《内分泌系统与代谢》课程教学资源（文献资料）2018ETA甲亢的管理（2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism）

Guidelines European Thyroid Journal Eur Thyroid J2018;7:167-186 Received:April 26,2018 D0t10.1159/000490384 2018 European Thyroid Association Guideline for the Management of Graves'Hyperthyroidism George J.Kahalya Luigi Bartalenab Lazlo Hegedus Laurence Leenhardt Kris Poppee Simon H.Pearcet Department of Medicine l,Johannes Gutenberg University (JGU)Medical Center,Mainz,Germany;Department of Medicine and Surgery,University of Insubria,Varese,Italy:Department of Endocrinology and Metabolism,Odense University Hospital,Odense,Denmark:Thyroid and Endocrine Tumors Unit,Pitie Salpetriere Hospital,Sorbonne issels.Belgium Newcastle University,Newcastle upon Tyne,UK Keywords dine(RAl)treatment or total thyroidectomy.Patients with Graves'hyperthyroidism-Management.Antithyroid drugs newly diaanosed graves hyperthvroidism are usually medi Radioiodine therapy.Thyroidectomy.Graves'orbitopathy cally treated for 12-18 months with methimazole(MMI)as the preferred drug.In children with GD,a 24-to 36-month course of MMI is recommended.Patients with persistently Abstract high TSH-R-Ab at 12-18 months can continue MMI treat- Graves'disease (GD)is a systemic autoimmune disorder ment,repeating the TSH-R-Ab measurement after an addi characterized by the infiltration of thyroid antigen-specific T tional 12 months,or opt for therapy with RAl or thyroidec- cells into thyroid-stimulating hormone receptor(TSH-R)-ex- tomy.Women treated with MMI should be switched to pro- pressing tissues.Stimulatory autoantibodies(Ab)in GD acti- pylthiouracil when planning pregnancy and during the first vate the TSH-R leading to thyroid hyperplasia and unregu- trimester of pregnancy.If a patient relapses after completing lated thyroid hormone production and secretion.Diagnosis a course of ATD,definitive treatment is recommended;how- of GD is straightforward in a patient with biochemically con- ever,continued long-term low-dose MMI can be considered. firmed thyrotoxicosis,positive TSH-R-Ab,a hypervascular Thyroidectomy should be performed by an experienced and hypoechoic thyroid gland (ultrasound),and associated high-volume thyroid surgeon.RAI is contraindicated in orbitopathy.In GD,measurement of TSH-R-Ab is recom- Graves'patients with active/severe orbitopathy,and steroid mended for an accurate diagnosis/differential diagnosis,pri- prophylaxis is warranted in Graves'patients with mild/active or to stopping antithyroid drug(ATD)treatment and during orbitopathy receiving RAl. 2018 European Thyroid Association pregnancy.Graves'hyperthyroidism is treated by decreas- Published by S.Karger AG,Basel ing thyroid hormone synthesis with the use of ATD,or by reducing the amount of thyroid tissue with radioactive io- KARGER R0saRTrdatia 岂 医脉通 http://guide.medlive.cn/

Guidelines Eur Thyroid J 2018;7:167–186 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism George J. Kahalya Luigi Bartalenab Lazlo Hegedüsc Laurence Leenhardtd Kris Poppee Simon H. Pearcef aDepartment of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany; bDepartment of Medicine and Surgery, University of Insubria, Varese, Italy; cDepartment of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark; dThyroid and Endocrine Tumors Unit, Pitié Salpêtrière Hospital, Sorbonne University, Paris, France; eEndocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium; f Department of Endocrinology, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK Received: April 26, 2018 Accepted after revision: May 24, 2018 Published online: July 25, 2018 Prof. George J. Kahaly JGU Medical Center DE–55101 Mainz (Germany) E-Mail george.kahaly@unimedizin-mainz.de © 2018 European Thyroid Association Published by S. Karger AG, Basel E-Mail karger@karger.com www.karger.com/etj DOI: 10.1159/000490384 Keywords Graves’ hyperthyroidism · Management · Antithyroid drugs · Radioiodine therapy · Thyroidectomy · Graves’ orbitopathy Abstract Graves’ disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-ex￾pressing tissues. Stimulatory autoantibodies (Ab) in GD acti￾vate the TSH-R leading to thyroid hyperplasia and unregu￾lated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically con￾firmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recom￾mended for an accurate diagnosis/differential diagnosis, pri￾or to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves’ hyperthyroidism is treated by decreas￾ing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive io￾dine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves’ hyperthyroidism are usually medi￾cally treated for 12–18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI treat￾ment, repeating the TSH-R-Ab measurement after an addi￾tional 12 months, or opt for therapy with RAI or thyroidec￾tomy. Women treated with MMI should be switched to pro￾pylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; how￾ever, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves’ patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves’ patients with mild/active orbitopathy receiving RAI. © 2018 European Thyroid Association Published by S. Karger AG, Basel http://guide.medlive.cn/

Epidemiology and Pathogenesis also predispose to GD [15-17].Oral contraceptive pill use appears protective,as is male sex,suggesting a strong Hyperthyroidism occurs due to an inappropriately influence of sex hormones [6,151. high synthe ) increases c rate,and edu Methodology eve The com The development of this guideline osteoporosis,fragilityfractures. by the Executive Committee(EC)and Publication Board ic events,and cardiovascular dysfunction 2-4].The of the European Thyroid Association(ETA),which se prevalence of hyperthyroidism is 1.2-1.6,0.5-0.6 overt lected a chairperson(G.J.K.)to lead the task force.Subse- and0.7-1.0%subclinical [1,5].The most frequent causes quently,in consultation with the ETA EC,G.J.K.assem he ve in iodine bled a team of European chnicians who authored this nuscript.Me d on chn s pe larly appr repres or en ar m nd has a of1-L.59%A %ofmen develop GD during ership.The tch their lifetime [71.The peak incidence of GD occurs among patients aged 30-60 years,with an increased incidence eres of specific recommendations.The strength of the are ow wing to ci was rated R)I the G ding to the approa of the gGisotpeandbindtoadiscontl one in the ETA task force for this guideline used the following cod- leucine-rich domain of the TSH-R extracellular domain stem (a)strong r ecommendation indicated by 1 bounded roughly by amino acids 20-26019.101 TSH-R and(b)weak recommendation or suggestion indicated by also interacts with IGFI receptors(IGFIR)on the sur- 2.The evidence grading is depicted as follows:o face of thyrocytes and on orbital fibroblasts,with the denotes very-low-quality evidence;00,low quality TSH-R-Ab interaction with ISH vating both 00,moderate qu ality:⑦，hig quality.The way k fo cellula to th L:: ite for 4 weel About 30%of GD patients have family members who also have GD or Hashimoto's thyroiditis.Twin studies Diagnosis Serology tweerbe with susceptibotypes [13].Other susceptibil- specificity of any sing e b eval tion c uspecte 98 n and ho be use tein ty os tes cted dia sine phosphatase nonr ptor-22,basic leucine es when hoth a s n TSH and free T4 are transcription factor 2,and CD40 [14].A noncoding at the time of the initial evaluation.The relationship be- variant within the TSH-R gene itself also confers suscep- tween free T4 and TSH(when the pituitary-thyroid axis tibility.Environmental factors,such as cigarette smok- is intact)is an inverse log-linear relationship;therefore, ing,high dietary iodine intake,stress,and pregnancy, small changes in free T4 result in large changes in serum 168 Kahaly/Bartalena/Hegeduis/Leenhardt/ Poppe/Pearce 医通 http://guide.medlive.cn/

Kahaly/Bartalena/Hegedüs/Leenhardt/ Poppe/Pearce 168 Eur Thyroid J 2018;7:167–186 DOI: 10.1159/000490384 Epidemiology and Pathogenesis Hyperthyroidism occurs due to an inappropriately high synthesis and secretion of thyroid hormone (TH) by the thyroid [1]. TH increases tissue thermogenesis and the basal metabolic rate, and reduces serum cholesterol levels and systemic vascular resistance. The complica￾tions of untreated hyperthyroidism include weight loss, osteoporosis, fragility fractures, atrial fibrillation, embol￾ic events, and cardiovascular dysfunction [2–4]. The prevalence of hyperthyroidism is 1.2–1.6, 0.5–0.6 overt and 0.7–1.0% subclinical [1, 5]. The most frequent causes are Graves’ disease (GD) and toxic nodular goiter. GD is the most prevalent cause of hyperthyroidism in iodine￾replete geographical areas, with 20–30 annual cases per 100,000 individuals [6]. GD occurs more often in women and has a population prevalence of 1–1.5%. Approxi￾mately 3% of women and 0.5% of men develop GD during their lifetime [7]. The peak incidence of GD occurs among patients aged 30–60 years, with an increased incidence among African Americans [8]. GD is an organ-specific autoimmune disease whose major manifestations are owing to circulating autoanti￾bodies (Ab) that stimulate the thyroid-stimulating hor￾mone receptor (TSH-R) leading to hyperthyroidism and goiter. TSH-R-stimulating Ab are predominantly of the IgG1 isotype and bind to a discontinuous epitope in the leucine-rich domain of the TSH-R extracellular domain, bounded roughly by amino acids 20–260 [9, 10]. TSH-R also interacts with IGF1 receptors (IGF1R) on the sur￾face of thyrocytes and on orbital fibroblasts, with the TSH-R-Ab interaction with TSH-R activating both IGF1R downstream pathways and TSH-R signaling [11]. Circulating stimulatory TSH-R-Ab binding to the TSH-R enhance the production of intracellular cyclic AMP, leading to the release of TH and thyrocyte growth. About 30% of GD patients have family members who also have GD or Hashimoto’s thyroiditis. Twin studies have shown that 80% of the susceptibility to GD is ge￾netic [12]. There are well-established associations be￾tween alleles of the major histocompatibility complex with GD, with susceptibility being carried with HLA￾DR3 and HLA-DR4 haplotypes [13]. Other susceptibil￾ity loci at which association has been replicated include those at cytotoxic T lymphocyte antigen-4, protein tyro￾sine phosphatase nonreceptor-22, basic leucine zipper transcription factor 2, and CD40 [14]. A noncoding variant within the TSH-R gene itself also confers suscep￾tibility. Environmental factors, such as cigarette smok￾ing, high dietary iodine intake, stress, and pregnancy, also predispose to GD [15–17]. Oral contraceptive pill use appears protective, as is male sex, suggesting a strong influence of sex hormones [6, 15]. Methodology The development of this guideline was commissioned by the Executive Committee (EC) and Publication Board of the European Thyroid Association (ETA), which se￾lected a chairperson (G.J.K.) to lead the task force. Subse￾quently, in consultation with the ETA EC, G.J.K. assem￾bled a team of European clinicians who authored this manuscript. Membership on the panel was based on clin￾ical expertise, scholarly approach, representation of en￾docrinology and nuclear medicine, as well as ETA mem￾bership. The task force examined the relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medi￾cine approach that incorporated the knowledge and ex￾perience of the panel was used to develop the text and a series of specific recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, De￾velopment, and Evaluation (GRADE system) [18]. The ETA task force for this guideline used the following cod￾ing system: (a) strong recommendation indicated by 1, and (b) weak recommendation or suggestion indicated by 2. The evidence grading is depicted as follows: ○○○∅ denotes very-low-quality evidence; ∅∅○○, low quality; ∅∅∅○, moderate quality; ∅∅∅∅, high quality. The draft was discussed by the task force, and then posted on the ETA website for 4 weeks for critical evaluation by the ETA members. Diagnosis Serology Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evalu￾ation of suspected hyperthyroidism and should be used as an initial screening test [19, 20]. However, when hyper￾thyroidism is strongly suspected, diagnostic accuracy im￾proves when both a serum TSH and free T4 are assessed at the time of the initial evaluation. The relationship be￾tween free T4 and TSH (when the pituitary-thyroid axis is intact) is an inverse log-linear relationship; therefore, small changes in free T4 result in large changes in serum http://guide.medlive.cn/

Biochemistry Serology Thyroid Imaging TSH TSH-R-Ab Ultrasound normal Low suppressed positive negative Nodules >2 cm yes no Graves'hyperthyroidism subclnical hyperthyroidism T3 toxicosis overt hyperthyroidism isotope scan serology suffices Fig1.Algorithm for investigating a patient with suspected Graveshyperthyroidism TSH concentrations.Serum TSH levels are considerably assays [26-33]exclusively differentiate between the TSH- more sensitive than direct IH measurements for asses R-stimulating Ab(TSAb)and TSH-R-blocking Ab [34, ing TH excess [20 1.Als Ab is a highly sensitive and predictive bio serun s a the extr al manifestatio hyperthy P43.44.F ffetal or ne only s ation of TSAb i al serum TSH (Fig.1. conferreda 6%shortened time to diagnosis of TSH-R-Ab are specific biomarkers for GD [2,22]. GD and a cost saving of 47%[45]. Most immunoassays today use a competitive-binding as- say and measure what are referred to as TSH-R binding Recommendations sensitive and report the pres or absence of )an specit 23.24 d that the and cificity of the tiation of TSH-R TSH-R-Ab concentration measured with second-and Ab functionality is helpful and predictive in graves third-generation binding assays were 97 and 98%.respec patients during pregnancy/postpartum,as well as for tively [25].In contrast,the highly sensitive cell-based bio- extrathyroidal manifestations.2, 16g 医肺通 http://quide medlive.cn/

2018 ETA Guideline for the Management of Graves’ Hyperthyroidism Eur Thyroid J 2018;7:167–186 169 DOI: 10.1159/000490384 TSH concentrations. Serum TSH levels are considerably more sensitive than direct TH measurements for assess￾ing TH excess [20, 21]. In overt hyperthyroidism, both serum free T4 and T3 concentrations are elevated, and serum TSH is suppressed; however, in milder hyperthy￾roidism, serum total T4 and free T4 levels can be normal, only serum free T3 may be elevated, with an undetectable serum TSH (Fig. 1). TSH-R-Ab are specific biomarkers for GD [2, 22]. Most immunoassays today use a competitive-binding as￾say and measure what are referred to as TSH-R binding inhibitory immunoglobulins (TBII). Binding assays only report the presence or absence of TSH-R-Ab and their concentrations, but do not indicate their functional activ￾ity [23, 24]. A meta-analysis of 21 studies showed that the overall pooled sensitivity and specificity of the serum TSH-R-Ab concentration measured with second- and third-generation binding assays were 97 and 98%, respec￾tively [25]. In contrast, the highly sensitive cell-based bio￾assays [26–33] exclusively differentiate between the TSH￾R-stimulating Ab (TSAb) and TSH-R-blocking Ab [34, 35]. Also, TSAb is a highly sensitive and predictive bio￾marker for the extrathyroidal manifestations of GD [36– 42] as well as a useful predictive measure of fetal or neo￾natal hyperthyroidism [43, 44]. Finally, the incorporation and early utilization of TSAb into current diagnostic al￾gorithms conferred a 46% shortened time to diagnosis of GD and a cost saving of 47% [45]. Recommendations 1 The measurement of TSH-R-Ab is a sensitive and specific tool for rapid and accurate diagnosis and dif￾ferential diagnosis of Graves’ hyperthyroidism. 1, ∅∅∅∅ 2 When technically available, differentiation of TSH-R￾Ab functionality is helpful and predictive in Graves’ patients during pregnancy/postpartum, as well as for extrathyroidal manifestations. 2, ∅∅∅○ Biochemistry Serology Thyroid Imaging TSH TSH-R-Ab Ultrasound normal Low / suppressed euthyroidism fT4↔ fT3↔ fT4↔ fT3↑ fT4↑ fT3↑ subclinical hyperthyroidism T3 toxicosis overt hyperthyroidism positive negative Graves’ hyperthyroidism other causes of hyperthyroidism: - toxic adenoma - toxic multinodular goiter - subacute thyroiditis Nodules >2 cm yes no isotope scan serology suffices Fig. 1. Algorithm for investigating a patient with suspected Graves’ hyperthyroidism. http://guide.medlive.cn/

Imaging Table 1.Mechanism of action of antithyroid drugs Considerable inter-and intraregional variation in di- for GD [22].In addi- Intrathyroidal inhibition of: ne ox tio m0 reque soun ten is (Us) ay con 9p92hc93.8 ofT4/T3 conversion (PTU) oid US 40.3%,respectively 6.Ordinarily,there is no indica tion for CT scan,MRI,or PET-CT of the thyroid gland. Thyroid US is a convenient,noninvasive,rapid,and ac- Management curate tool in the initial work-up of GD patients.It aids Medical Treatment rradiat ying e sm is treated by reducing TH and det cting con thy D,or by red acing the ar nt of thy dthe ATD A high-freau used.GD is of Asia and in the m nti me in the USA 53.541.The ma ATD are thionamides,such as propylthiouracil (PTU). enlargement and by hypoechogenicity,both assessed by carbimazole(CBZ),and the active metabolite ofthe latter. US and conventional grey scale analysis [6] methimazole (MMI).CBZ is not an active substance;it A color-flow or po er Dopple examination character nas to be decarboxylated to MMI in the liver. it the coupling o is sign rea the biosyn :l hy 11 11 dal flow seen diffusely throughout the gland [51.Accurate first-line treatment of GD, OU measurement of thyroid artery flow velocity and peak sys tolic velocity(PSV)requires adjustments ofpulser repetition the frequency of wall filters and control of the insonation angle at.In untreatedGD,thyroidal artery flow therapy.PI U at higher doses inhibits deiodination of T are significantly increa can to T3 [56 How this effect is en thyr and is 2)Te 01 type 30 ombined with yate the the s pidism (CBZ 15 ever,thyroid scintig aphy may be useful in the assessment divided doses are given throughout the course.The start- of patients prior to radioactive iodine(RADtreatment,es- ing dose ofATD can be gradually reduced (titration regi- pecially when facing coexistent multinodular goiter [6]. men)as thyrotoxicosis improves.Thyroid function tes re reviewed. 4 weeks atter star ommendations titrated ati comprising conv al grey scale ntia op nded asthowe opp edu months nd the do e nsitive index of early treatment re e.The usual daily maintenance doses of ATD in the titration 4 Scintigraphy of the thyroid is suggested when thyroid are 2.5-10 mg of MMI and 50-100 mg of PTU.Alterna- nodularity coexists with hyperthyroidism,and prior to tively,MMI daily doses of 30 mg may be given combinec RAI therapy.2,oo with levothyroxine (L-T4)supplementation (block and Kahaly/Bartalena/Hegeduis/Leenhardt/ Poppe/Pearce 医通 http://guide.medlive.cn/

Kahaly/Bartalena/Hegedüs/Leenhardt/ Poppe/Pearce 170 Eur Thyroid J 2018;7:167–186 DOI: 10.1159/000490384 Imaging Considerable inter- and intraregional variation in di￾agnostic practice has been reported for GD [22]. In addi￾tion to thyroid function and TSH-R-Ab determination, most clinicians would request thyroid ultrasound (US) and less often isotope scanning [22]. In a study conducted among 263 endocrinologists in 992 hyperthyroid pa￾tients, thyroid US and scintigraphy were used in 93.8 and 40.3%, respectively [46]. Ordinarily, there is no indica￾tion for CT scan, MRI, or PET-CT of the thyroid gland. Thyroid US is a convenient, noninvasive, rapid, and ac￾curate tool in the initial work-up of GD patients. It aids in the diagnosis, without exposing the patient to ionizing irradiation, and assists in determining the underlying eti￾ology of thyrotoxicosis and detecting concomitant thy￾roid nodules [47–49]. Imaging results are highly depen￾dent on equipment and the experience of the investigator. A high-frequency linear probe should be used. GD is of￾ten, but not invariably, characterized by diffuse thyroid enlargement and by hypoechogenicity, both assessed by US and conventional grey scale analysis [6]. A color-flow or power Doppler examination character￾izes vascular patterns and quantifies thyroid vascularity [50]. The latter is significantly increased in untreated GD and typically shows a pulsatile pattern called “thyroid in￾ferno” that is multiple small areas of increased intrathyroi￾dal flow seen diffusely throughout the gland [51]. Accurate measurement of thyroid artery flow velocity and peak sys￾tolic velocity (PSV) requires adjustments of pulse repetition frequency of wall filters and control of the insonation angle at between 0 and 60°. In untreated GD, thyroidal artery flow velocity and PSV are significantly increased. The PSV can differentiate between thyrotoxicosis owing to GD from subacute thyroiditis or amiodarone-induced thyrotoxicosis type 2, where the blood flow is reduced [52]. Typical US patterns combined with positive TSH-R-Ab obviate the need for scintigraphy in the vast majority of cases. How￾ever, thyroid scintigraphy may be useful in the assessment of patients prior to radioactive iodine (RAI) treatment, es￾pecially when facing coexistent multinodular goiter [6]. Recommendations 3 US examination, comprising conventional grey scale analysis and color-flow or power Doppler examina￾tion is recommended as the imaging procedure to sup￾port the diagnosis of Graves’ hyperthyroidism. 1, ∅∅∅∅ 4 Scintigraphy of the thyroid is suggested when thyroid nodularity coexists with hyperthyroidism, and prior to RAI therapy. 2, ∅∅∅○ Management Medical Treatment Graves’ hyperthyroidism is treated by reducing TH synthesis, using ATD, or by reducing the amount of thy￾roid tissue with RAI treatment or total thyroidectomy [6, 47]. ATD represent the predominant therapy in Europe, Asia, and in the meantime in the USA [53, 54]. The main ATD are thionamides, such as propylthiouracil (PTU), carbimazole (CBZ), and the active metabolite of the latter, methimazole (MMI). CBZ is not an active substance; it has to be decarboxylated to MMI in the liver. Thion￾amides inhibit the coupling of iodothyronines and hence reduce the biosynthesis of TH [55]. All inhibit the func￾tion of thyroperoxidase, reducing oxidation and the or￾ganification of iodide (Table 1). ATD are indicated as a first-line treatment of GD, particularly in younger sub￾jects, and for short-term treatment of GD before RAI therapy or thyroidectomy [2, 6, 22]. ATD reduce TSH-R￾Ab levels and enhance rates of remission compared to no therapy. PTU at higher doses inhibits deiodination of T4 to T3 [56]. However, this effect is of minor benefit, except in severe thyrotoxicosis, and is offset by the much shorter half-life of this drug compared to MMI (Table 2). The initial dose of MMI is usually 10–30 mg once daily de￾pending on the severity of hyperthyroidism (CBZ 15–40 mg/day). PTU is given at a dose of 100 mg every 8 h, and divided doses are given throughout the course. The start￾ing dose of ATD can be gradually reduced (titration regi￾men) as thyrotoxicosis improves. Thyroid function tests are reviewed 3–4 weeks after starting treatment, and the dose is titrated based on free T4 and free T3 levels. A sub￾stantial proportion of patients reach euthyroidism within 3–4 weeks of treatment. TSH levels often remain sup￾pressed for several months and therefore do not provide a sensitive index of early treatment response. The usual daily maintenance doses of ATD in the titration regimen are 2.5–10 mg of MMI and 50–100 mg of PTU. Alterna￾tively, MMI daily doses of 30 mg may be given combined with levothyroxine (L-T4) supplementation (block and Table 1. Mechanism of action of antithyroid drugs Intrathyroidal inhibition of: Iodine oxidation/organification Iodotyrosine coupling Thyroglobulin biosynthesis Follicular cell growth Extrathyroidal inhibition of T4/T3 conversion (PTU) http://guide.medlive.cn/

Table2.Pharmacologyand pharmacokineticsofantithyroid drugs GD have been published [60-62).Relapse is most likely within the first 6-12 months after ATD withdrawal.bu MMI PTU may occur years later.Patients with severe hyperthyroid- ism,large goiters,or persistent high titers of TSH-R-Ab rapid are most likely to relapse when treatment stops,but the 20 min outcome is difficult to predict.All patients should be fol TthroidconcEatratian 5×10mol/L 8-12h 75% mendation 5 Patients with newly diagnosed Graves'hyperthyroid- 40 ism should be treated with ATD.RAI ther py or thy 20L rena renal roidectomy may be considered in patients who prefer daring ne this approach.1,0 6 MMI(CBZ)should be used in every non-pregnant pa 三m olonged nt who chooses ATD therapy for Graves hyperthy eeks is red for 12-18 s then 1-1.5% TSH ndsc aRaa CrosIa ion of adverse events 52% Measurement of TSH-R-Ab levels prior to stopping low moderate ATD therapy is recommended,as it aids in predicting MMI,methimazole PTU,propylthiouracil. which patients can be weaned from the medication with normal levels indicating a greater chance of re. mission.1, Patients with pe TSH-R -Ab at 12. TSH-R-Ab replace regimen)to avoid drug-induced hypothyroidisn or opt for RAI roider omy.1,0o0 ing su rior remission rates with the blrepacrm have not been reproduced Adverse Events 57].The titration regimen is often preferred to minimize Common side effects of ATD(Table 3)are rash,urti- the dose of ATD. caria,and arthralgia(1-5%).Minor cutaneous reactions regime 57) are managed witl trea se n ATD th rapy oes n pro alle ates (50-556 ide effect within 12-18 months.Measurement of TSH-R-Ab levels 63]include hepatitis.a lupus-like syndrome.and ag ran. prior to stopping ATD therapy is recommended,as itaids ulocytosis(neutrophil count <500/mL),which occurs in in predicting which patients can be weaned from the 0.1-1.0%of cases [64,65].Agranulocytosis tend to occur medication,with normal abruptly within 3 months after the initiation of ATD chance ofre ission ers offunc- atory and blo therapy [65].The cumulative incidence of ATD- cking TSH sis and iTSH-RA A78opeaat100 150 day espe 11g tinue MMI the h y9 the TSH-R-Ab (671 hav tha surement after an 1 months or opt for RAI and HLA-DRB1*08:03 are inder endent suscentibility am3noaaaaam ments for loci for a anulocytosis.Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases the odds ratio to 48.41(95% 171 医肺润 http://quide medlive.cn/

2018 ETA Guideline for the Management of Graves’ Hyperthyroidism Eur Thyroid J 2018;7:167–186 171 DOI: 10.1159/000490384 replace regimen) to avoid drug-induced hypothyroidism. Initial reports suggesting superior remission rates with the block-replace regimen have not been reproduced [2, 57]. The titration regimen is often preferred to minimize the dose of ATD. The optimal duration of ATD therapy for the titration regimen is 12–18 months [57]. Continued L-T4 treat￾ment following initial ATD therapy does not provide any benefit in terms of the recurrence of hyperthyroidism [5, 57]. Maximum remission rates (50–55%) are achieved within 12–18 months. Measurement of TSH-R-Ab levels prior to stopping ATD therapy is recommended, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating a greater chance of remission [5, 22]. Monitoring the titers of func￾tional stimulatory and blocking TSH-R-Ab during treat￾ment help in predicting the outcome [58, 59]. Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI therapy, repeating the TSH-R-Ab mea￾surement after an additional 12 months, or opt for RAI or thyroidectomy (Fig. 2). In line with this, arguments for an extended use of ATD in both adults and children with GD have been published [60–62]. Relapse is most likely within the first 6–12 months after ATD withdrawal, but may occur years later. Patients with severe hyperthyroid￾ism, large goiters, or persistent high titers of TSH-R-Ab are most likely to relapse when treatment stops, but the outcome is difficult to predict. All patients should be fol￾lowed closely for relapse during the first year after treat￾ment and at least annually thereafter. Recommendations 5 Patients with newly diagnosed Graves’ hyperthyroid￾ism should be treated with ATD. RAI therapy or thy￾roidectomy may be considered in patients who prefer this approach. 1, ∅∅∅∅ 6 MMI (CBZ) should be used in every non-pregnant pa￾tient who chooses ATD therapy for Graves’ hyperthy￾roidism. 1, ∅∅∅∅ 7 MMI is administered for 12–18 months then discon￾tinued if the TSH and TSH-R-Ab levels are normal. 1, ∅∅∅∅ 8 Measurement of TSH-R-Ab levels prior to stopping ATD therapy is recommended, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating a greater chance of re￾mission. 1, ∅∅∅∅ 9 Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI therapy, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for RAI or thyroidectomy. 1, ∅∅∅○ Adverse Events Common side effects of ATD (Table 3) are rash, urti￾caria, and arthralgia (1–5%). Minor cutaneous reactions are managed with concurrent antihistamine therapy without stopping the ATD. These may resolve spontane￾ously or after substituting an alternative ATD [56]. In the case of a serious allergic reaction, prescribing the alterna￾tive drug is not recommended. Rare but major side effects [63] include hepatitis, a lupus-like syndrome, and agran￾ulocytosis (neutrophil count 24 h 8–12 h Serum protein binding nil >75% Crosses placenta ++ + Levels in breast milk ++ + Volume of distribution 40 L 20 L Excretion renal renal Metabolism during illness Renal nil nil Liver prolonged nil Potency 10× 1× Normalization T3/T4 6 weeks 12 weeks Adverse events 15% 20% Agranulocytosis 0.6% 1–1.5% Cross-reaction of adverse events 13.8% 15.2% Compliance high fair Costs low moderate MMI, methimazole; PTU, propylthiouracil. http://guide.medlive.cn/

Untreated GD Persistent Relapse Hyperthyroidism () At18(36)m After stopping MMI MMI(CBZ) or Definitive or treatment RAl or Tx or MVP on Th Table3.Adverse events of antithyroid drugs CI 21.66-108.22).In Caucasians,a different HLA-Ballele (B*27:05;OR7.3,95%CI3.81-l3.96)and rare NOX3 Com Aaila,porahrits MMICBd PTUrience similar incidence rates Fever 701 In a study c ing 71.379 ATD initiato gf711 Abnormalities of taste and smell MMI was associated in a dose-dependent manner with an increased risk for hepatitis and cholestasis.ATD are stopped and not restarted ifa patient develops major side effects.Patients should be given written instructions re- er,mouth s)and the neec nd ete Recommendations 10 Patients should be informed of potential side effectsof ATD and the necessity of informing the physician promptly if they should develop jaundice,light-col- Kahaly/Bartalena/Hegeduis/Leenhardt/ Poppe/Pearce 医脉通 http://guide.medlive.cn/

Kahaly/Bartalena/Hegedüs/Leenhardt/ Poppe/Pearce 172 Eur Thyroid J 2018;7:167–186 DOI: 10.1159/000490384 CI 21.66–108.22). In Caucasians, a different HLA-B allele (B*27:05; OR 7.3, 95% CI 3.81–13.96) and rare NOX3 variants have been tentatively associated [68, 69]. MMI (CBZ) and PTU exert dissimilar incidence rates of hepatotoxicity. PTU-associated hepatotoxicity occurs foremost in children in contrast to that associated with MMI, which is usually milder with a cholestatic pattern [70]. In a study comprising 71,379 ATD initiators [71], MMI was associated in a dose-dependent manner with an increased risk for hepatitis and cholestasis. ATD are stopped and not restarted if a patient develops major side effects. Patients should be given written instructions re￾garding the symptoms of possible agranulocytosis (e.g., sore throat, fever, mouth ulcers) and the need to stop treatment pending a complete blood count. The use of routine hematological and liver function tests is not use￾ful, as the onset of agranulocytosis is abrupt [56]. Recommendations 10 Patients should be informed of potential side effects of ATD and the necessity of informing the physician promptly if they should develop jaundice, light-col￾Table 3. Adverse events of antithyroid drugs Common (1.0–5.0%) Skin rash Urticaria Arthralgia, polyarthritis Fever Transient mild leukopenia Rare (0.2–1.0%) Gastrointestinal Abnormalities of taste and smell Agranulocytosis Very rare (<0.1%) Aplastic anemia (PTU, CBZ) Thrombocytopenia (PTU, CBZ) Vasculitis, lupus-like, ANCA+ (PTU) Hepatitis (PTU) Hypoglycemia (anti-insulin Abs; PTU) Cholestatic jaundice (CBZ/MMI) PTU, propylthiouracil; MMI, methimazole; CBZ, carbimazole; ANCA, antineutrophil cytoplasmic antibody. negative Untreated GD Persistent Hyperthyroidism Relapse MMI (CBZ) Adults: 18 months Children: 36 months - MMI intolerance - Noncompliance Tx - Nodules - Goiter ˃50 mL - Active GO MMI for further 12 months Recent onset (adults & children) At 18 (36) months positive TSH-R-Ab After stopping MMI Long-term low-dose MMI Then TSH-R-Ab measurement Definitive treatment RAI or or or or or positive Personal decision RAI - Small thyroid - No / inactive GO Stop MMI RAI or Tx Tx Fig. 2. Algorithm for the management of a patient with Graves’ hyperthyroidism. GD, Graves’ disease; MMI, methimazole; CBZ, carbimazole; GO, Graves’ orbitopathy; RAI, radioactive iodine; Tx, total thyroidectomy. http://guide.medlive.cn/

ored stools,dark urine,fever,pharyngitis,or cystitis. 000o on in the MMI group (p65 years with serum TSH levels that are persistently and HLA subtypes DQB1*02,DQA1*05,and DRB1*03 0.1mlU/ ,0000 e the first choice of treatment of Graves ong-term ATD SH.1.000 GD relapse after the dis soAahen 12-24 months 176).Either RAI treatment and L-T4 re With a mortality rate estimated at 10%,the life-threat- placement or MMI (2.5-7 mg/daily)were used.No no- ening thyroid storm demands a rapid diagnosis and table side effects were observed.Thyroid dysfunction was emergency treatment [84,85].The condition manifests 13 医通 http://guide.medlive.cn/

2018 ETA Guideline for the Management of Graves’ Hyperthyroidism Eur Thyroid J 2018;7:167–186 173 DOI: 10.1159/000490384 ored stools, dark urine, fever, pharyngitis, or cystitis. 1, ∅∅○○ 11 In patients taking ATD, a differential white blood cell count should be obtained during febrile illness and/or pharyngitis, and liver function should be assessed in those who experience jaundice, light-colored stools, or dark urine. 1, ∅∅○○ Beta-Adrenergic Blockade Propranolol (20–40 mg every 6 h) or longer acting be￾ta-blockers (i.e., atenolol/bisoprolol), are useful to con￾trol adrenergic symptoms such as palpitations and trem￾or, especially in the early stages before ATD take effect. High doses of propranolol (40 mg 4 times daily) inhibit peripheral conversion of T4 to T3. Cardioselective beta￾blockers with higher cardioprotective effects and superi￾or prevention of atrial fibrillation represent an alternative choice, especially for patients with asthma. Anticoagula￾tion with warfarin or direct oral anticoagulants should be considered in all patients with atrial fibrillation. If digox￾in is used, increased doses are often needed in the thyro￾toxic state [2, 5, 6, 72]. Recommendation 12 Beta-adrenergic blockade is recommended in all suit￾able patients with Graves’ hyperthyroidism. 1, ∅∅∅∅ Relapse after a Course of ATD Treatment A meta-analysis [73] has confirmed the high relapse rate following ATD therapy (52.7%) in comparison with RAI (15%, OR 6.25) or surgery (10%, OR 9.09), along with a significant side-effect profile for these drugs (13%). Another meta-analysis evaluating 54 trials and 7,595 par￾ticipants showed several risk factors predicting persis￾tence (49%) in GD [74]. Orbitopathy, smoking, thyroid volume, free T4, total T3, and TSH-R-Ab were signifi￾cantly associated with relapse. In a prospective study in￾troducing the quantitative predictive “GREAT” score for GD [75], 37% of patients with a first episode of Graves’ hyperthyroidism relapsed within 2 years after ATD with￾drawal. Lower age, higher serum TSH-R-Ab and free T4, larger goiters at diagnosis, PTPN22 C/T polymorphism, and HLA subtypes DQB1*02, DQA1*05, and DRB1*03 were independent predictors for recurrence. On the other hand, the benefits of long-term ATD treatment after recurrence were shown in patients with GD relapse after the discontinuation of ATD therapy for 12–24 months [76]. Either RAI treatment and L-T4 re￾placement or MMI (2.5–7 mg/daily) were used. No no￾table side effects were observed. Thyroid dysfunction was predominant in the RAI group (p 65 years with serum TSH levels that are persistently <0.1 mIU/L. 1, ∅∅○○ 15 ATD should be the first choice of treatment of Graves’ SH. 1, ∅∅○○ Thyroid Storm With a mortality rate estimated at 10%, the life-threat￾ening thyroid storm demands a rapid diagnosis and emergency treatment [84, 85]. The condition manifests http://guide.medlive.cn/

as decompensation of multiple organs with impaired ralysis are candidates for RAI.Only one study has com- consciousness,high fever,heart failure,diarrhea,and pared the ATD,surgery,and RAI head-to-head [90].In in pa- tients with severe Graves't ferences in sic m, e p which Point Scale” the aim of ranid hynothyroidism other side-effects are manifestations,with a point total of 245 consistent with not different from those in adults [95].RAIis contraindi- thyroid storm,25-44 points classified as impending thy- cated in pregnancy and during breast feeding,and con roid storm,and <25 points indicating that thyroid storm ception should be postponed until at least 6 months after onw mental effectso idity a aormvynalgothscoanod the therapy.There is noevidence of det ty rate ong-term ty,misc ns,or c quently offe MMI mu month per dnisol nle iv heta-hlocker anolol 4p thyroidism and postponing hypot mon cause of death from thyroid storm was multiple or- many have given up meticulous dose calculation and of- gan failure,followed by heart and respiratory failure,ar- fer fixed activities of,for example,185,370,or 555 MBq rhythmia,disseminated intravascular coagulation,gas based on validated clinical parameters,such as thyroic size89. Effect o y tion in 3-12 month 16A multimodality treatment after RAI ther in 50-90%of patients [89].The patient used,including ATD therapy,glucocorticoid administration,beta-adrener should bein med that repeated doses of RAI may be needed.The incidence rate of hypothyroidism is 5-50% gic blockade,cooling blankets,volume resuscitation, after the first vear,and is positively associated with the nutritional support,respiratory care,and monitoring thyroid RAI dose.This s is followed by a yearly hypothy in an intensive care unit.1,C ism rate of 3-5%,wh ch is largely independent of the RA 97 Even w been few since 19 h sm is there have ble 198).Thy ective trials le ntra ndicated in lar dose,efficacy,and partially retrosternal or intrathoracic.ATD should be side-effects ).The cellular effect of the ionizing radia- temporarily paused for a week before and after RAI ther- tionleads to genetic damage,mutations,or celldeath.The apy [99]. DNA damage from radiation is mediated via a combi nation of direct ects,thi Adverse Effects of RAI Therapy thyroid fu here may be th d pain,swelli cals.Thi n and/o on orb3andsaloaden rideal methods of 100,101.I 102 radio e do es not ir tality (89) e is nei predicting the clinical response to RAI therapy 6 ed thyroid ca nor total ca mortality following RAI therapy 1031.Posttherapy thv Indications and Applied RAI Dose roid storm is extremely rare,and in non-ATD-pretreated Patients with side-effectstoor recurrenceafteracourse patients TH levels are normally not elevated post-RAl of ATD,cardiac arrhythmias,and thyrotoxic periodic pa- but decline after a few days 104.Transient hyperthy Kahaly/Bartalena/Hegeduis/Leenhardt/ Poppe/Pearce 医通 http://guide.medlive.cn/

Kahaly/Bartalena/Hegedüs/Leenhardt/ Poppe/Pearce 174 Eur Thyroid J 2018;7:167–186 DOI: 10.1159/000490384 as decompensation of multiple organs with impaired consciousness, high fever, heart failure, diarrhea, and jaundice. Diagnostic criteria for thyroid storm in pa￾tients with severe Graves’ thyrotoxicosis include hyper￾pyrexia, tachycardia, arrhythmia, congestive heart fail￾ure, agitation, delirium, psychosis, stupor, coma, nausea, vomiting, diarrhea, hepatic failure, and the presence of an identified precipitant [86]. The “Burch-Wartofsky Point Scale” system grades the severity of individual manifestations, with a point total of ≥45 consistent with thyroid storm, 25–44 points classified as impending thy￾roid storm, and <25 points indicating that thyroid storm as unlikely. Nationwide surveys in Japan have revealed the high morbidity and mortality rates of this condition and have subsequently offered a multimodality treat￾ment, including intravenous MMI or PTU (40 or 400 mg every 8 h), glucocorticoids (methylprednisolone 50 mg i.v.), beta-blockers (propranolol 40 mg every 6 h), and monitoring in an intensive care unit [87]. The most com￾mon cause of death from thyroid storm was multiple or￾gan failure, followed by heart and respiratory failure, ar￾rhythmia, disseminated intravascular coagulation, gas￾trointestinal perforation, hypoxic brain syndrome, and sepsis [88]. Recommendation 16 A multimodality treatment approach to GD patients with thyroid storm should be used, including ATD therapy, glucocorticoid administration, beta-adrener￾gic blockade, cooling blankets, volume resuscitation, nutritional support, respiratory care, and monitoring in an intensive care unit. 1, ∅∅○○ RAI Treatment RAI has been used since 1941; however, there have been few well-designed prospective trials, leaving many questions about indications, optimal dose, efficacy, and side-effects [89]. The cellular effect of the ionizing radia￾tion leads to genetic damage, mutations, or cell death. The DNA damage from radiation is mediated via a combi￾nation of direct effects, through breakage of molecular bonds, or indirectly through the formation of free radi￾cals. This leads to a decrease in thyroid function and/or reduction in thyroid size. There are neither good mea￾sures of individual radiosensitivity nor ideal methods of predicting the clinical response to RAI therapy. Indications and Applied RAI Dose Patients with side-effects to or recurrence after a course of ATD, cardiac arrhythmias, and thyrotoxic periodic pa￾ralysis are candidates for RAI. Only one study has com￾pared the ATD, surgery, and RAI head-to-head [90]. In that randomized study, the risk of relapse was highest af￾ter ATD, but there were no significant differences in sick leave or satisfaction with the therapy. There are contra￾dictory reports pertaining to the cost effectiveness of GD treatment [91–94]. Some centers use RAI in pediatric pa￾tients, in which case ablative doses should be used with the aim of rapid hypothyroidism. Other side-effects are not different from those in adults [95]. RAI is contraindi￾cated in pregnancy and during breast feeding, and con￾ception should be postponed until at least 6 months after the therapy. There is no evidence of detrimental effects on long-term fertility, miscarriage, stillbirths, or congenital defects in the offspring [96]. The same 6-month period applies for males. ALARA (as low as reasonably achiev￾able) is an important principle with radiation treatment, but an elusive goal when balancing rapid relief of hyper￾thyroidism and postponing hypothyroidism. Therefore, many have given up meticulous dose calculation and of￾fer fixed activities of, for example, 185, 370, or 555 MBq, based on validated clinical parameters, such as thyroid size [89]. Effect on Thyroid Function and Size Thyroid function is normalized within 3–12 months after RAI therapy in 50–90% of patients [89]. The patient should be informed that repeated doses of RAI may be needed. The incidence rate of hypothyroidism is 5–50% after the first year, and is positively associated with the thyroid RAI dose. This is followed by a yearly hypothy￾roidism rate of 3–5%, which is largely independent of the RAI dose [97]. Even with low-dose RAI, which increases persistent/recurrent disease, hypothyroidism is inevita￾ble [98]. Thyroid size is normalized within a year of RAI [97]. RAI is not contraindicated in large goiters, even if partially retrosternal or intrathoracic. ATD should be temporarily paused for a week before and after RAI ther￾apy [99]. Adverse Effects of RAI Therapy There may be thyroid pain, swelling, and sialoadenitis. GD is associated with increased morbidity and mortality [100, 101]. Its treatment decreases mortality [102], while RAI per se does not increase mortality [89]. There is nei￾ther evidence of increased thyroid cancer nor total cancer mortality following RAI therapy [103]. Posttherapy thy￾roid storm is extremely rare, and in non-ATD-pretreated patients TH levels are normally not elevated post-RAI, but decline after a few days [104]. Transient hyperthy￾http://guide.medlive.cn/

Table4.Advantages and disadvantages of total thyroidectomy for Graves'hyperthyroidism Advantages Disadvantages t on the course of r surgery Graves'orbitopathy Hospitalization Permanent scar roidism can be prevented by pre-RAIATD treatment,but Surgery Thyroidectomy is the least commonly selected treat- Ab levels. een tre ean que tonnaire-bas nth、e ent ir ient hyp en in 3-20%6 of cases and doe s an effective t when goiter is lar not invariably lead to permanent hypothyroidism,but there is coincident primary hyp rparathyroidism or sus treatment with TH is generally recommended to avoid picion of malignant nodules,the patient wishes to avoid the development of or a flare-up of GO.De novo or flare- exposure to ATD or RAI[109],or facilities for RAI treat- up of GO is seen in 15-33%of cases after RAI therapy ment are not available [2].Advantages of thyroidectomy 6].Prophylacti nclud e the absence of radiation risk,the rapid control mate outcome of thyroi erthyro DS ce ts on O 4).H recommendations nent sca 17There are no absolute indications for RAI therapy,but there may be complications similar to ral long-term it is often recommended for patients with side-effects L-T4 replacement therapy is required to maintain euthy- to or recurrence after a course of ATD.1, roidism. 18 Verbal as well as written information on all aspects of If surgery is selected,total thyroidectomy is the pro side-effects of RAI therapy cedure of cho eral st are used apy they should be hyperthyro rapy f h oidism is a matter of debat e due to conflicting 20 No dose calculation can secure long-term euthyroid- two systematic reviews-favoring thyroidectomy [110]. ism and it is fully acceptable to offer a fixed dose of or showing no significant differences between the two RAL.1,O☑C reatments[73]. astfeedingconstituteabsolutecon- therapy.I, sm,larynge e palsy woun n both postpone t ge).surgery s illed by les ablativ id h Surgeon (112 n of thy pothyroidism should be administered.1, roidism should be adequately controlled by ATD treat- ment prior to surgery [109].The use of a saturated solu- tion of potassium iodide(SSKI)is helpful in the immedi- 2018 ETA Guideline for the Management 175 of GravesHyperthyroidism 医肺通 http://quide medlive.cn/

2018 ETA Guideline for the Management of Graves’ Hyperthyroidism Eur Thyroid J 2018;7:167–186 175 DOI: 10.1159/000490384 roidism can be prevented by pre-RAI ATD treatment, but only if ATD are resumed post-RAI [105]. Posttherapy flare-up relates to high TSH-R-Ab levels. It is difficult to differentiate between treatment failure and transient hy￾perthyroidism. However, if thyrotoxicosis has not im￾proved after 3 months, treatment failure is likely. Tran￾sient hypothyroidism is seen in 3–20% of cases and does not invariably lead to permanent hypothyroidism, but treatment with TH is generally recommended to avoid the development of or a flare-up of GO. De novo or flare￾up of GO is seen in 15–33% of cases after RAI therapy [106]. Prophylactic glucocorticoids prevent this without influencing the ultimate outcome of thyroid function [107]. Recommendations 17 There are no absolute indications for RAI therapy, but it is often recommended for patients with side-effects to or recurrence after a course of ATD. 1, ∅∅○○ 18 Verbal as well as written information on all aspects of efficacy and potential side-effects of RAI therapy should be provided. 1, ∅∅○○ 19 If ATD are used before RAI therapy they should be paused around 1 week before and after therapy in or￾der not to decrease the efficacy of RAI therapy. 1, ∅∅∅∅ 20 No dose calculation can secure long-term euthyroid￾ism and it is fully acceptable to offer a fixed dose of RAI. 1, ∅∅∅○ 21 Pregnancy and breast feeding constitute absolute con￾traindications to RAI therapy. 1, ∅∅∅○ 22 Conception should be postponed until at least 6 months after RAI in both males and females. 1, ∅∅∅○ 23 If used in children, ablative doses aiming at rapid hy￾pothyroidism should be administered. 1, ∅∅○○ Surgery Thyroidectomy is the least commonly selected treat￾ment for newly diagnosed Graves’ hyperthyroidism. In recent American and European questionnaire-based sur￾veys, surgery represented the first-line treatment in 0.9% [108] and 2.1% [22] of cases, respectively. However, thy￾roidectomy is an effective treatment when goiter is large, there is coincident primary hyperparathyroidism or sus￾picion of malignant nodules, the patient wishes to avoid exposure to ATD or RAI [109], or facilities for RAI treat￾ment are not available [2]. Advantages of thyroidectomy include the absence of radiation risk, the rapid control of hyperthyroidism, and the usual absence of detrimental effects on GO (Table 4). However, thyroidectomy is a high-cost procedure requiring hospitalization, it bears an anesthetic and surgical risk, a permanent scar is left, and there may be complications. Similar to RAI, long-term L-T4 replacement therapy is required to maintain euthy￾roidism. If surgery is selected, total thyroidectomy is the pro￾cedure of choice, because it bears the same risk of com￾plications as bilateral subtotal thyroidectomy, while the rate of recurrent hyperthyroidism is lower [110, 111]. Whether thyroidectomy is more effective than RAI as a definitive treatment preventing relapses of hyperthy￾roidism is a matter of debate due to conflicting results of two systematic reviews – favoring thyroidectomy [110], or showing no significant differences between the two treatments [73]. To minimize the risk of complications (hypoparathy￾roidism, laryngeal nerve palsy, wound infection, hemor￾rhage), surgery should be performed by a skilled high￾volume surgeon [112]. To minimize the risk of intra- or postoperative exacerbation of thyrotoxicosis, hyperthy￾roidism should be adequately controlled by ATD treat￾ment prior to surgery [109]. The use of a saturated solu￾tion of potassium iodide (SSKI) is helpful in the immedi￾Table 4. Advantages and disadvantages of total thyroidectomy for Graves’ hyperthyroidism Advantages Disadvantages No recurrent hyperthyroidism Risk of postoperative hypoparathyroidism No radiation risk Risk of recurrent nerve palsy Rapid control of hyperthyroidism Permanent hypothyroidism No reported detrimental effect on the course of Graves’ orbitopathy Risks related to anesthesia or surgery Hospitalization Costs Permanent scar http://guide.medlive.cn/

ate preoperative period(10 days)to decrease thyroid vascularity and intraoperative blood loss [113].However. Trement of hyprhyoddein the pene Degree of severity and activity of GO ATD RAI Tx tomy must be performed be in add ade r6 and Mild and inactive SKI ed be Moderate-tovrand Yes ce the risk of RAI,radio recommendations 24 If surgery is selected,total thyroidectomy is the proce entation for 6 month dure of ch by a skilled eroid prophylaxis warranted (see text) dism should be restored by ATDprior to avoid Mild and inactive Treatment for by rthyroidism is unlikely to cause od 26 Vitamin d deficiency should be corrected to reduce ular changes and.therefore.is chosen irrespective of GO the postoperative risk of hypocalcemia.1, [116,117].If RAI treatment is selected,steroid prophy- 27 A solution containing potassium iodide can be given laxis is not indicated unless other risk factors for GOpro for 10 days prior to surgery.2,00C gression exist [115].Rehabilitative surgery may be re- quired for cosmetic or functional reasons Mild and Ac ve GO of GO and relies established criteria 2].There is no Thyroid dysfunction.both hy RCT evidence that the long-term outcome of go of thi degree is better using atd than definitive treatment ETA/EUGOGO guideline[115]and an Italian consensus Steroid prophvlaxis is indicated if RAI treatment is em statement [116]recommended that prompt restoration ployed [130].If ATD treatment is chos enium supplementation chall and prevents its progression to more severe forms [132 Thetate-to-5e Moder vere and Inactive GO might be beneficial for GO indirectly. id tr the restoration of euthyroidism [118,119].Hypothyroid. of GO.If RAI is selected,steroid prophylaxis can be ism can also cause the progression of GO 1201.RAI avoided if other risk factors for go reactivation are ab causes the progression or de novo occurrence ofGO[119, sent [1171. 121,122],particularly in smokers [123],those with pre existing]and recent-onset GO 24],lat m12 ated GO and tanc fheomiismnhATD sm are,per se 151T 1211 and two taanalyses 129,1301.Steroid p 133l.P mpt therapy for GO is warranted. laxis can be avoided in patients with absent or inactive GOifother risk factors for RAI-associated progression of Sight-Threatening go GO are absent 115.130.Thvroide my doe s not seem Sight-threatening GO is an endocrine emergency be to impact the natural history of GO 122,131 (Table 5). cause of the risk of sight loss due to dysthyroid optic neu 6 Kahaly/Bartalena/Hegeduis/Leenhardt/ Poppe/Pearce 医通 http://guide.medlive.cn/

Kahaly/Bartalena/Hegedüs/Leenhardt/ Poppe/Pearce 176 Eur Thyroid J 2018;7:167–186 DOI: 10.1159/000490384 ate preoperative period (10 days) to decrease thyroid vascularity and intraoperative blood loss [113]. However, this preparation is used by less than 40% of thyroidolo￾gists [22]. When thyroidectomy must be performed be￾fore an adequate control of hyperthyroidism is achieved, in addition to ATD, beta-blockers, glucocorticoids, and eventually SSKI may be helpful. Vitamin D deficiency should be corrected prior to surgery to reduce the risk of postoperative hypocalcemia [114]. Recommendations 24 If surgery is selected, total thyroidectomy is the proce￾dure of choice, and should be performed by a skilled surgeon with high annual volumes of thyroidectomies. 1, ∅∅∅∅ 25 Euthyroidism should be restored by ATD prior to sur￾gery to avoid peri- or postoperative exacerbation of thyrotoxicosis. 1, ∅∅∅∅ 26 Vitamin D deficiency should be corrected to reduce the postoperative risk of hypocalcemia. 1, ∅∅∅∅ 27 A solution containing potassium iodide can be given for 10 days prior to surgery. 2, ∅∅∅○ Treatment of Graves’ Hyperthyroidism in Patients with Orbitopathy Thyroid dysfunction, both hyper- and hypothyroid￾ism, can influence the course of GO. Accordingly, the ETA/EUGOGO guideline [115] and an Italian consensus statement [116] recommended that prompt restoration and stable maintenance of euthyroidism are priorities in patients with GO. How to manage hyperthyroidism when GO is present is, however, a challenging dilemma [117]. ATD per se do not influence the natural course of GO, but might be beneficial for GO indirectly, as a consequence of the restoration of euthyroidism [118, 119]. Hypothyroid￾ism can also cause the progression of GO [120]. RAI causes the progression or de novo occurrence of GO [119, 121, 122], particularly in smokers [123], those with pre￾existing [119] and recent-onset GO [124], late correction of post-RAI hypothyroidism [125, 126], and high TSH-R￾Ab levels [127]. In patients at risk of RAI-associated GO occurrence or progression, oral low-dose steroid prophy￾laxis [115, 128] is effective, as shown by two RCTs [119, 121] and two meta-analyses [129, 130]. Steroid prophy￾laxis can be avoided in patients with absent or inactive GO if other risk factors for RAI-associated progression of GO are absent [115, 130]. Thyroidectomy does not seem to impact the natural history of GO [122, 131] (Table 5). Mild and Inactive Treatment for hyperthyroidism is unlikely to cause oc￾ular changes and, therefore, is chosen irrespective of GO [116, 117]. If RAI treatment is selected, steroid prophy￾laxis is not indicated unless other risk factors for GO pro￾gression exist [115]. Rehabilitative surgery may be re￾quired for cosmetic or functional reasons. Mild and Active GO Treatment of hyperthyroidism is mostly independent of GO and relies on established criteria [2]. There is no RCT evidence that the long-term outcome of GO of this degree is better using ATD than definitive treatment. Steroid prophylaxis is indicated if RAI treatment is em￾ployed [130]. If ATD treatment is chosen, a 6-month se￾lenium supplementation improves mild and active GO and prevents its progression to more severe forms [132]. Moderate-to-Severe and Inactive GO The choice of thyroid treatment is mostly independent of GO. If RAI is selected, steroid prophylaxis can be avoided if other risk factors for GO reactivation are ab￾sent [117]. Moderate-to-Severe and Active GO Rapid correction of hyperthyroidism with ATD and stable maintenance of euthyroidism are, per se, beneficial for GO and therefore strongly recommended [60, 61, 115]. Thyroid ablation has been alternatively advocated [133]. Prompt therapy for GO is warranted. Sight-Threatening GO Sight-threatening GO is an endocrine emergency be￾cause of the risk of sight loss due to dysthyroid optic neu￾Table 5. Treatment of hyperthyroidism due to GD in the presence of GO Degree of severity and activity of GO ATD RAI Tx Mild and inactive Yes Yes1 Yes Mild and active Yes2 Yes3 Yes Moderate-to-severe and inactive Yes Yes1 Yes Moderate-to-severe and active Yes No No Sight threatening Yes No No ATD, antithyroid drugs; RAI, radioactive iodine; Tx, total thyroidectomy; GD, Graves’ disease; GO, Graves’ orbitopathy. 1  Steroid prophylaxis in selected cases. 2  Selenium supplementation for 6 months. 3  Steroid prophylaxis warranted (see text). http://guide.medlive.cn/