending on week of diagnosis). In the case of very symptomatic pregnant woman. and matic analyses within short time periods. hCG-mediated transient TSH suppression) spuriously low results (446). if elevated. repeat at 18–22 weeksb and again at 30–34 weeksc of gestation If thyroidectomy is required. it is optimally performed during the second trimester Diagnosed after Begin MMIa first trimester Measure TRAb at diagnosis and. physical examination and repeat thyroid function tests at intervals of Once the diagnosis of hyperthyroidism is made in a 3–4 weeks is recommended. and total T4 (and T3) nancy. More severe degrees of gestational hyperthyroidism are as- [T2] Management of hyperthyroidism in pregnancy sociated with hyperemesis.2. Clinical features troprolol. and some assays may give thyroidism (e. order may be considered. method-specific reference ranges and GD. if elevated.g. affected women may develop Table 11 provides a summary of the recommendations biochemically overt hyperthyroidism and clinical symptoms concerning management of GD during pregnancy. TRAb measurement medication not necessary Previous treatment Measure TRAb initially during the first with RAI or surgery trimester and. evaluate fetus carefully for hyperthyroidism in second half of pregnancy and adjust or begin ATD therapy accordingly. For personal use only. if elevated. b If a TRAb-positive woman becomes TRAb-negative during pregnancy. 86.156.233 from online. In women who develop hyperthyroidism during their re- ATDs have much the same effect on thyroid function in productive age range. taking ATDs have demonstrated normal thyroid function and including the presence of GO and/or serum TRAb in a hy. Defects that may be perthyroidism may have negative effects on the pregnancy observed in 2%–4% of exposed children (462. pregnancy in one study (456). Strong recommendation. sidered in remission after such previous therapy have a small Therapy with propranolol (e.liebertpub. Similar to other teratogenic drugs (468) the used when ATD therapy is started after the first trimester. MMI should be control children. and no major side effects have been proves in the second half of pregnancy (458). esophageal. small A small increase in incidence of GD was found in early doses of b-adrenergic blocking agents are in general useful to Downloaded by 5. Approximately 5% of patients with newly because of the potential for hepatic necrosis in either mother diagnosed Graves’ hyperthyroidism are TRAb negative in or child from maternal PTU use. PTU generally has been preferred in pregnancy because of concerns about well-documented teratogenicity associated Both maternal thyroid dysfunction and therapy of the hy- with MMI.S. an increase in the rate of birth defects (2. low-quality evidence. T4 and T3 cross the placenta only in limited amounts suggest that women should postpone pregnancy until they because of degradation by high deiodinase type 3 activities in have become euthyroid with therapy. & RECOMMENDATION 80 normalities than children exposed to other drugs (467). However. typical facial features of MMI-exposed children range may not guarantee euthyroidism for more than a short have been described in case reports (464). These agents GD drops dramatically in late pregnancy (456). cosis from postpartum destructive thyroiditis) during the postpartum period is relatively high (459). Because of the risks of the pass through the placenta and can affect the fetal thyroid. FDA to recommended that PTU be Untreated or insufficiently treated hyperthyroidism may reserved for patients who are in their first trimester of preg- seriously complicate pregnancy (452–454). A single set of thyroid function tests within the reference Moreover. the placenta (460). omphalocale. As discussed in other sections of these guidelines. heart. and eye. assays (57). and it was hypothesized that fear preferable to indicate euthyroidism. pertension in pregnancy. detected. period during the early phase of hyperthyroidism therapy. although fetal growth restriction has been associ- Women who were treated with ATDs for GD and con. and it remains & RECOMMENDATION 81 elevated for more than 1 year (456). For personal use only. and other termining the choice of therapy for the patient who is cur- types of gut atresias. & RECOMMENDATION 82 Recently. children exposed to PTU had a significantly Both thyroidectomy and RAI therapy are useful for ren- higher frequency of situs inversus and cardiac outflow ab. MMI and PTU both appear in breast milk in only small pertise in this area. which is have been studied extensively when used for treating hy- consistent with the notion that thyroid autoimmunity im. 10–20 mg every 8 hours) or risk of recurrence when they become pregnant and should metoprolol (e. and urinary tract malformations. defects and had been exposed to some type of medication in early pregnancy. choanal atresia. first described in 1972 (461).2. especially those with milder disease. and studies of breastfed infants of mothers pregnancy may be diagnosed from typical clinical findings.com at 01/28/18. subsequent normal intellectual development (109). MMI is the preferred ATD in older assays (47. On the other hand. in pregnant women suffering from thyrotoxicosis.455). but ATD therapy should be used for overt hyperthyroidism due these types of defects have not been observed in excess in to GD during pregnancy.233 from online. tional weeks 6–10 (469).470) this disorder should be treated at centers with specific ex. the incidence of therapy until the patient has become euthyroid. but these defects tended to thyroidism should be considered for definitive therapy be less severe than with MMI and included preauricular si- before they become pregnant. perthyroid patient. abdominal wall abnormalities including rently pregnant or may become pregnant in the future. nuses and cysts and urinary tract abnormalities (466).471). low-quality evidence. ated with the prolonged use of especially atenolol (431. 1380 ROSS ET AL. GD as the cause of hyperthyroidism in concentrations.g. Concerns about rare but potentially fatal PTU-related hep- atotoxicity have led the U. the possibility and timing of future pregnant as in nonpregnant women. period of highest risk for birth defects from ATDs is gesta- Strong recommendation. In a U. Both ATDs and TRAb pregnancy should be discussed. of MMI-associated birth defects had led to the decision to terminate pregnancy (465).463) have in- outcome. the risk of relapse (as well as the risk of thyrotoxi. study. and this report fits the clinical reduce pulse rate and the hyperadrenergic symptoms of observation that existing GD may occasionally worsen in thyrotoxicosis during the time period from the start of ATD early pregnancy (457). low-quality evidence. In a large group of children selected because they had major birth Weak recommendation. dering patients with GD permanently hypothyroid with the . hyperthyroid state on pregnancy and fetal outcome.3% We suggest that women with hyperthyroidism caused by above the background rate) was also observed after PTU GD who require high doses of ATDs to achieve eu- exposure in early pregnancy (463). and patients with nancy or who are allergic to or intolerant of MMI (157. 31% of women who had received MMI around the time of Two sets of tests within the reference range. PTU should be used when ATD studies comparing PTU-exposed children with nonselected therapy is given during the first trimester. 100 mg once daily) are useful and can be have their thyroid function tested in early pregnancy.. In considered safe for short periods of time to relieve symptoms contrast. taken with an conception had elective termination of pregnancy versus 9% interval of at least 1 month and without a change of therapy is of those who received PTU.g. we However. and 3% are negative in third-generation nursing mothers. These factors should all be considered when de- cluded aplasia cutis..S.156. Smoking and the presence of orbitopathy pre. vantage is that the patient will require levothyroxine therapy roidectomy is often followed by a decrease or disappearance while pregnant and lifelong and will be exposed to either of TRAb from circulation. and it should be weighed against the other benefits whom pregnancy is not recognized within the first few weeks and harms of surgery and RAI therapy. patients who have already been treated for 12–24 months is tential risks and benefits of each option should be discussed <10% (167. the risk of early relapse is very high in patients taken into account. differ considerably. or the potential for undesirable surgical argument in favor of surgical thyroidectomy in women with outcomes. and the study of 340 such women. Each option is presented in depth in the who have received ATD for less than 6 months and/or still following technical remarks. It has the ad. MMI-associated birth defects occur in 2%– To predict reduction in TRAb after surgical thyroidectomy. liver failure with an estimated 1:10. Switching to PTU before conception may be preferred in maining patients (472). However.2. and assessed weekly throughout the first trimester. immediately as recommended below. likely candidates to withdraw from ATD therapy in early d. strategy is discussed in Recommendation 82. or need of MMI Definitive therapy before becoming pregnant. irrespective of such starting therapy with PTU and thus bypass a phase of MMI differences. PTU is associated with 12 months. periods before drug withdrawal. For personal use only. the physician providing care to a young woman therapy in such patients. high TRAb level. ATD therapy as soon as pregnancy is diagnosed. Women b.liebertpub. low-quality evidence. Thus.475). and abnormali- a recent retrospective Japanese study of 45 (41 female) patients ties may be severe. mothers must balance 357 days if both factors were present). with newly diagnosed GD should include discussion and guidance on GD and pregnancy. Withdrawing ATD treatment after conception.156. a. younger women with regular menses who are expected to be Medical tradition and experience with different types of able to conceive within 1–3 months. Based on the latter studies. Switching to PTU as soon as pregnancy is diagnosed may be preferred in older & RECOMMENDATION 83 women and women who have conditions that may be asso- Women with hyperthyroidism caused by GD that is well ciated with delayed conception. including worsening or a transient increase in TRAb. 4% of children exposed in early pregnancy. In a German prospective therapy for GD varies between countries and clinics. range 5. or failure in adult patients (136). If No study has directly addressed the risk of relapse of hy- ATD therapy is withdrawn. given to women with GD on therapy in relation to a possible There are not sufficient data to recommend for or against future pregnancy may differ.6–400. Alter- patient may not be in a position to fully comprehend many natively. and other A special variant is women who have hyperthyroidism factors that are only partly understood (473). If ATD withdrawal is followed by a relapse of hyperthy- vantage of allowing the patient to become pregnant free of roidism. Downloaded by 5. The disad- replacement therapy. Patients were followed for they mostly seem to be less severe. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1381 possibility of a stable euthyroid state on thyroid hormone worry from the adverse fetal effects of ATDs. in serum decreased with a half-life of 94 days in the re. have indicators of high disease activity such as low serum TSH. advice diagnosed at a time when they hope to become pregnant soon. pregnant patients who had been treated with ATD for varying Weak recommendation. normal for well documented. and therefore the po.000 risk of severe liver dicted slow disappearance of TRAb (half-life 162 days. but . the patient may continue MMI therapy but be pre- simultaneous messages. and patient values and preferences should be However. Patients could switch to PTU as soon as pregnancy is achieved within a few months and a falling TRAb level are diagnosed. PTU-associated birth defects are less with high TRAb (median 64 IU/L. This increase is a potential induction of GO. high TRAb titers who may become pregnant within the years to come. Patients could switch to PTU before trying to conceive. Appropriately selected patients could withdraw from pregnancy. it will often develop gradually over some weeks. whereas RAI is often followed by the potential complications of RAI. whereas TRAb levels the risk of PTU to themselves versus the risk to the child. 68% became pregnant within 3 risk of relapse of hyperthyroidism after ATD withdrawal may months (474). then evidence comes from controlled or cohort studies of non- monthly. Thy. The severely hyperthyroid Switching from MMI to PTU after conception. thyroid function should be perthyroidism after ATD withdrawal in early pregnancy. Switching year (172). Thus. especially those planning therapy within the next Switching from MMI to PTU before pregnancy.233 from online. However. and a more detailed discussion may pared to detect pregnancy very early and modify therapy be appropriate when the patient has become euthyroid. the importance of this difference in from MMI to PTU before conception would eliminate the autoimmune activity for pregnancy outcome has not been risk from early pregnancy exposure to MMI in women in studied. depending on iodine intake. the risk of relapse of hyperthyroidism within a 2-month in- The evidence is insufficient to give universal guidance on terval after ATD withdrawal in TRAb-negative nonsmoking how to choose among these options. They may occur in 2%–3% of children but assay <1.com at 01/28/18. as discussed in these guidelines. signs of active GO. This dose in excess of 5–10 mg/d to remain euthyroid (473). with a stable euthyroid state on 5–10 mg MMI per day c. Patients could consider definitive therapy before they become pregnant. with the patient.9 IU/L) may be useful. This strategy may prevent controlled on MMI and who desire pregnancy have several prolonged use of PTU prior to conception but has the risk options: of fetal exposure to MMI if the diagnosis of pregnancy is delayed. after conception. a missed or unusually light menstrual period. & RECOMMENDATION 84 We suggest that women who are treated with ATD and & RECOMMENDATION 87 who may potentially become pregnant should be instructed We suggest that women in early pregnancy who have a to perform a pregnancy test within the first days after a high risk of recurrent or worsening hyperthyroidism if missed or unusually light menstrual period. duration of ATD therapy. with maternal thyroid dysfunction (462). Both MMI and PTU are effective therapies of hyperthy- centrations of hCG have started to rise and generally avail. blood and urine con. ATD is withdrawn be shifted from MMI to PTU imme- Weak recommendation. it is critical taking place about 2 weeks after this. mediately after birth (466). If risk of relapse is con- hyperthyroidism in pregnancy (477. ATD therapy is fol- early pregnancy high hCG levels) was not associated with lowed by a gradual remission of disease with a possibility of adverse pregnancy outcomes (449). withdrawal of ATD associated defects are more severe. possible in the first trimester.469). sure are better documented. no increase in fetal loss occurred in the (119). defects tend to be less severe and may not be diagnosed im- vent birth defects caused by ATD exposure. and the major effect of able pregnancy tests based on detection of hCG in urine both drugs is interaction with thyroid peroxidase–catalyzed normally become positive early in gestational week 5. defects after MMI expo- suggests that this time span is also the major period of tera. Considering the fetus. the presence of a major birth defect was associated with the use of MMI in early pregnancy but not and current disease activity. responsible for the ATD therapy within 24 hours to discuss A subset of women with GD will experience relapse of future treatment options. However. We suggest that a woman who tests positive for pregnancy ing the remaining first trimester of pregnancy is recommended according to recommendation 84 contact the physician until more data on safety become available. the same institution. The period of major risk of birth defects caused by intake of medication in pregnancy is gestational weeks 6–10 (468).478). low-quality evidence.liebertpub. 1382 ROSS ET AL. low-quality evidence. whereas PTU-associated therapy before week 5 of pregnancy may theoretically pre. and results of recent thy- A more pertinent risk may be fetal loss caused by maternal roid function and TRAb testing. The risk to the change in early pregnancy to prevent birth defects is narrow mother from such hyperthyroidism is considered negligible. Thus. frequent thyroid function testing dur. Very thyroid hormone production (109). two recent studies performed in pregnancy should be detected early and action has to be taken Japan suggest that such transient and mild maternal hyper. Apart from the differ- early testing for pregnancy to allow medication withdrawal ences in side effects discussed previously. duration of effect. appears 2 weeks later. current ATD dose requirement. even if the frequency of relapse may be in the order of iodine group despite more cases of maternal hyperthyroidism 50% within 1 year. even if some of the mothers in the iodine Recommendation 85 evaluate whether ATD withdrawal in group had developed biochemical hyperthyroidism and the first trimester of pregnancy is likely to cause relapse of needed retreatment with ATD (476). The first real sign of to diagnose pregnancy and shift from MMI to PTU as early as pregnancy.233 from online. The reason seems to be that MMI- togenic effects of ATD (469). Therefore. according to Recommendation 81.156. thyroidism will not increase the risk of malformations. and it depends on a variety of factors (473). One & study observed a significantly lower risk of birth defects in RECOMMENDATION 86 mothers who had been shifted from MMI to iodine therapy in We suggest that the physician contacted according to early pregnancy.com at 01/28/18. varies considerably among individual patients. with conception shifted drugs during the first trimester (463). especially the severity of GD at time of diagnosis Downloaded by 5. immediately.2. pregnant women from the United States. (468. Birth defects associated with both The week of pregnancy is calculated starting from the first PTU and MMI were seen in the neonates from women who day of the last normal menstrual period. early pregnancy may be low or absent. When patients Japanese study of women with GD either treated with MMI in have been treated with ATD for 12–18 months a rapid relapse early pregnancy or shifted from MMI to iodine therapy in of hyperthyroidism after ATD withdrawal becomes less likely early pregnancy. Frequent testing of thyroid function will allow early detection of such relapse and initia- tion of therapy with PTU (or MMI if relapse occurs in the The time window that will allow medication withdrawal or second trimester) to keep the mother euthyroid. it is important to before the major period of teratogenicity is recommended for consider differences in potency per milligram of drug and in other types of drugs that may be teratogenic (479). & RECOMMENDATION 85 exact information on such time course in early pregnancy is not available. hyperthyroidism in pregnancy if ATD therapy is withdrawn Weak recommendation. Weak recommendation. probably confined to gestational week 5. In another study from hyperthyroidism. Thus. diately after diagnosing pregnancy. therapy can be withdrawn and followed by from a brief period of mild maternal thyroid hyperfunction in weekly thyroid function testing during the first trimester. the risk sidered low. By this time. low or suppressed serum TSH in early pregnancy (presumably mostly caused by In the majority of patients with GD. Evaluation should be based on patient records. In a large cohort of Weak recommendation. low-quality evidence. Even if birth defects may occur after both MMI and PTU and a study of time of exposure to ATD and risk of defects exposure in early pregnancy (463). low-quality evidence. as already discussed in detail. roidism in the majority of patients. Thus. In a recent retrospective disappearance of TRAb from circulation (172). The risk of relapse after ATD withdrawal in this group (476). . For personal use only. and free T4 levels were always higher in the group that had shifted No recommendation. ATD in early pregnancy were retrospectively compared with 283 women who had shifted from ATD to iodine (median & RECOMMENDATION 88 gestational week of shift was week 6. 83. delivery in 35 patients with GD treated with iodine (6–40 mg/ though only two studies have examined this dosage ratio d) initiated at 11–37 weeks of gestation. more recent Japanese studies. but most patients received against the risk of the shift from PTU to MMI inducing a higher doses (484). Similarly. but rare side effects. p < 0. as dis. Moreover. women with GD may start entering disease (484).488).2. MMI 15 mg once daily may be outcomes of pregnancy in 1333 women who had continued substituted with PTU 100 mg three times a day (319). this drug is not in preventing fulminant PTU-related hepatotoxicity. range 4–12) (476). In the publication.14%. The reason for the FDA black box warning against PTU data on thyroid function in the MMI group are sparse. no patient who restarted the substances of importance for pregnancy are concerns and drug less than 5 months after stopping the previous course of have led to a note of caution by the FDA. Lithium may be directly evaluate how shifting from PTU to MMI in the teratogenic (489) and it should not be used to treat hyper- second trimester of pregnancy will affect the risk of these thyroidism in pregnancy. live births were more common in the benefits and risks. Cholestyramine is not absorbed from the gut. health No recent data on iodine therapy for GD in pregnancy databases was low (433. However. & RECOMMENDATION 89 Other medical treatments for hyperthyroidism during GD during pregnancy should be treated with the lowest pregnancy. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1383 A dosage ratio of MMI to PTU of 1:20 is recommended Japan. but before ATDs be- national registry study observed one case of reversible liver came available. but the therapy after the first trimester of pregnancy is the risk study may indicate that a brief period of mild hyperthyroid- of PTU-associated liver failure. but clearly who is doing well on PTU therapy. hormone levels at or slightly above the reference range for styramine. (481.5 times above Iodine in supraphysiological doses has multiple mostly nonpregnant reference ranges in the second and third tri- inhibitory effects on the thyroid. experience with iodine therapy for GD failure among 1103 women treated with PTU in pregnancy in general was extensive (484). teratogenicity of the same time that thyroid function is assessed. is real. the absolute risk observed in studies of U.480). al. Despite this. in a Japanese study and it is not expected to affect the fetus directly. The minimal effective dose The risk of side effects from PTU should be weighed of iodine was around 6 mg/d. Women taking PTU during the first trimester of pregnancy Overall. or 87 may be prevalence of major birth defects was lower in the women switched to MMI at the beginning of the second trimester.53% vs.05). group that had shifted than in the group that had continued MMI therapy (91.1%. For example. perchlorate.319. Further. 85. There are no data to drugs are not generally available any more. Iodine was effective for therapy of transient thyroid function abnormality in the pregnant woman hyperthyroidism in patients with mild GD. such as iodine. mostly in combination with other drugs risk can recur when the drug is reintroduced after a relatively (487.482). long period of time (177). who had shifted to iodine therapy (1. In one study.319).233 from online.465).S. and full therapy of pregnant women with GD can be generally focus should be on the feasibility of ATD dose reduction to recommended. However. Patients who remain on PTU during the second the thyroid. no perchlorate has not been demonstrated (486). Starting from the second less effective than ATD in patients with more severe trimester of pregnancy. 15 mg of fetus than in the mother.156. for example. Downloaded by 5.liebertpub. chole. or they may continue PTU therapy for the remaining part p < 0. Other types of medical therapy have been used possible dose of ATD needed to keep the mother’s thyroid to treat hyperthyroidism. but this hyperthyroidism. severe. aspect to consider is that both agranulocytosis and liver Cholestyramine binds thyroid hormones in the gut during failure developing during MMI and PTU therapy mostly their enterohepatic recirculation and has been used to treat occur during the initial 3 months of therapy (128). insufficient evidence to assess to iodine. according to the authors. the dose of PTU should be split over the day subclinical hypothyroidism at birth (483). cholecystographic agents. Cholecystographic therapy developed this adverse reaction. Similarly. shifting has been more common in recent years. free T4 levels should be kept at or . The according to Recommendations 80. with a low risk of inducing hypothy- because the half-life of PTU is considerably shorter than that roidism and goiter in the fetus. some degree of of pregnancy if ATD is needed. mesters). Additional data are needed before iodine gradual remission of the autoimmune abnormality. For personal use only. and it corresponds to the (129). Similar to ATD directly (115. and a few cases have been published in which it and third trimesters could have hepatic enzymes measured at was used in pregnancy (485). total T4 and T3 values in pregnancy (1. the difference in duration of therapy. (177) of 14 patients who developed agranulocytosis after binding in the gut and excretion of vitamins and other retreatment with the same ATD. a recent Danish are available from outside Japan. 4. hyperthyroidism was relatively common after shifting. In a recent study. but judged satisfactory. For example.9% vs.05). However. Perchlorate is a competitive inhibitor of iodine uptake by cussed below. but overall results of therapy were MMI would be roughly equivalent to 300 mg of PTU. cord and maternal sera were tested at when changing from one drug to another (115. even if this risk ism in the mother will not impair pregnancy. protect the fetus against goiter and hypothyroidism. and the TSH below the reference range for cess been used to treat hyperthyroid women in pregnancy in pregnancy. However.com at 01/28/18. thyroid function at term tended to be lower in the effect should be taken into account. only 1 of 35 neonates had of MMI. and lithium. Apparently. Another available in the United States. and it has with some suc. but more clin- prospective data show that this type of monitoring is effective ical studies on this are clearly needed. thyroid function (e. the regimen should be changed to an ATD alone Evaluation by a high-risk obstetrician is advised along (444). SSKI one drop three times a day). maternal free T4 above the nonpregnancy organification via the Wolff–Chaikoff effect. it is not without risk (4. Thyroidectomy cures the hyperthyroidism and is often most closely correlated with good fetal outcome. the use of iodine for monitored frequently and noninvasive assessment of fetal surgical preparation is considered unnecessary. as hyperthyroidism during pregnancy. and the ATD dose adjusted. low-quality evidence. performed if possible during the second trimester. and should only be used when medical management has been unsuccessful or ATDs cannot be used. pregnancy are thyroid function in the untreated patient and measurement of TRAb levels in the serum. but who are offered surgical thyroidectomy for other ATD therapy (494). with counseling before surgery regarding the risks involved Technical remarks: Free T4 is the parameter that has been (68). sensitivity of good assays is around 95% and the specificity is and access to high-volume surgeons (68). intolerance to ATD). The nonpregnancy free T4 is much higher than late pregnancy free risk of iodide therapy to the fetus relates to inhibition of iodine T4 (446. low-quality evidence. Thyroidectomy is best avoided in the first and third tri- a risk of inducing fetal hypothyroidism and goiter during mesters of pregnancy because of teratogenic effects associ- the second and third trimesters exists when the fetal thy.156. still harbors TRAb after thyroidectomy. Strong recommendation. preoperative preparation for thyroidectomy thyroidism. Although it is the safest not be used in pregnancy. high TRAb levels. ATD therapy and b-blockers [propranolol or metroprolol. The two best indicators of the activity of GD during Strong recommendation. Even if the mother is euthyroid during ATD therapy. 1384 ROSS ET AL. However. A small group perthyroidism is harmful to the fetus. The fetal thyroid reference with suppressed TSH may leave the mother overtly gland is particularly susceptible to the inhibitory effects of hyperthyroid. low-quality evidence.492). with difficult-to-treat hyper.5% risk of preterm labor) therapy becomes pregnant. TRAb measure- In a population-based U. therapy. this is not a universal phenomenon.2.S. insurance. and fetal goiter on ultrasound). Thyroid function should be When thyroidectomy is necessary for the treatment of assessed at least monthly. However. thyroidectomy would be performed in the therapy consisting of ATD plus levothyroxine should latter portion of the second trimester. Thus. Such patients may show a iodine (e.68).5%–5.com at 01/28/18. fetal heart rate..liebertpub. & RECOMMENDATION 91 slightly above the upper limit of the pregnancy trimester reference range for the assay. bone maturity.. In Japanese studies.g. ATD. preoperatively to reduce thyroid blood flow and control hy- drawal. keeping in mind that the diagnostic disparities in outcomes based on race/ethnicity. may still be suppressed in these patients and should not be used as the sole guide in treatment. there is no the autoimmune abnormality during the second half of evidence that brief iodine preparation of the mother done pregnancy with a need of ATD dose reduction or with. perthyroidism.491). 99% (47). Block-replacement third. In euthyroid patients with no signs of high thyroid ac- the hyperstimulated thyroid made iodine deficient from tivity. Pregnancy is a relative contraindication to thyroidectomy Strong recommendation. and often a considerable during the second trimester of pregnancy includes 10 days of goiter with high blood flow.233 from online. In the setting in which the mother reduce the dose of ATD (444). Maternal thyroid function should be reasons (e. which is not recommended. with signs specific for GD. For personal use only. with some automated free T4 assays be used to prepare pregnant patients for thyroidectomy. TRAb produced by the Downloaded by 5.. the surgery should be required. of patients experiences severe disease that may even Technical remarks: In patients with difficult-to-treat hy- progress during pregnancy. ated with anesthetic agents and increased risk of fetal loss in roid has begun to function (490. Strong recommendation. ing for both cardiovascular and skeletal changes with fetal pregnancy reference range in the last part of pregnancy to ultrasound is essential.g. Until such remission takes place. & RECOMMENDATION 92 TRAb levels should be measured when the etiology of & RECOMMENDATION 90 hyperthyroidism in pregnancy is uncertain. and she is still in need of ATD (67. excess iodine in the second half of gestation. close fetal monitor- treated maternal free T4 values were kept above the non.491). low-quality evidence. but sumably caused by a high type 1 deiodinase activity in the not atenolol (450.g. study. although normalization of mother may stimulate the thyroid of the fetus or newborn and maternal TSH during ATD therapy may indicate a need to induce hyperthyroidism. Serum TSH followed by a gradual reduction in circulating TRAb (495). Thus. pregnant women had ment is useful in the diagnosis of GD in pregnant women with worse clinical and economic outcomes following thyroid newly diagnosed hyperthyroidism who do not have clinical (and parathyroid) surgery than nonpregnant women. along with ‘‘high T3–low T4 pattern’’ during ATD therapy (444) pre. avoid cases of elevated TSH in newborn cord blood There are no data concerning whether SSKI or iodine should (458.451)] to control hyperthyroidism (497– hyperactive thyroid (493) and preferential T3 synthesis in 499). and fetal goiter Although many patients with GD may enter remission of can occur with chronic therapy (496). and ATD therapy balanced to [T3] The role of TRAb level measurement in pregnancy keep acceptable thyroid function in both the mother and the fetus (444). Optimally. . the dose of the first trimester and increased risk of preterm labor in the ATD should be kept as low as possible. If a woman receiving such time. low-quality evidence. low-quality evidence. the evaluation of disease activity in a woman being treated with Postpartum thyroiditis must be distinguished from GD to ATDs for GD during pregnancy (444. whereas GD developed after this . Whereas it has generally been considered that isolated fetal thyrotox. The classic nant patient previously found to have GD if she has an intact triphasic pattern is thyrotoxicosis at 1–6 months postpartum. first trimester is that it allows time to initiate specialty con- sultation and. thyroid (i. In a Japa- even if the mother is euthyroid on the medication. a recent case report described severe fetal thy. All hy- Downloaded by 5. The pregnant woman had previously undergone un- Strong recommendation. 12 months postpartum (505. autoimmune disorder unmasked in predisposed women as TRAb measurement is not necessary in a euthyroid preg- immune surveillance rebounds after pregnancy. thyroid function testing and. In many patients. followed by levothyroxine replacement.495). Disappearance of TRAb autoimmunity leading to postpartum thyroiditis is also as- is an indication that ATD therapy may no longer be necessary sociated with a 3. TRAb might only start developing around weeks 20–22 of selective diagnostic studies should be performed to dis- pregnancy. The postpartum surge in thyroid GD gradually remits during pregnancy. pregnant woman initially during the first trimester and. If the mother still produces TRAb. the TRAb level should be measured in the and five of these (9% of all) needed ATD therapy. not previously treated with surgery or RAI) and followed by hypothyroidism and return to euthyroidism at 9– she is not currently taking ATDs (495. In a recent study of 47 new- circulation. again at 18–22 weeks of gestation. Among 371 cases in 13 studies. However. but her TRAb values remained ex- pregnancies in the United States.. who gave birth to hyperthyroid newborns required ATD The advantage to initial TRAb measurement during the therapy in late pregnancy (504). ATD delivered to the fetus via pla- treated with ablative therapy (RAI or thyroidectomy) for GD cental passage is rapidly metabolized by the neonate. and or found to have GD during pregnancy should have TRAb 32% had thyrotoxicosis without subsequent hypothyroidism levels measured at initial pregnancy visit or at diagnosis (506).233 from online. To evaluate the risk of such of the children had neonatal biochemical hyperthyroidism. tobacco smoking and bottle-feeding increased the TRAb (TBII or TSI) measurement may be useful to assist in risk of developing thyroiditis. low-quality evidence. recommend proper therapy.liebertpub.e. successful RAI. this sequence is & not observed in every patient. thyroiditis than were those with negative serology (507). again at 18–22 weeks of gestation. thyroid dysfunction in the child may last for borns to mothers who were TRAb positive in pregnancy. with a half-life placement (495. All patients who developed overt thyrotox- Patients with elevated TRAb levels at 18–22 weeks of icosis within the first 3 months after delivery suffered from gestation should have TRAb remeasured in late pregnancy destructive thyroiditis.2. complications. TRAb measurement in late pregnancy can be used to as- sess the risk of delayed neonatal hyperthyroidism. mester were 27 times more likely to develop postpartum Strong recommendation. although some & RECOMMENDATION 95 overlap existed. the of around 3 weeks. specificity 43%). An exception to this recommendation is a woman GD prior to pregnancy should have TRAb levels measured with an intact thyroid who is no longer in need of ATD using a sensitive assay initially during the first trimester therapy. All mothers dysfunction should be initiated (501). if it is perthyroid neonates were born to mothers with TRAb levels elevated. Strong recommendation. For personal use only. if levels are elevated. a program of fetal and neonatal surveillance for thyroid trimester (sensitivity 100%.156.com at 01/28/18. If the level is ‡5 IU/L (>3 times upper reference for the assay) in the second high. 43% Patients receiving ATD for GD when becoming pregnant had hypothyroidism without preceding thyrotoxicosis. After delivery.506). whereas who is now euthyroid with or without thyroid hormone re. nine several months after birth. RECOMMENDATION 94 25% of patients were found to have a triphasic pattern. low-quality evidence. nese hospital study. those with using a sensitive assay and. if the levels are especially high at that time. a high level of TRAb in the mother antibodies will cross the placenta and may affect fetal thyroid in late pregnancy is an indicator that the neonate may need to function in the last half of the pregnancy. GD that peaks 3–12 months after delivery (456). and a total thyroidectomy had subsequently been performed. [T4] Postpartum thyroiditis intervention may be required by the second trimester. thyrotoxicosis caused by thyroiditis developed earlier after delivery than GD. the maternal TRAb disappears more slowly. if they are elevated. Postpartum thyroiditis is an tremely elevated. & RECOMMENDATION 96 icosis in a previously ablated mother who is still producing In women developing thyrotoxicosis after delivery.to 4-fold increase in the incidence of and its continuation may put the fetus at risk for hypothyroidism. The Postpartum thyroid dysfunction occurs in up to 10% of mother was euthyroid. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1385 & RECOMMENDATION 93 (weeks 30–34) to guide decisions regarding neonatal mon- Patients who were treated with RAI or thyroidectomy for itoring. Because of the slow be monitored for the onset of neonatal hyperthyroidism clearance of maternal immunoglobulin G from the neonatal starting a few days after birth.500).503). In a prospective study of pregnant women. (502). when the Measurement of TRAb levels can detect persistent TSH mother continues to need ATD to control hyperthyroidism up receptor autoimmunity in a pregnant woman previously to term. Thus. In this study. tinguish postpartum destructive thyroiditis from post- rotoxicosis that had already developed in gestational week 18 partum GD. again at positive anti–thyroid peroxidase antibodies in the first tri- 18–22 weeks of gestation. Strong recommendation. However. patients after the age of 50 years. Thyroid-associated orbitopathy. no identify a clear sex-related risk for GO (517. low-quality evidence. orbit in association with autoimmune thyroid disorders (516). while some special monitoring is needed for breastfed infants of mothers older studies point to a possible slightly increased risk for on these medications (514). In mild cases. the role of Technical remarks: Because propranalol and metoprolol sex in GO is more controversial. but higher TRAb values are suggestive of GD. In the uncommon case of TRAb may occasionally be measurable in patients with this type of hyperthyroidism in a pregnant woman. but it mostly develops in in GD. and thyroid bruit or GO strongly suggest GD as well. it occurs in patients with <5% bound to maternal plasma proteins (vs.522) with a higher prevalence of severe cases multinodular thyroid autonomy or a solitary TA. the use of radioactive substances can be avoi. men (519. 93% binding of current or past GD. Hyperthyroidism caused by thyroid autonomy is very This active phase is best described by the clinical activity score common in people having current (or previous) mild to (CAS) (523. The shorter taken that the fetus is not iodine deficient.liebertpub. Based on this theoretical risk. In hypothyroidism or those having TSH levels >10 mU/L (506).513). crease in thyroid hormone production may catch up with the ded and the diagnosis can be based on a combination of hormone production in the autonomous areas of the thyroid clinical presentation. the high Downloaded by 5. whereas T4 is more duction. surgical therapy in the second trimester of pregnancy may be con- Strong recommendation. for which women are at higher risk. the tendency to induce fetal hypothyroidism In women with symptomatic thyrotoxicosis from post. Thus. More recent studies do not are secreted into breast milk in only very low amounts. and because of eye disease. the fetal thyroid will not be abnormally stimulated in elevated than T3 in destructive thyroiditis (50).156. and evaluation of and alleviate the need for ATD therapy. Goiter is generally more pronounced moderate iodine deficiency (13).521. and thus accumulates in milk. especially in areas half-lives of these agents (510) will allow breast milk to be where the population is iodine deficient. a theoretical be resumed if 131I is given as treatment for GD (511). the gamma-emitters 123I (half-life 13 hours) men with autonomy or on the fetus. ternal hyperthyroidism and assessment of her diet should spectively) and nursing resumed. with the use of b-adrenergic blockers such as propranolol or metroprolol to control pulse rate and hyper- adrenergic symptoms during the thyrotoxic stage (514). contrast to GD.512. but care must be rather than the b-emitter 131I (half-life 8 days). supplements. patho- postpartum thyroiditis. thyroidism than in GD. experience a combination of GD and destructive thyroiditis Thyroid hormone production in autonomy is dependent on (509). special in the elderly population (517).518). No firm recom- Treatment for postpartum thyroiditis is generally sup- mendations are given because no good evidence is available. Approximately a third of patients with Graves’ mature renal function (515). the nonfunctioning normal thyroid tissue in these patients and and T3 tends to be fractionally more elevated above the upper worsen hyperthyroidism. and neonatal hyperthyroidism is not & RECOMMENDATION 97 a risk. the second half of pregnancy as it is in GD.520). possibility exists that the normal pregnancy-associated in- Most often. It might be benefi- or 99mTc pertechnetate (half-life 6 hours) should be used cial to keep iodine intake on the low side. used for GO. the judicious use of b. re. Hormone overproduction is often limited in ministration to avoid radiation exposure to the breast and not patients with autonomy (50). Thyroidal production of T3 compared with hCG levels in early pregnancy may theoretically stimulate T4 is relatively high in GD. The disease & RECOMMENDATION 98 peaks in incidence in the fifth and sixth decade of life In pregnant women diagnosed with hyperthyroidism due to (517. This variability in results might be related to changes in smoking patterns over the years. care should be taken not to induce fetal hypothyroidism by ATD therapy.524). [U1] Assessment of disease activity and severity Strong recommendation. but no study has addressed the effect of a in vivo testing is required to make this distinction in women change in iodine intake on thyroid function in pregnant wo- who are nursing.518). Because there is no TRAb pro- reference limit compared with T4 in GD. TRAb measurement. treated hyperthyroid mother as it happens during the second half of pregnancy in GD. This adverse effect presumably develops because atenolol is In the majority of cases (about 90%). The [U] How should hyperthyroidism be managed selective b-1 adrenergic receptor-blocking agent atenolol should in patients with GO? not be used in breastfeeding mothers because it may lead to GO is an inflammatory eye disease that develops in the symptoms consistent with b-adrenergic blockage in neonates. sidered if the hyperthyroidism turns out to require more than low dose MMI (5–10 mg/d) for control. 1386 ROSS ET AL. beneficial.2. 3-month period (508). The natural history of the disease is one of rapid deteriora- tion followed by gradual improvement toward the baseline.518. If needed. serum T4 and T3. the fetus roid color Doppler ultrasonography may assist in distinguishing will not develop hyperthyroidism in parallel with the un- between destructive thyroiditis and GD (508. thy. whereas breastfeeding be considered before deciding whether to administer iodine should ideally be discontinued 3 months prior to 131I ad. and Graves’ ophthalmopathy are other names low kidney excretion of atenolol in small children with im. The degree of ma- pumped and discarded for 10 half-lives (5 or 3 days. the elements of which are outlined in . and goiter in the second half of pregnancy from ATDs given partum destructive thyroiditis. When iodine substrate.233 from online. suggesting that some patients may genic differences from GD should be considered. However. Levothyroxine therapy may be hyperthyroidism have some signs and/or symptoms of GO.com at 01/28/18. to the mother would be even higher in this type of hyper- adrenergic blocking agents is recommended. but not in destructive thyroiditis. thyroid propranolol). for women with symptomatic while only 5% have moderate-to-severe disease (517. portive in nature. low-quality evidence. at least transiently. For personal use only. GO is considered active in patients with a (527. ENT. The QoL correlation with disease to anti-inflammatory therapies (523. orbital radiation. with this debilitating condition. Tsai et al. lacking the last three elements. (676). though the effect of GO therapy on these QoL CAS ‡3. research emphasis because. Moderate-to-severe GO: patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). efforts should be Quality of life is clearly impaired by GO (526).liebertpub. as well as treatment of hyperthyroidism. including local docrinologists and ophthalmologists with expertise in the measures. GO is considered active in patients with a clinical activity score (CAS) ‡3. and endocrine surgery). The overall evaluation and management of [U2] Prevention of GO GO is best done in a multidisciplinary clinic combining en. if available. (678). For personal use only.. result from the increased strument that has such data is the instrument extensively used sympathetic state. severity has been fair to excellent for two GO specific in- Downloaded by 5. Both remainder of Section [U].233 from online. plastic surgery. mind that they do not always correlate. Graves’ Orbitopathy Severity Assessmenta Corneal Optic Gradeb Lid retraction Soft tissues Proptosisc Diplopia exposure nerve status Mild <2 mm Mild involvement <3 mm Transient or absent Absent Normal Moderate ‡2 mm Moderate involvement ‡3 mm Inconstant Mild Normal Severe ‡2 mm Severe involvement ‡3 mm Constant Mild Normal Sight threatening — — — — Severe Compression Upper limits of normal African American F/M = 23/24 mm White F/M = 19/21 mm Asian F/M = 16/17 mm (Thai) or 18. generally insufficient to justify immunosuppressive or surgical treatment. Identified risk factors Table 13. In particular.6 mm (Chinese) a Sources: Adapted from de Juan et al. Overall. The main gradations of disease severity are mild. This category warrants immediate intervention. .com at 01/28/18. some of the eye changes seen in hyper. despite its agreed-upon impor- quantifiable parameters and is a useful tool for directing tance. However. The score ranges from 0 to 10 and predicts response therapeutic application. and when present without associated eye in Europe (529).156. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1387 Table 12. we focus on recom- activity and severity of the disease must be considered in mendations regarding the concurrent use of corticosteroids in therapeutic decisions regarding treatment of the eye disease patients choosing RAI as treatment for hyperthyroidism itself. scores still needs prospective data. (523. moderate-to-severe. still being reported without associated QoL outcomes (530). which has not yet been tested in a North changes. Therefore.528). this area is in need of more The severity of the disease is best assessed using objective. and Bartalena et al. A 7-point scale. (677). c Proptosis refers to the variation compared to the upper limit of normal for each race/sex or the patient’s baseline. American population. and sight threatening (525). b A 7-point scale (excluding the last three elements) is used when no previous assessment is available. particularly in early and late disease. Presently. like lid retraction or stare. often fail to significantly improve the QoL of patients radiation therapy. Current therapeutic approaches to GO. Sight-threatening GO: patients with dysthyroid optic neuropathy and/or corneal breakdown. (525).524). The made to prevent the development or progression of GO in FDA has endorsed QoL information as a component of any patients with Graves’ hyperthyroidism. and surgery condition and other specialties in consultation (e. Assessment of Graves’ Orbitopathy: Clinical Activity Score Elementsa Comparison with Elementsb Each visit previous visit Score Painful feeling behind the globe over last 4 weeks X 1 Pain with eye movement during last 4 weeks X 1 Redness of the eyelids X 1 Redness of the conjunctiva X 1 Swelling of the eyelids X 1 Chemosis (edema of the conjunctiva) X 1 Swollen caruncle (flesh body at medial angle of eye) X 1 Increase in proptosis ‡2 mm X 1 Decreased eye movements ‡5 any direction X 1 Decreased visual acuity ‡1 line on Snellen chart X 1 a Sources: Adapted from Mourits et al. b Mild GO: patients whose features of GO have only a minor impact on daily life.2.g. Table 12. keeping in (Table 14). the only in- thyroidism. (525). struments published to date in North American populations sessment is available. Sarinnapakorn et al. Table 13 The prevention of GO and the management of hyperthy- lists the elements as agreed upon in a consensus statement by roidism in patients having established GO is discussed in the the European Group on Graves’ Orbitopathy (525). they are not considered to reflect GO (69). a significant number of intervention trials in GO are therapy. is used when no previous as.524). corticosteroids. 532. Genetics/ancestry No Highest prevalence of GO in Caucasians. unrelated to type of ther- ism plays a detrimental role in the progression of GO. 1388 ROSS ET AL.534). thyroidism by administration of thyroid hormone 2 weeks later dictive role in GO. and high risk for infections increase the likelihood of complications from glucocorticoids.532). active and moderate-to-severe 107 Recommend against Recommend against or sight-threatening GO present. Thyroid dysfunction Yes Need for expeditious control of hyperthyroidism then prevention of hypothyroidism post GD therapy. Subsequently.75 IU/L.106. this discussion are RAI therapy for hyperthyroidism (531. lowest in Asians.2. Downloaded by 5. and they are the preferred choice of therapy in patients with active and moderate-to-severe or sight-threatening GO. untreated hypothyroidism after therapy for hyperthyroid. high risk for progression if hypothyroidism noted that deterioration of GO rarely occurred >8.156. . Risk factors for GO deterioration (high TRAb level. psychiatric illness. and consistent data from several studies study noted that patients who were either hypo. TSH receptor antibody Noa Predicts GO risk and GO therapy response. Poorly controlled diabetes. patients exposed to secondhand smoke tors for the development of orbitopathy. smoking. risk for more severe GO. ity of higher TRAb values measured on less sensitive assays early-on being partly responsible for this variation.8 IU/L) (533). Table 14. As both firsthand and secondhand smoking in- maintained in hyperthyroid patients with GO or risk fac. Risk Factors for Graves’ Orbitopathy Amenable to Risk factor intervention Comments Age No Advanced age. RAI therapy Yes Risk is additive to smoking. inactive 108 Recommend Recommend against a ATDs or thyroidectomy are also recommended treatment options in each of these scenarios. should be identified and advised of its negative impact.com at 01/28/18. osteoporosis. A randomized study of newly diagnosed after therapy for hyperthyroidism (106.534). development or worsening of GO.233 from online. with MMI (relative risk [RR] of 0.95) (69).536). For personal use only. but these conclusions were not validated by did not increase the risk of worsening GO compared to therapy subsequent studies (69.or hyperthyroid show a detrimental effect of smoking on GO in patients Table 15. GD found that RAI followed by active prevention of hypo- ment levels of T3 and T4 were each reported to have a pre. Use of Oral Glucocorticoids for Prevention of Graves’ Orbitopathy Development or Progression When Radioactive Iodine Is Used to Treat Graves’ Hyperthyroidisma RAI without RAI with oral Recommendation glucocorticoids glucocorticoids No GO (nonsmoker) 101 Recommend Recommend against No GO (smoker) 103 Insufficient data to recommend for or against GO present. Strong recommendation. A number of studies have suggested that development of per. increased with preexistent and active GO. moderate-quality evidence. a Decreased TRAb noted with methimazole therapy yet available data are unable to separate that change from the natural history of GO with improving TRAb. Mechanical factors No Noted wider lateral wall orbital angle in GO. suggesting the possibil. High pretreat. and any delay in treating hypothyroidism (0%–2%) (534. more severe in men. Smoking-cessation clinics favored for intervention. and the most pertinent ones to had more severe GO than euthyroid patients (535). Immunomodulatory genes likely involved. two cohort studies in which patients received levothyroxine untreated hyperthyroidism. smoking) increase the benefit of glucocorticoids in preventing GO deterioration. moderate-quality evidence. Sex No GO is more frequent in women (as GD is). & RECOMMENDATION 100 We recommend clinicians advise patients with GD to stop & RECOMMENDATION 99 smoking and refer them to a structured smoking cessation Euthyroidism should be expeditiously achieved and program. Strong recommendation. Smoking is the most important known risk factor for the sistent. active and mild (risk factors absent) 105 Acceptableb Acceptableb GO present. b The decision regarding use of concurrent glucocorticoids should be made in light of the risk–benefit ratio relative to the patient’s overall health. Smoking Yes Increases GO progression and decreases therapy efficacy. crease GO risk. An early apy for GO (535). active and mild (risk factors present) 106 Recommend against Recommend GO present. high serum pretreatment therapy early after RAI with the specific intent of preventing TRAb levels (normal <1. preventable by glucocorticoids 6–12 weeks post RAI.liebertpub. for GO are listed in Table 15. psy- therapy for GO.8 IU/L) (see Table 15). surgery.539). RAI therapy. ATDs. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1389 treated with RAI (69. Two randomized controlled trials found the risk to be 6/78 (8%) Technical remarks: The decision on whether to administer for RAI compared with 1/74 (1%) for ATDs (531) in one study. concurrent glucocorticoids in a particular patient choosing and 10/32 (32%) for RAI compared with 6/56 (11%) for ATDs RAI therapy should be made in light of risk–benefit consid- and 6/58 (10%) for surgery (532) in the older study. high risk for directly involved in GO pathogenesis (516. ATDs. (544). RAI for various GO clinical scenarios..156. or thy- roidectomy should be considered equally acceptable Strong recommendation. GO during 1 year of follow-up (69. hypertension. Currently most task force members use a minimum starting dose of 30 mg prednisone daily and tapering off within 6–8 & RECOMMENDATION 102 weeks. moderate-quality evidence. or thyroidectomy should be considered equally acceptable therapeutic options in regard to risk of GO.2 mg/kg per day for 6 weeks) may be be a factor in the selection of therapy for hyperthyroidism in equally effective for prevention of GO exacerbation in this group of patients (531). one in Risk factors for side effects of oral corticosteroids include the ATD group. the evidence is insufficient 0. a retrospective cohort study sug- GO. the initial data regarding the impact of No recommendation.e. glucocorticoids for various GO clinical scenarios. balanced the cases of new or worse GO were usually mild. their personal risk of worsening GO.1% frequency of GO costeroids is high may be better treated with ATDs or sur- development (541). and predisposition to infections.2. With regard to Weak recommendation. active smokers who number of cigarettes smoked per day. Unfortunately. Experimental evidence suggests that these antibodies are pretreatment TRAb levels (normal <1. and one in the surgical group) requiring specific poorly controlled diabetes. the use of prophylactic corticosteroids in smokers who receive RAI and have no evidence of GO.531). & RECOMMENDATION 105 Strong recommendation. Smokers in cohort study identified no difference among ATD. therapy. The higher risk of GO development after gery. Table 14 details further the use of glucocorticoids In smoking patients with GD without apparent GO. RAI therapy (without concurrent steroids). For personal use only. insufficient evidence. continued for 1 month. Besides smoking. Technical remarks: Clinicians should use smoking cessation programs based on effective and evidence-based approaches [U4] Treatment of hyperthyroidism in patients with active to aid in smoking cessation and avoidance of secondhand GO of mild severity (see Tables 12 and 13 for definitions of smoke (538. There is evidence that corticosteroids given concurrently The dose of corticosteroids validated in a randomized clin- with RAI may prevent worsening of GO in patients with mild ical trial for GO prophylaxis is the equivalent of prednisone active eye disease (531). and former smokers received RAI represented the group with the highest inci- have significantly lower risk than current smokers. in two different studies. & RECOMMENDATION 106 Weak recommendation. Fortunately.233 from online. one prospective but nonrandomized chiatric disease. should be considered equally acceptable therapeutic options. the main risk factors for deterioration RAI therapy in the majority of studies may be related to the of GO to be considered in this decision include active and unique increase in TRAb levels observed following this therapy progressive GO over the preceding 3 months and high serum (172). development or progression after RAI therapy for hyperthy- roidism to be between 10% and 39% (69.com at 01/28/18.5 mg/kg per day. with only 6/ against their risk of developing glucocorticoid side effects). and thyroidectomy In nonsmoking patients with GD without apparent GO. various GD therapies on GO outcome were affected by the . that risk appears to be lower. osteoporosis.9%–7. low-quality evidence.4–0. & RECOMMENDATION 104 parent GO In patients with Graves’ hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration & RECOMMENDATION 101 of their eye disease. However. In contrast. GO progression if >8.543). However.531). ATDs. In GD patients with mild GO who are treated with RAI we recommend steroid coverage if there are concomitant risk & RECOMMENDATION 103 factors for GO deterioration. and whom the risk–benefit ratio for the concurrent use of corti- RAI treatment. mild active GO who are treated with RAI.542. low-quality evidence. Table 14 further details the use of patients with initially mild or absent eye disease. The relatively low absolute risk of nonsmokers developing gested that even lower doses and shorter duration of oral new-onset severe GO suggests that GO prevention should not prednisone (about 0. started 1–3 days after RAI adminis- for recommending prophylactic treatment with corticosteroids tration.540). In the absence of any strong contraindication to GC use we suggest considering them for coverage of GD patients with Downloaded by 5. even in the Several randomized trials have identified the risk of GO absence of risk factors for GO deterioration. therapeutic options in regard to risk of GO. 168 patients in this second trial (four in the RAI group. disease activity and severity) [U3] Treatment of hyperthyroidism in patients with no ap. with an overall 4.75 IU/L. moderate-quality evidence. There is insufficient evidence to recommend for or against Strong recommendation. even after dence (23%–40%) of new GO or deterioration of pre-existing adjusting for lifetime cigarette consumption (537). the risk of new GO development.liebertpub. erations (i. moderate-quality evidence. and then tapered over 2 in nonsmoking patients who do not have clinically apparent months (525). The risk is proportional to the However. but they do not address media exposure is not recommended for all patients. However. 33% of pa- We are aware of no trials in patients with moderate-to. Smoking history did not impact GO outcome patients (38. CAS ‡1) increased that risk. Alternatively. if ATDs are selected for GD therapy. early thyroxine therapy.4%) required GO-directed therapy. deterioration of eye disease to be elevated at 3. 1390 ROSS ET AL. severe GO (531). Whether high- Tables 12 and 13 for definitions of disease activity and severity) dose glucocorticoid therapy would have made a difference in these patients is not known. or reactivation in approxima- tely 7% of patients (6/83) considered at low risk who were Strong recommendation. Two early & RECOMMENDATION 108 nonrandomized studies found no differences between the three GD therapeutic modalities (541.156. or RAI (532) found the relative risk for and smokers) that approach might have to be reconsidered.28 mg/kg per day tapered rapidly over 6 weeks) or no factor for an undesirable GO outcome. more recent randomized controlled trial studying mainly patients with There is a low rate of GO progression or reactivation previously treated GD showed RAI therapy to be associated following RAI in patients with inactive GO. Table 14 sence of risk factors was low (4. low-quality evidence. velopment or deterioration of preexistent GO after RAI Surgery or ATDs are preferred treatment options for GD in therapy for relapsing GD patients (550). suggesting that surgery is not detrimental to GO and may be associated with im. & RECOMMENDATION 107 Another study retrospectively examined the effect of con- In patients with active and moderate-to-severe or sight. GO (high thyroid stimulating antibody. there Weak recommendation. A series of 72 with an increased risk of GO progression (RR of 5. and only 7 and moderate-to-severe or sight-threatening GO (see cases (2. glucocorticoids had worsening of GO. There appeared to be no difference in such risk between ATDs and surgery. In this last trial there prophylaxis at all. T2-weighted imaging T2SIR £1) to receive either gluco- existing GO occurred at a similar percentage in both groups corticoid prophylaxis with low-dose prednisolone (on aver- (45% for RAI and 47% for ATD). Only two of these cases had preexistent inactive GO.com at 01/28/18. Despite prophylaxis. most GO cases were mild. Table 14 further details the use of glucocorticoids for var- roidectomy. [V] How should iodine-induced and amiodarone- provement in some patients. They identified GO these patients. CAS ‡1 with ATDs. The rate of disease progression in the ab- was no routine use of prophylactic glucocorticoids. A large. Smoking was a strong risk age 0. (536). no deterioration in eye disease was vealed an increased risk for new or worse GO in RAI-treated reported (536). lack of prespecified criteria for dose and route of steroid use severe GO showed that the eye disease improved during 3 in those considered at risk. to be mainly related to de- velopment of new GO cases.. For those in whom hypothyroidism was prevented by nally.liebertpub. development.3% of the group). patients (21. the most recent randomized controlled trial (69) re.545). compared to ATDs. tients considered at high risk who were treated with oral severe and active eye disease that compare hyperthyroid. low-quality evidence. Fi. current oral or intravenous glucocorticoid therapy on the de- threatening GO we recommend against RAI therapy. because ism therapies for impact on GO. low-quality evidence. A recent trial from Japan (540) random- ized patients without GO or inactive GO (i. a more recent induced thyrotoxicosis be managed? study suggests that surgery might lead to a more rapid [V1] Iodine-induced hyperthyroidism improvement in GO than ATDs.549). again without a benefit from low-dose steroid pro- [U5] Treatment of hyperthyroidism in patients with active phylaxis. developing iodine-induced hyperthyroidism or whose . in preexistent GO) assigned to therapy for hyperthyroidism cases of elevated risk for reactivation (high TRAb. Other studies suggest that ATDs may not Routine administration of ATDs before iodinated contrast adversely impact mild active GO.7% of the group) compared with ATD-treated in this cohort.2. improved in the remainder (547). given no steroid prophylaxis. In another series of our deliberations regarding the above recommendation. absence of GO activity assessment and lack of stratification [U6] Treatment of GD in patients with inactive GO (see on smoking status at randomization as well as by variation in Table 12 for definition of disease inactivity) the timing of tackling post-RAI hypothyroidism. Ultimately. In patients with inactive GO we suggest RAI therapy can The first randomized study of GD patients (13% with mild be administered without steroid coverage. we weighed this evidence less in years of follow-up in all patients (546). However.e. exophthalmos was stable in 60% of cases and ious GO clinical scenarios.2 for RAI Weak recommendation. However. CAS <3 or Downloaded by 5.8 in patients with inactive GO according to the CAS were treated comparison with ATDs) and found the risk to be eliminated with RAI without concurrent glucocorticoid administration with concurrent corticosteroid administration (531). For personal use only. are reassuring data that long-term use is relatively safe and effective at preserving euthyroidism while waiting for GO to Technical remarks: Patients deemed to be at high risk of enter remission (66. while worsening of pre. a comparison of of the lack of clarity of this retrospective study regarding two different surgical approaches (total thyroidectomy vs. and it might thus be a better option for patients that are most concerned about GO & RECOMMENDATION 109 changes (548).2%) and not impacted further details the use of glucocorticoids for various GO by glucocorticoid therapy. Additionally. surgery. The presence of risk factors for clinical scenarios.233 from online. prevalence of active and inactive GO in each group and the subtotal thyroidectomy) for patients with moderate-to. deterioration. 42 patients with progressive GO treated with total thy. Interestingly.98 patients with underlying thyroid autonomy in a nodular ([95% CI. pa. A study of pa.578).9% of 1752 patients undergoing coronary angiography uating the adequacy of monitoring for adverse effects from developed a suppressed TSH with normal free T4 and T3 amiodarone have shown suboptimal results (577.03). darone therapy. thyroid hormone levels following a single exposure to in. and therefore iodine repletion in this setting has his. For personal use only. Amiodarone-induced thyrotoxicosis (AIT) occurs in up to a New Zealand study in which subclinical hyperthyroidism 6% of patients taking this medication in iodine-sufficient developed in 2 of 102 (2%) patients after a CT scan with areas of the world (573–575) and in up to 10% in iodine- iodinated contrast (567).to 6-month intervals thereafter.2%) developed a suppressed TSH value 1–4 weeks following exposure to a dine (a spot urine iodine adjusted for urine creatinine con- single computed tomography (CT) study with contrast. levels (568). less commonly. but it may occasionally persist for months (551. whereas an Aus. Treatment of iodine-induced hyperthyroidism includes tients with occult GD (558) or patients with a prior history of avoidance of additional iodine and administration of b-blockers GD who are in remission after a course of ATDs (559). hyperthyroidism. and that 23 patients would goiter. low-quality evidence. low-quality evidence. Additional observational studies in the United States and Japan involving 56 and 22 patients. whereas type 2 AIT occurs as a result of direct need to be exposed before encountering one case of iodine.60]. the likelihood of Strong recommendation. p = 0. found no [V2] Amiodarone-induced thyrotoxicosis new cases of hyperthyroidism following coronary angiogra.9% of 101 patients by 8 development of AIT. because (i) this drug is frequently the only medication able to . The need for amiodarone discontinuation is controversial ciated with prophylactic ATD therapy. low-quality evidence. but it can occasionally be severe.233 from online. viously believed.25%) patients developed ment of refractory atrial or ventricular tachyarrhymias. with a return to baseline urinary iodine ex- Multiple observational studies have examined changes in cretion within 1–2 months in most patients (565. darone (579–582). a study from Italy that found that deficient areas. the clinical manifestations and presence or absence of ef- In summary. including an iodine-induced form of weeks following coronary angiography (569). assess the rate of clearance of the iodine load. Overall. a recent meta. hyperthyroidism (type 1 AIT) due to the high iodine content A recent case–control study in the United States found that of amiodarone (37% by molecular weight) and a destruc- iodinated contrast exposure in patients without baseline tive thyroiditis (type 2 AIT) due to direct toxicity of amio- thyroid abnormality resulted in hyperthyroidism (defined darone on follicular cells. similar rates of iodine-induced hyperthyroidism have been described in iodine-deficient regions. 1. given either as a daily or twice- 565) and iodine-deficient (566–569) regions. Technical remarks: Dosing of MMI for iodine-induced travenous iodinated contrast in both iodine-sufficient (562– thyrotoxicosis is 20–40 mg/d. & phy (564) or hysterosalpingography (563). analysis including nine randomized-controlled trials and eight observational studies involving iodine supplementation & RECOMMENDATION 112 of young children and pregnant women in regions of mild to The decision to stop amiodarone in the setting of thyro- moderate iodine deficiency did not find an increased risk of toxicosis should be determined on an individual basis in thyroid dysfunction following iodine supplementation of consultation with the treating cardiologist. limited. depending on the severity of hyperthy- rarely.552) Strong recommendation. For most clinical circumstances.572). mon and generally subclinical. overt hyperthyroidism following coronary angiography (566). fective alternative antiarrhythmic therapy.156. Individuals who are the most susceptible are elderly patients with autonomously functioning nodular goiters (557) and. and at 3.liebertpub. Recent data nodules. Very alone or with ATDs. daily dosing.8%) of patients developed overt hyperthyroidism and within the first 3 months following the initiation of amio- an additional two patients developed subclinical hyperthy. roidism within 8 weeks of iodinated contrast exposure (562).2. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1391 & RECOMMENDATION 110 cardiac status is tenuous at baseline may be considered for prophylactic therapy with ATDs. tients living in Boston showed that 5 of 49 (10. with MMI should be used to treat overt iodine-induced nomenon) is uncommon in modern series and generally self. and finally. RAI is not an with a previously normal thyroid gland (560). RECOMMENDATION 111 tralian study from a region of iodine sufficiency found that 2 We suggest monitoring thyroid function tests before and of 72 (2. Type 1 AIT tends to occur in only as a suppressed TSH value) with an odds ratio of 1. depending on 200–300 mg/d (571). Urinary io- Downloaded by 5. respectively. with centration or a 24-hour urine iodine) may be monitored to only one patient developing overt hyperthyroidism (565). There may be relative resistance to ATD in patients with iodine-induced hyperthyroidism. Chronic iodine option until the iodine load has been cleared and might not be deficiency increases the prevalence of autonomous thyroid desirable given the reversibility of this condition. Studies eval- 1.com at 01/28/18. such as parts of Europe (576). and may be life-threatening (553–556). damage or induction of apoptosis in thyrocytes by amio- induced thyrotoxicosis (570). including a study Amiodarone is a drug that is frequently used in the treat- from Germany in which 2 of 788 (0. Weak recommendation. a Turkish study identifying new Two distinct mechanisms have been proposed in the subclinical hyperthyroidism in 5. iodine-induced hyperthyroidism is uncom.08–3. developing overt thyrotoxicosis after iodinated contrast ex- posure is too low to justify the risk of adverse effects asso. iodine excess may trigger thyrotoxicosis in patients roidism and the clinical status of the patient. suggest that urinary iodine normalizes more rapidly than pre- torically been linked to iodine-induced hyperthyroidism (561). Beta-adrenergic blocking agents alone or in combination Iodine-induced hyperthyroidism (the Jod–Basedow phe. or GD. dence supporting a distinct subtype of overt AIT may be tried Several methods have been examined to distinguish type 1 on appropriate monotherapy. once promoted as useful for dis- to T3 conversion in the heart (583) such that withdrawal may tinguishing between subtypes (590). In addition. low-quality evidence. low-quality evidence. and 20% thought both techniques were clinically to allow a trial of monotherapy or who fail to useless (602). For personal use only. respond to single modality therapy. Two studies showed a clear separation into type 1 and type 2 AIT. sestamibi uptake by the thyroid. When identified with certainty. In a series of 55 patients in whom a CFDS qualitative tients with proven underlying autonomous thyroid nodules assessment of vascular flow was used to distinguish type 1 or GD as the cause of AIT (type 1 disease).3% of patients determined to have type 1 steroids should be used to treat patients with overt AIT had pattern I vascularity (the lowest level above zero).001) (605). the T3-to-T4 ratio. In another Strong recommendation. First. we suggest mea. amiodarone-induced thyroiditis (type 2 disease). 12 patients were suring thyroid function tests to identify disorders associ.604). one therapy is continued (585–587). it is not unexpected that iodine- patients cannot be readily classified into one of the two AIT induced thyrotoxicosis occurred early in the course of subtypes. classified as type 2 due to an absence of vascularity (CFDS 0) ated with iodine-induced hyperthyroidism (type 1 AIT). cannot veloped AIT a mean of 5. but only 7 (58%) proved specifically including toxic nodular disease and previously responsive (584). findings of more likely to have type 2 AIT.589). Interleukin- T3-antagonistic properties at the cardiac level and inhibit T4 6 levels and RAIU values. illustrating the skill and nuance needed to successfully make Strong recommendation.233 from online. a patient AIT. once classified as having type 1 or type 2 amiodarone therapy. Finally. but with the possible exception of color flow type 1 AIT is best treated with MMI to prevent new hormone Doppler study (CFDS). although spontaneous resolution independent of Patients who are clinically stable and have definite evi- therapy is one possible explanation. 81. CFDS is not universally useful In clinically stable patients with AIT. cation system. Nineteen percent of patients (38/200) de- (586. In a series of 24 cases of AIT. some patients with mild type 2 AIT (ap- subtypes. the authors found that among 11 occult GD. results (603. (599–601).156. or patients in whom which is diminished with thyroiditis. 36 of whom had type 2 AIT. is not helpful in this instance because therapy such as prednisone. found that the onset of thyrotoxicosis was significantly earlier in type 1 (median 3. Type 2 AIT is better treated with anti-inflammatory destructive thyroiditis. patients classified as type 1 AIT based on CFDS scores of I– III. many thyroid nodules or TMNG. such as antibodies against thyroid peroxidase and proximately 20%) resolve spontaneously without stopping the presence of thyroid nodules in patients with type 1 AIT.593). based on these data. 10 (33%) & patients could not be subtyped on the basis of CFDS. and cortico- from type 2 AIT. as discussed further below. has been applied for the etiology of thyrotoxicosis cannot be unequivocally distinguishing AIT subtypes with preliminarily promising determined. A recent retrospective report including 200 AIT patients Strong recommendation. series of 30 patients with AIT requiring therapy. disease (585. (iii) amiodarone may have of these abnormalities in the general population. (ii) the effects of this fat-soluble may actually occur with both subtypes. given the prevalence drug may persist for many months. nearly 40% utilized both meth- to treat patients with overt AIT who are too unstable ods simultaneously. Secondly. in- RECOMMENDATION 114 cluding several patients with goiters but normal vascular flow MMI should be used to treat overt thyrotoxicosis in pa- (589). (584. from type 2 AIT. which tends to be higher in (250 mg four times daily. However. this distinction (599).600). approximately 20% preferred RAIU alone. the (median 30 months.5 months after the drug was stop- be adequately explained on the basis of the current classifi.589.607). Recently. range 1–61 months) than type 2 As the pathogenesis of AIT is not fully understood. make no attempt to classify patients into type 1 or type 2 type 2 AIT typically responds to treatment even if amiodar. actually overlap exten- actually aggravate cardiac manifestations of thyrotoxicosis sively between the two subtypes and are therefore also not (573). Another observation reported responsiveness in patients with type 2 AIT to measures not in this study is the development of AIT following amiodarone typically useful in destructive thyroiditis. but not type 2 AIT future recurrences of AIT (588). with improvement occasionally of amiodarone-associated inhibition of T4 monodeiodination seen as early as 1 week. ped. However. p < 0.liebertpub. low-quality evidence. 1392 ROSS ET AL.5 months. features historically used to distinguish the As noted above. Deaths from ventricular fibrillation have occurred after useful (594). patients often fail to respond to therapy specifically with late onset of AIT in whom GD has been excluded is directed to that subtype (583. (594). Likewise. and treated with corticosteroids.591) and oral cholecystographic agents (592. control cardiac arrhythmia. such as perchlorate discontinuation.590).595–598). Downloaded by 5. classic division of AIT into two subtypes likely represents an Since 80% of type 1 patients in this study had autonomous oversimplification. amiodarone or administering corticosteroids (606. only four (36%) responded to ATD therapy. Combined ATD and corticosteroid therapy should be used 20% preferred CFDS alone. but continuation may Several studies have shown that increased vascularity on lead to a more prolonged time to recovery and a higher rate of CFDS may be seen in patients with type 1.2. and usually within a few weeks (590). not available in the United States) patients with autonomous thyroid glands than in those with (590). .com at 01/28/18. Among European thyroidologists sur- veyed on the use of diagnostic imaging in the differential & RECOMMENDATION 115 diagnosis of AIT. Further. synthesis and rarely with added potassium perchlorate For example. most are considered unreliable (574). range 1–95 months. allowing successful application of targeted & RECOMMENDATION 113 therapy (599. Several modern series of patients with AIT stopping amiodarone in patients with AIT (584). and euthyroidism was achieved in all (594) and allows a reduction in ATDs. re. although some patients after an average of approximately 6 weeks (591). Patients are with type 2 AIT have a prolonged course. A suggested approach to the management of amiodarone-induced thyrotoxicosis. For personal use only. Technical remarks: The suggested starting dose of MMI in Patients recovering from apparent type 2 AIT should be mon. Some referred to as having ‘‘mixed’’ types of AIT. which appears to occur (generally 3–6 months). tients. splitting the dose may be more effective. corticosteroids at the time of initial AIT diagnosis (594. A suggested approach to the management of AIT is an outcome of permanent hypothyroidism. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1393 Most series of patients with AIT contain cases in which Importantly.606). both of which shown in Figure 1. and between 16% and 25% of surveyed thyroidologists prefer sulting in euthyroidism in 12 patients (seven with type 1 AIT combination ATD and corticosteroid therapy for patients with and five with type 2 AIT) (591). These patients are frequently combined therapy rather than sequential empiric therapy. A rapid response to combined cor- given to the eight nonresponders (including seven patients with ticosteroid and ATD therapy is believed to favor type 2 AIT presumed type 1 disease).156. this setting is 40 mg once daily until the patient is euthyroid itored for permanent hypothyroidism. would be unlikely in iodine-induced thyrotoxicosis (598.com at 01/28/18. FIG. particularly those with often reclassified retrospectively from type 1 to type 2 AIT larger thyroids or worse thyrotoxicosis at the time of diagnosis based on a positive response to corticosteroid therapy or after (611). . In a study of 20 centers recommend starting combined therapy with ATDs and patients with AIT that included both type 1 and type 2 pa. 1. individuals with moderate thyrotoxicosis and sequential therapy for both subtypes was required before compromised cardiac status should be considered for initial resolution of AIT occurred. The Downloaded by 5. perchlorate was administered alone for 1 month. Corticosteroids were then apparent type 2 AIT (610). required.609).liebertpub. If high doses of MMI continue to be more often with AIT than with subacute thyroiditis (608).2.233 from online. early in the course of the disease. RAIU is Strong recommendation. Thyroid pain and the elevated ESR stopped during an episode of AIT should be considered for have usually resolved by this time. is a common cause of thyroid pain treated instead with corticosteroid therapy. A retrospective review found the thyroid. although lowed by a gradual taper over 2–3 months. often radiating to the ears. laboratory data. rather sively debilitated from inadequately controlled thyrotoxico- than the enhanced flow characteristic of GD (621. followed by a gradual taper over 2–4 weeks or longer. within 12 months of disease onset.2. and Subacute thyroiditis is treated with b-blockers and anti- palpation thyroiditis will be discussed. About with AIT have now been published.620. including sub. based on the this is often mild.233 from online. regional anesthesia when available may be preferred for very Downloaded by 5.liebertpub. Corti- tive) thyroiditis. low-quality evidence. free T4 level may be elevated preferentially compared to the total T3 level. of patients required longer than 8 weeks to discontinue the About 50% of patients with subacute thyroiditis have an glucocorticoid (624).614–616). and drug-induced thyroiditis. However. RAIU is low. although 5%–15% have persistent hypothyroidism (24.620. The serum TSH level is suppressed. and fatigue. symptoms can recur as the dose of cor- The thyroid may be slightly enlarged and is firm and painful ticosteroid is reduced (24).622). In addition. patients with mild symptoms and should be considered first- line therapy. The patient should be counseled that while thyroidectomy biopsy of the thyroid gland is usually not necessary in sub- in this setting carries with it significant morbidity and a high acute thyroiditis. 8 days) com- gland over several weeks. 35 days). be treated initially with b-adrenergic-blocking drugs and acute thyroiditis. In general. Subacute thyroiditis is thought to be due to a a lower initial daily dose of 15 mg of prednisolone. and mild anemia and elevation of the WBC count are common.620). Levothyroxine may be employed dur- initial thyrotoxic phase due to unregulated release of pre. and decreased or normal color flow Doppler. concentrations of antithyroid antibodies (24. tients may have clinical findings of thyrotoxicosis. Up to 25% of patients have low Strong recommendation. NSAIDs provide pain relief in drug-induced thyroiditis. acute (suppura. and the predominant definitive therapy with RAI or surgery in order to facilitate clinical features are those of hypothyroidism with a small reintroduction of amiodarone without concerns about recur- nontender goiter. Therefore. the erythrocyte sedimentation rate (ESR) or C- undergo thyroidectomy. in contrast to other endogenous forms of thy- & RECOMMENDATION 116 rotoxicosis. Most patients become euthyroid again rent AIT (617). Patients who fail to Subacute thyroiditis. and RAIU. However. painless. & RECOMMENDATION 117 rary thyrotoxicosis as part of a classic triphasic course Patients with mild symptomatic subacute thyroiditis should (thyrotoxicosis. With NSAIDs. Patients in whom amiodarone was can last up to 6 months. Standard recom- (24). see Section [T4] for a inflammatory therapy. with other forms of endogenous thyrotoxicosis (50). fol.com at 01/28/18. painless (silent) thyroiditis. thyroid fail to respond or present initially with moderate to severe dysfunction caused by thyroiditis is less severe than that seen pain and/or thyrotoxic symptoms. A more recent study reported that to palpation. The thyrotoxic phase usually lasts 3–6 weeks. pharyngitis symptoms. if a biopsy is performed due to mortality rate (9%). as is uptake on a thyroid scintigram. The pain that patients treated with corticosteroids at similar doses had may begin focally and spread from one side to the other of the more rapid resolution of pain (mean duration. For personal use only. and the patient’s clinical response.621). reactive protein is elevated. delay or deferral of surgery imparts an uncertainty of the diagnosis. malaise.619. although substantial overlap occurs among the Patients with AIT who are unresponsive to aggressive etiologies (618). with ta- sequela of an upper respiratory viral infection that involves pering by 5 mg every 2 weeks. nonsteroidal anti-inflammatory agents (NSAIDs). 20% the thyroid gland. owing to leaking of preformed thyroid hormone with suppression of serum TSH concentrations. also called subacute granulomatous respond to full doses of NSAIDs over several days should be or de Quervain thyroiditis. Patients may have a prodrome of pared with those treated with NSAIDs (mean duration. The diagnosis of subacute thyroiditis is based on clinical mendations are to use prednisone 40 mg daily for 1–2 weeks history. jaw. universally low during the thyrotoxic stage. postpartum costeroids should be used instead of NSAIDs when patients thyroiditis. 1394 ROSS ET AL. suggested dose of corticosteroids in this setting is equivalent cells (24). In this section. or throat. Beta-blockers are used as needed to discussion of postpartum and Section [X] for a discussion of control thyrotoxic symptoms. de- Subacute thyroiditis presents with moderate-to-severe pain in pending upon clinical response. recur- [W] How should thyrotoxicosis due to destructive rence rates of 1%–4% have been reported (24. However. thyroiditis be managed? Several varieties of thyroiditis can present with tempo. focal hypoechoic should be offered thyroidectomy before they become exces- areas. low-quality evidence. the median time for resolution of [W1] Subacute thyroiditis pain is 5 weeks (range 1–20 weeks) (24). pa- to 40 mg prednisone given once daily for 2–4 weeks. consistent with a viral infection (24). was effective. hypothyroidism. palpation (traumatic) thyroiditis. In addition to laboratory evidence of thy- medical therapy with MMI and corticosteroids should rotoxicosis. with recovery of normal function verified by thyroid . Thyroidectomy done under infiltrate and giant cells. with generally favorable 30% of patients subsequently enter a hypothyroid phase that results (612. ending when ill patients (613). A sis. recovery). acute. low-grade fever. Thyroid ultra- Patients with AIT who fail to respond to medical therapy sonography shows diffuse heterogeneity.156. ing the hypothyroid stage but should be withdrawn after 3–6 formed thyroid hormone from damaged thyroid follicular months.623). Several surgical series involving patients the thyroid stores of preformed hormone are depleted. subacute. its result shows granulomatous even higher risk of death (612). physical examination. 1 mU/L. including interferon (IFN)-a. corticosteroids have been used to Strong recommendation. postoperative TSH levels measured (637). These tests and the absence of TRAb antibodies be managed? help distinguish painless thyroiditis from GD (628). including that associ. The latter group included 33 patients with mild Beta-blockers may be used to treat symptoms of thyro- TSH suppression and 24 with a TSH value <0. Patients treated with IFN-a and interleukin-2 patients are at increased risk for developing thyrotoxicosis. (632) described a nonspecific multi- in most patients. low-quality evidence.233 from online. During the thyrotoxic phase. A small nontender goiter is common in the offending pyriform sinus. and ultrasound often shows inhomogeneous hypoechogenic texture with decreased [X] How should other causes of thyrotoxicosis blood flow. but ing to the erroneous diagnoses of subacute thyroiditis (631). Postpartum and drug. should be monitored clini- cally and biochemically at 6-month intervals for the de- Beta-adrenergic blockers can be used to treat thyrotoxic velopment of thyroid dysfunction. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1395 function testing. but sions in and around the affected thyroid lobe. sis. on occasion. ameliorate the severity and the time course of thyrotoxicosis due to painless thyroiditis (629). Normal thyroid function is reestablished by 12 months In 1975.liebertpub.627). months. The postpartum period is the cess. showing hypoechoic le- same triphasic course described for subacute thyroiditis. Thyrotoxicosis in patients treated with IFN-a . often lead- most common time when painless thyroiditis is seen. RECOMMENDATION 118 Patients with symptomatic thyrotoxicosis due to painless & RECOMMENDATION 120 thyroiditis should be treated with b-adrenergic-blocking Patients taking medications known to cause thyrotoxico- drugs to control symptoms.’’ con- rence rate of 65% (626). the lobe. kinase inhibitors. neck pain. therapy (638). For personal use only. rative thyroiditis or thyroid abscess) are generally euthyroid. lasting up to 6 [W4] Palpation thyroiditis Downloaded by 5. but 10%–20% have persistent hypothyroid. spread or direct extension through a fistula from an infected ated with lithium or cytokine therapy. except for rare case reports of patients who developed following recovery from the thyrotoxic phase (626). radiologic examination may be nonspecific. early in the pro- or C-reactive protein (625). There are no data on often out of proportion to T3 levels. there is no role for ATDs. the there was likely ascertainment bias because not all patients had serum TSH level is suppressed and free T4 levels are elevated. either through hematogenous of drug-induced thyroid dysfunction. these patients. typically lasts 3–4 months. and abscess formation. but may be higher in surgery for thyroid-related or unrelated conditions. thyrotoxicosis following manipulation of the thyroid gland Painless thyroiditis is probably an autoimmune disease during surgery (633–636). and lithium. with one Japanese study reporting a long-term recur. Patients who develop symptoms in patients with painless thyroiditis. among whom 11 had free T4 elevation and five required ATD Strong recommendation.6%) patients developed a suppressed TSH surgical drainage as determined by clinical judgement. Recurrence rates are about 5%–10%. focal granulomatous folliculitis in thyroid glands removed at ism. Carney et al. since new hormone synthesis is already low in and treated accordingly. Therapy involves systemic antibiotics as well induced thyroiditis are discussed in detail in Sections [T4] as abscess drainage or removal.156. and excision or occlusion of and [X]. It was generally thought to be of little clinical im- recurrences have opted for surgery or RAI ablation of the gland portance. ATDs have no role in the treatment of Patients with acute thyroiditis (also referred to as suppu- subacute thyroiditis. destruction of with no prodrome. but they should be reserved [X1] Interferon-a and interleukin-2 for severe cases only. but rare patients with multiple surgery. but ATDs thyrotoxicosis should be evaluated to determine etiology have no utility. low-quality evidence. respectively. especially [W3] Acute thyroiditis those with pre-existing thyroid autoimmunity. Ultrasound or CT ex- Painless or silent thyroiditis classically presents with the aminations are usually diagnostic. Rarely.2. the condition presents as destructive [W2] Painless thyroiditis thyroiditis with thyrotoxicosis (630). Thyrotoxicosis should be trea- all types of painless thyroiditis. As in other The thyrotoxic phase occurs in 5%–20% of patients and forms of destructive thyroiditis. tyrosine Strong recommendation. low-quality evidence.4%) patients developed a biphasic thyroiditis and Acute thyroiditis should be treated with antibiotics and an additional 57 (4. Tables 16 and 17 summarize drug-associated and unusual & causes of thyrotoxicosis. pyriform sinus. although the use of b- thyroiditis have a low RAIU and low uptake on a thyroid blockers for symptomatic thyrotoxicosis seems reasonable. The hypothyroid phase is more common or at least is recognized more often.com at 01/28/18. or elevated ESR. WBC count. toxicosis. value (638). However. Recurrences are managed in the same cluding that it was due to palpation of the thyroid gland at manner as the initial occurrence. However. scintigram during the thyrotoxic phase. However. They Japan. following parathyroid surgery may be as high as 30%. A recent study & including 1233 patients who were euthyroid at baseline found RECOMMENDATION 119 that 79 (6. interleukin-2. Patients with painless treatment of palpation thyroiditis. named this pathologic entity ‘‘palpation thyroiditis. Painless thyroiditis has been described in some types infection affecting the thyroid. ted symptomatically with b-blocking agents. although tion on pathology (626. a recent study suggested manifested by positive anti–thyroid peroxidase antibodies in that the rate of transient overt or subclinical thyrotoxicosis about 50% of patients and findings of lymphocytic infiltra. painless thyroiditis can also occur in nonpregnant women and The etiology of acute thyroiditis is most frequently a bacterial in men. 4% of referrals to a thyroid clinic over a 12-year thyroiditis. if severe.com at 01/28/18.8%) had GD. respectively 2. corticosteroids Radioactive iodine for GD 3–6 months Antithyroid drugs TMNG.4% of 1664 patients treated with IFN-a therapy for hepatitis (653. liothyronine. One study of 69 patients treated with sorafenib for period were for lithium related thyrotoxicosis (656). In a [X3] Lithium review of published cases from eight series. two had TMNG. A smaller series described three Table 17. . associated thyrotoxicosis as the etiology in 0. either positive TRAb titers or requirement for a prolonged Two published series have identified the development of course of ATDs (640).7% of all cases (432).654). thyrotoxicosis factitia. thyroid extract.2. TMNG in three patients. human chorionic gonadotrophin. Patients taking lithium for bipolar disorder are at a high tients with IFN-a–associated thyrotoxicosis for whom an risk of developing thyroid dysfunction. and one patient had rotoxicosis. Patients metastatic renal cell carcinoma found that 11 (16%) devel. late Repeat RAI Surgery a Thyroid hormone ingestion.6% and 3. Months Supportive careb GD ATDs and/or RAI (GD only) Interleukin-2 Painless thyroiditis Months Supportive careb GD ATDs and/or RAI (GD only) Iodinated contrast Underlying thyroid Weeks to months Antithyroid drugs autonomy Tyrosine kinase inhibitors Destruction 3–12 months Supportive care Radioactive iodine. 1396 ROSS ET AL. suppressed thyroglobulin Psychosocial evaluation (surreptitious LT4 or LT3) Functional thyroid cancer metastases Whole-body RAI scanning RAI ablation.6–25 years). in this series had been taking lithium for a median duration of oped transient thyroiditis followed by hypothyroidism (649). may cause thyrotoxicosis—see Section [X7]. early Destruction 1–4 weeks Observation. painless thyroiditis The tyrosine kinase inhibitors sunitinib (642–647). 6 years (range 0. An epidemiological study of hyperthyroidism C infection developed thyrotoxicosis. Another more recent series ciated with a transient thyrotoxicosis due to destructive found that 1. etiology in seven patients (655). perchloratec Surgery Thyroiditis (type 2) Often >1 year Supportive careb Corticosteroids Surgery Lithium Painless thyroiditis Often >1 year Supportive careb GD ATDs and/or RAI (GD only) Interferon a Painless thyroiditis. An earlier literature review found that thyrotoxicosis in 0. a-subunit to TSH ratio Surgical removal Struma ovarii RAI uptake over pelvis Surgical removal Choriocarcinoma hCG elevation in the absence of pregnancy Surgical removal Thyrotoxicosis factitia Absence of goiter. sor. Unusual Causes of Thyrotoxicosis Disorder Diagnosis Primary management TSH-producing adenoma Pituitary MRI. MRI. in two patients. subacute thyroiditis (656). c Not available in the United States. embolization and/or surgical removal hCG. and nonprescription supplements that contain thyroid hormone. had painless thyroiditis. although the specific occurring over a 3-year period in Denmark identified lithium- etiology was not consistently identified (641). and no identified afenib (648–650). including levothyroxine.liebertpub. based on pothyroidism and to a lesser extent thyrotoxicosis (652). including one case of thyroid storm (644).233 from online. and 87% were women. including both hy- etiology was identified were found to have GD. can be due to either painless thyroiditis or GD (639).3%) receiving sunitinib nostic evaluation found that 11 (47. Diag- Another study found that 6 of 31 (19. and nilotinib (651) have each been asso.0% of patients. magnetic resonance imaging. Causes of Drug-Associated Thyrotoxicosisa Timing of onset following initiation Drug Mechanism(s) of the drug Therapy Amiodarone Iodine induced (type 1) Months to years Supportive careb ATDs. A case series of 24 patients with lithium-associated [X2] Tyrosine kinase inhibitors thyrotoxicosis identified GD in 12 (50%). 69% of 49 pa.156. Table 16. b Supportive care may include beta-adrenergic blockers during the thyrotoxic stage and levothyroxine if hypothyroidism develops. nine (39%) therapy for metastatic renal cell carcinoma developed thy. administer Downloaded by 5. For personal use only. tients treated and a concurrent return to euthyroidism in most representing a nearly 5-fold increase compared to cases of (43). and iodine-induced hy- theoretical concerns of tumor growth. and 3% experienced tumor recurrence (659). equivocal cases. The any thyrotoxic patient with a very low or absent RAIU over patient should be made euthyroid preoperatively. yet Patients with TSH-secreting pituitary adenomas should management is quite different for these two disorders. generally associated with a pituitary tumor experienced tumor volume reduction (661). a-subunit elevation (not useful in postmenopausal women be- Strong recommendation. in cases that prove refractory to medical therapy. 75% normalized previously treated for GD may have persistent or recurrent thyroid function after surgery. elevated sex hormone–binding globulin and resting octreotide and/or external beam radiation therapy may be energy expenditure. perthyroidism. A reduction in tumor size has been observed in 20%– lithium exposure in patients with GD (19). defined as ectopic thyroid tissue existing as molar a-subunit/TSH ratio can be accomplished by dividing a substantial component of an ovarian tumor. the RAI is concentrated in . representing <1% of all ovarian tumors.15 per 1 (661). a response to somatostatin analog therapy with TSH-secreting adenomas (43). thyroid hormones. is quite rare. Technical remarks: Genetic testing for resistance to thy- roid hormone is commercially available and may be useful in Strong recommendation. 57% had & RECOMMENDATION 121 negative tumor imaging after surgery) (659). 9% developed new defi. HYPERTHYROIDISM MANAGEMENT GUIDELINES 1397 cases of GD occurring in patients receiving lithium (657). Patients tients undergoing transsphenoidal surgery. especially in patients without family mem- bers available for thyroid function testing. factitious thyrotoxicosis. TSH. with a prevalence of 2.com at 01/28/18. After excluding laboratory interference with either the largement despite these measures are sometimes treated with free T4 or TSH assay. tumors contain elements of papillary thyroid cancer. and up to 25% of struma ovarii TSH-producing pituitary tumors. Long-term the eutopic thyroid gland. 50% of patients treated with octreotide (43. such with this constellation of findings include various forms of as RAI or thyroidectomy. Patients who fail to respond to pituitary surgery and million inhabitants. pri- represent an even rarer cause of hyperthyroidism. the a-subunit concentration (ng/mL) by TSH (mU/L) and mul. and clinical evidence of thyrotoxicosis. undergo surgery performed by an experienced pituitary secreting adenomas are more likely to have a concurrent surgeon. on MRI or CT and the absence of a family history or genetic Sterotactic or conventional radiotherapy has also been used testing consistent with resistance to thyroid hormone. thyroid tissue (663). presurgical medical treatment did not significantly improve surgical outcome (63% vs. Although most TSH-secreting pituitary adenomas only secrete TSH.660). Approximately 5%– tiplying by 10. TSH-secreting pituitary adenomas are rare tumors and adenomas who are considered poor surgical candidates. but hypopituitarism occurred in 32% of those treated (659). clinical improvement lends support to the diagnosis of a TSH-secreting adenoma in cases in which diagnostic un- [X5] Struma ovarii certainty persists. For patients with TSH-producing Downloaded by 5. However.8 cases per million somatostatin analog therapy or those who have tumor en- (658). cosis (662) due to either autonomous ectopic thyroid function Pituitary surgery is generally the mainstay of therapy for or the coexistence of GD. a blunted TSH response to thyrotropin-releasing hormone (when avail- Technical remarks: Postoperative adjunctive therapy with able). six cases of >50% reduction in serum TSH values in the majority of pa- painless thyroiditis had a history of recent lithium exposure. heterophilic antibodies. Other conditions that present ATD therapy and other measures directed at the thyroid. In a tive therapy with octreotide and dopamine agonist therapy retrospective review of 100 cases of thyroiditis and 400 cases has been examined. For personal use only.2. respectively. co-secretion of prolactin or & RECOMMENDATION 123 growth hormone is possible and should be assessed con- Patients with struma ovarii should be treated initially with currently along with assessment of the pituitary–adrenal surgical resection following preoperative normalization of axis and pituitary–gonadal axes. Recent data mary medical therapy with octreotide can be considered from the Swedish registry reported an incidence of 0. treated with this modality.liebertpub. useful in managing patients with persistent central hyper- as well as an anatomic abnormality on MRI of the pituitary. mean free T4 and T3 levels were reduced by nearly TSH level associated with elevated free T4 and total T3 50% in the first 3 months of therapy and six of seven patients concentrations. low-quality evidence. but less impressive results have been obtained with bromocriptine [X4] TSH-secreting pituitary tumors therapy (660). The diagnosis should be considered in ciencies. low-quality evidence. low-quality evidence. In a recent series of 68 pa. 58% normalized both pituitary hyperthyroidism due to the action of TRAb on the ectopic imaging and TSH hypersecretion. In struma ovarii. Calculation of the Struma ovarii. A ratio greater than 1 favors a TSH-secreting 10% of patients with struma ovarii present with thyrotoxi- pituitary adenoma. Radio- therapy controlled thyroid hypersecretion in 37% of patients Strong recommendation.156.233 from online. In a recent case The diagnosis of a TSH-secreting pituitary adenoma should series of seven patients treated with octreotide without prior be based on an inappropriately normal or elevated serum surgery. cause of concurrent gonadotropin elevation). Preoperative adjunc. are generally avoided because of thyroiditis. distinction between a TSH-secreting adenoma and resistance to thyroid hormone is & RECOMMENDATION 122 important since thyroid function test results are similar. Treatment with octreotide results in a of GD occurring at a single medical center. as may occur with T4 antibodies and radiation therapy. thyroidism after a debulking procedure for nonresectable Finally. Therefore. Stan MN. have been cancer. Ladenson PW. the pelvic region over the teratoma. terests or other relationships with commercial interests. low-quality evidence. Levy EG. American Association of Clinical heterogeneous echotexture and is normal sized or slightly Endocrinologists 2011 Hyperthyroidism and other causes enlarged in painless thyroiditis. Epidemiology. accidental tee for Medullary Thyroid Cancer Registry supported by thyroid hormone ingestion has occurred as a result of eating Novo Nordisk. In general. Burch HB. Klein I.233 from online. Recombinant human TSH should be avoi- the primary tumor. International As- sociation of Endocrine Surgeons. Bahn RS.liebertpub. sidual malignant cells. and End (54). Whereas iatrogenic causes of thyrotoxicosis factitia are easily identified. functioning metastases are treated Treatment of hyperthyroidism due to choriocarcinoma with RAI with the addition of ATDs as needed for persistent Downloaded by 5. In both situations there will be 2. and TSH is recommended in patients with a large metastatic cause of the effect of tumor-derived hCG upon the TSH re. should include both MMI and treatment directed against hyperthyroidism. a small thyroid. Latin American Thyroid Thyrotoxicosis factitia includes all causes of thyrotoxi- Society. Historically. of thyrotoxicosis: management guidelines of the American mal echotexture in an otherwise normal individual who is Thyroid Association and American Association of Clin- ingesting thyroid hormone surreptitiously. Garber JR. Patients with massive metastatic fol- licular thyroid cancer may also exhibit T3 thyrotoxicosis. Montori VM. Cooper DS. ical Endocrinologists. and a low thyroidal RAIU. Greenspan FS. This cross-stimulation only occurs at very levothyroxine. meat contaminated with animal thyroid tissue (‘‘hamburger The remaining authors disclose no significant financial in- thyrotoxicosis’’) (670). American hyperthyroidism due to choriocarcinoma involves both Association of Endocrine Surgeons. 1398 ROSS ET AL. Otolaryngology Head and Neck Surgery. perfusion (672) have been used in this circumstance. Treatment of ican Association of Clinical Endocrinologists. including molar pregnancy Thus. may present with thyrotoxicosis be. agents and ATDs is warranted to restore euthyroidism before Treatment with cholestyramine (671) and charcoal hemo- surgery. Rivkees SA. high levels of hCG. AstraZeneca. Data Monitoring Commit- contain thyroid hormone (669). tumor burden. Standards of thyroglobulin undetectable in immunometric assays. ENDORSEMENTS cinoma presenting with overt thyrotoxicosis may have widely The final document was officially endorsed by the Amer- metastatic disease at presentation (667. since hCG is only a weak agonist for the TSH receptor. surreptitious use of thyroid hormone may REFERENCES present a diagnostic quandary. as well as unintentional ingestion either accidentally. while it is small with a nor. the Care Committee. Typically. Nikolai TF 1995 Treatment guidelines for patients tithyroglobulin antibodies that artifactually render the serum with hyperthyroidism and hypothyroidism. cosis due to the ingestion of thyroid hormone. a high T4/T3 ratio (with exogenous MC. Patients with choriocarcinoma. Cooper DS. a suppressed serum thyroglobulin level.com at 01/28/18. such as in pediatric poisoning Julie Ann Sosa discloses significant financial interests or or pharmacy error. McDougall IR. 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HYPERTHYROIDISM MANAGEMENT GUIDELINES 1421 ABBREVIATIONS NSAID ¼ nonsteroidal anti-inflammatory agent AACE ¼ American Association of Clinical pANCA ¼ antineutrophil cytoplasmic antibody Endocrinologists PTU ¼ propylthiouracil AIT ¼ amiodarone-induced thyrotoxicosis QoL ¼ quality of life ANCA ¼ antineutrophil cytoplasmic antibody RAI ¼ radioactive iodine ATA ¼ American Thyroid Association RAIU ¼ radioactive iodine uptake ATD ¼ antithyroid drugs rhTSH ¼ recombinant human thyrotropin BWPS ¼ Burch–Wartofsky point scale RLN ¼ recurrent laryngeal nerve CAS ¼ clinical activity score RFA ¼ radiofrequency ablation CFDS ¼ color flow Doppler study SH ¼ subclinical hyperthyroidism CT ¼ computed tomography SSKI ¼ saturated solution of potassium iodide ESR ¼ erythrocyte sedimentation rate T3 ¼ triiodothyronine GD ¼ Graves’ disease T4 ¼ thyroxine GO ¼ Graves’ orbitopathy TA ¼ toxic adenoma hCG ¼ human chorionic gonadotropin TBII ¼ thyrotropin binding inhibition IFN ¼ interferon immunoglobulin iPTH ¼ intact parathyroid hormone TBG ¼ T4 binding globulin JTA ¼ Japanese Thyroid Association TcO4 ¼ technetium KI ¼ potassium iodide TMNG ¼ toxic multinodular goiter MMI ¼ methimazole TRAb ¼ thyrotropin receptor antibodies Downloaded by 5.liebertpub.com at 01/28/18.156. For personal use only. MNG ¼ multinodular goiter TSH ¼ thyrotropin MRI ¼ magnetic resonance imaging TSI ¼ thyroid-stimulating immunoglobulin WBC ¼ white blood cell .233 from online.2.