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/