台大 張天鈞 解密 抗甲狀腺藥 (methimazole, carbimazole and propylthiouracil) 致死原因 登 “Nature Communications”

甲狀腺機能亢進治療副作用之謎 台大破解了 2015年07月09日 16:35 林宜慧／台北報導 台大醫院研究破解甲狀腺機能亢進治療的副作用之謎！在治療上，使用抗甲狀腺藥後，少數病人會發生可能致死的「無顆粒性白血球症」，而台大團隊找出2個高風險基因，未來可望經過基因檢測得知高風險族群，並幫他們省掉額外醫療與生命危險。此研究刊登於最新一期的國際知名期刊Nature Communications（自然通訊）。台大醫院內科部教授張天鈞表示，甲狀腺機能亢進症是十分常見的疾病，在人口中約為千分之3，女男比約4-5比1，尤其好發於10多歲到40、50歲生育年齡階段；傳統上病人會先使用抗甲狀腺藥物治療，若持續反覆發病，可使用第二線治療放射性碘治療，若仍不行或有結節，甚至是甲狀腺癌，最後才考慮手術。雖使用抗甲狀腺藥物治療已經歷數十載，但有10％的過敏反應，也就是10位病人中會有1位使用後出現皮膚發癢的副作用，更嚴重的是引可能致死的「無顆粒性白血球症」。台大醫院基因體暨蛋白體醫學研究所與基因醫學部醫師陳沛隆指出，罹患「無顆粒性白血球症」將因白血球嚴重減少，抵抗力變弱，病人恐因細菌感染致死；正常人每C.C.血液中有2000至5000顆「顆粒性白血球」，而這類患者到每C.C.500顆以下會出現發燒症狀，若不及時處置，恐降至0；因此醫師通常會請病人有皮膚發癢、發燒、喉嚨痛症狀等症狀時，就應通知醫師。正因此副作用無法預測，台大研究團隊與中研院、高雄長庚醫院合作，進行長達15年的研究，終於找到抗甲狀腺藥引起無顆粒性白血球症副作用的基因：HLA-B*38:02 和HLA-DRB1*08:03。研究針對1242名接受抗甲狀腺藥物治療患者，其中42名有免疫力低下問題，發現帶有HLA-B*38:02基因的服藥病患，發生無顆粒性白血球症風是為未帶有患者的21.48倍；而帶有HLA-DRB1*08:03基因者，風險增加6.13倍；當兩者都有，風險更高出48.41倍。張天鈞表示，另一方面，台灣人帶有HLA-DRB1*08:03基因者約10％，帶有HLA-B*38:02基因者約6％，而有免疫力低下的甲狀腺機能亢進患者中，高達60％帶有HLA-B*38:02。不過因族群基因頻率的差異，此研究發現只適用於亞洲人。(中時即時)

Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study  Nature Communications 6, Received 14 April 2015 Accepted 26 May 2015 Published 07 July 2015  Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals. Graves' Disease (GD, MIM 27500) is the leading cause of hyperthyroidism, manifested with diffuse goitre, thyroid hyperfunction, thyroid-specific auto-antibodies, ophthalmopathy and/or dermopathy. Its prevalence in the general population is as high as 1.0–1.6%, more common in females. Antithyroid drugs (ATDs, including methimazole, carbimazole and propylthiouracil) are relatively simple molecules known as thionamides4, which have been cornerstones of GD treatment across the globe4. ATD-induced agranulocytosis, namely thionamide-induced agranulocytosis (TiA, defined as an absolute granulocyte count <500 mm−3 while taking ATDs), is the most feared adverse effect of ATDs and can occur in 0.1–0.37% of GD patients receiving these medications. Agranulocytosis is life-threatening and can be induced by a variety of non-chemotherapy drugs. Among the 11 most common offending drugs summarized in a recent review, ATDs accounted for 3 of the 11, and the other drugs included clozapine, dapsone, dipyrone, penicillin G, procainamide, rituximab, sulfasalazine and ticlopidine. Drug-induced adverse effects could be broadly categorized into several types, including type A (dose-related, augmented) and type B (non-dose-related, bizarre), and can have different genetic predisposition. TiA belongs to type B. Overall, pharmacogenetic studies related to drug-induced agranulocytosis were scanty and very often were inconclusive. On the other hand, non-genetic risk factors remain elusive as well. Human leukocyte antigen (HLA) genes have been associated with many drug-induced adverse effects, including carbamazepine-induced Stevens–Johnson syndrome (HLA-B*15:02 and HLA-A*31:01), abacavir-induced hypersensitivity syndrome (HLA-B*57:01), lapatinib-induced liver injury (HLA-DQA1*02:01) and so on. Non-HLA genes also cause numerous drug-induced adverse effects through various pharmacokinetic and pharmacodynamic mechanisms. To comprehensively identify HLA and non-HLA genetic susceptibility to TiA, we conducted both direct HLA genotyping and genome-wide association study (GWAS) on GD patients with or without TiA. We demonstrate HLA-B*38:02 and HLA-DRB1*08:03 as independent, major susceptibility loci. Importantly, the GWAS data identify the same HLA signals, as well as one association peak at chromosome 3q13 with borderline significance. Three-dimensional (3D) structure modelling of the two HLA proteins and ATDs provides possible binding modes.