《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 <500/mL), which occurs in 0.1–1.0% of cases [64, 65]. Agranulocytosis tend to occur abruptly within 3 months after the initiation of ATD therapy [65]. The cumulative incidence of ATD-induced agranulocytosis and pancytopenia at 100 and 150 days after the initiation of ATD was 0.28 and 0.29%, respec￾tively [66]. Genetic determinants of ATD-induced agran￾ulocytosis [67] have shown that the alleles HLA-B*38:02 and HLA-DRB1*08:03 are independent susceptibility loci for agranulocytosis. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases the odds ratio to 48.41 (95% Table 2. Pharmacology and pharmacokinetics of antithyroid drugs MMI PTU Absorption rapid rapid Bioavailability ~100% ~100% Peak serum level 60–120 min 60 min Serum half-life 6–8 h 90 min Thyroid concentration 5 × 105 mol/L unknown Thyroid turnover slow moderate Duration of action >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/