Volume 41 Issue 2
Apr.  2017
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Follow-up study on children and adolescents with Graves hyperthyroidism after 131I treatment

  • ObjectiveTo investigate the therapeutic effects and safety of 131I treatment on children and adolescents with Graves disease.MethodsIn this study, 89 children and adolescents with Graves hyperthyroidism cases were treated using 131I. 131I was given at a dosage of 2.59 to 4.44 MBq per gram of thyroid tissue and calibrated according to the course of disease, thyroid weight, and the highest iodine rate. The treatment was via oral medication on an empty stomach once a day. All cases were required to undergo a proper medical follow-up at the end of 3, 6, and 12 months after treatment and once a year later. The cure, hypothyroidism rates and incidence rates of benign and malignant thyroid tumors and the health of their offspring were studied. The safety of radioiodine treatment for children and adolescents'growth, development were also evaluated.ResultsFollow-up was conducted on 80 cases, with 30 males and 50 females, aged from 6 to 19(12.2±2.3) years; nine patients were lost to follow-up(10.1%). The maximum dose of 131I ranged from 177.6 to 555 MBq per patient; the mean dose was 203.5 MBq. After one year of radioiodine treatment, the cure rate was 82.50%, and the effective rate was 98.75%; no efficiency is very low(1.25%). As time passed, the incidence of hypothyroidism increased, reaching 35% within 15 years. All cured patients had normal growth and produced offspring whose intelligence and development were normal. No one was diagnosed with thyroid carcinoma or leukemia in his/her medical follow-ups.ConclusionsUsing 131I for treating children and adolescents with Graves hyperthyroidism was effective and safe. The minimal side effects make it worthy of wide application in clinics.
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  • [1] Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis:management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists[J]. Thyroid, 2011, 21(6):593-646. DOI:10. 1089/thy. 2010. 0417.
    [2] 潘中允.实用核医学[M].北京:人民卫生出版社, 2014:177.Pan ZY. Practice of nuclear medicine[M]. Beijing:People's Medical Publishing House, 2014:177.
    [3] Lavard L, Ranløv I, Perrild H, et al. Incidence of juvenile thyrotoxicosis in Denmark, 1982-1988. A nationwide study[J]. Eur J Endocrinol, 1994, 130(6):565-568. doi: 10.1530/eje.0.1300565
    [4] Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood:a National population based study in the UK and Ireland[J]. Clin Endocrinol(Oxf), 2010, 72(3):358-363. DOI:10.1111/j.1365-2265.2009.03717.x.
    [5] Ohye H, Minagawa A, Noh JY, et al. Antithyroid drug treatment for graves' disease in children:a long-term retrospective study at a single institution[J]. Thyroid, 2014, 24(2):200-207. DOI:10.1089/thy.2012.0612.
    [6] Rivkees SA. Pediatric graves' disease:controversies in management[J]. Horm Res Paediatr, 2010, 74(5):305-311. DOI:10. 1159/000320028.
    [7] 谭天秩.临床核医学[M]. 2版.北京:人民卫生出版社, 2003:1224.Tan TZ. Clinice of nuclear medicine[M]. 2nd ed. Beijing:People's Medical Publishing House, 2003:1224.
    [8] 陈丹云, 陈棠华. 131I与抗甲状腺药物治疗儿童Graves病的疗效对照研究[J].中华儿科杂志, 2005, 43(7):507-509. DOI:10.3760/j.issn:0578-1310.2005.07.007.Chen DY, Chen TH. Comparison of efficacy of 131I and antithyroid drugs in the treatment of Graves' disease in children[J]. Chin J Pediatr, 2005, 43(7):507-509. doi: 10.3760/j.issn:0578-1310.2005.07.007
    [9] Ma C, Kuang A, Xie J, et al. Radioiodine treatment for pediatric Graves' disease[J/OL]. Cochrane Database Syst Rev, 2008(3):CD006294[2016-11-10]. http://www.ncbi.nlm.nih.gov/pubmed/18646146. DOI:10.1002/14651858.CD006294.pub2.
    [10] 郑艳, 赵德善, 付松海, 等.儿童和青少年Graves甲亢患者131I治疗剂量的分析研究[J].国际放射医学核医学杂志, 2013, 37(2):69-73. doi: 10.3760/cma.j.issn.1673-4114.2013.02.002Zheng Y, Zhao DS, Fu SH, et al. The dose analysis of 131I treatment in pediatric patients with Graves hyperthyroidism[J]. Int J Radiat Med Nucl Med, 2013, 37(2):69-73. DOI:10.3760/cma.j.issn.1673-4114.2013.02.002.
    [11] Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive Iodine in treating young Graves' patients[J]. J Clin Endocrinol Metab, 2004, 89(9):4229-4233. DOI:10.1210/jc.2003-031223.
    [12] West JD, Cheetham TD, Dane C, et al. Should radioiodine be the first-line treatment for paediatric Graves' disease?[J]. J Pediatr Endocrinol Metab, 2015, 28(7/8):797-804. DOI:10.1515/jpem-2014-0176.
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Follow-up study on children and adolescents with Graves hyperthyroidism after 131I treatment

    Corresponding author: Chunyin Zhang, zhangchunyin345@sina.com
  • 1. Department of Nuclear Medicine, the Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
  • 2. Department of Nuclear Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China

Abstract: ObjectiveTo investigate the therapeutic effects and safety of 131I treatment on children and adolescents with Graves disease.MethodsIn this study, 89 children and adolescents with Graves hyperthyroidism cases were treated using 131I. 131I was given at a dosage of 2.59 to 4.44 MBq per gram of thyroid tissue and calibrated according to the course of disease, thyroid weight, and the highest iodine rate. The treatment was via oral medication on an empty stomach once a day. All cases were required to undergo a proper medical follow-up at the end of 3, 6, and 12 months after treatment and once a year later. The cure, hypothyroidism rates and incidence rates of benign and malignant thyroid tumors and the health of their offspring were studied. The safety of radioiodine treatment for children and adolescents'growth, development were also evaluated.ResultsFollow-up was conducted on 80 cases, with 30 males and 50 females, aged from 6 to 19(12.2±2.3) years; nine patients were lost to follow-up(10.1%). The maximum dose of 131I ranged from 177.6 to 555 MBq per patient; the mean dose was 203.5 MBq. After one year of radioiodine treatment, the cure rate was 82.50%, and the effective rate was 98.75%; no efficiency is very low(1.25%). As time passed, the incidence of hypothyroidism increased, reaching 35% within 15 years. All cured patients had normal growth and produced offspring whose intelligence and development were normal. No one was diagnosed with thyroid carcinoma or leukemia in his/her medical follow-ups.ConclusionsUsing 131I for treating children and adolescents with Graves hyperthyroidism was effective and safe. The minimal side effects make it worthy of wide application in clinics.

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  • 格雷夫斯病(Graves disease,GD)是甲状腺功能亢进症(hyperthyroidism)最常见的原因之一。青少年及儿童格雷夫斯甲状腺功能亢进症(以下简称Graves甲亢)也并不少见,其治疗方式主要有手术、内科抗甲状腺药物(antithyroid drug,ATD)和131I治疗。手术治疗风险大、创伤大;ATD治疗时间长且易复发;131I治疗方法简便、一次性治愈率高。国际上将青少年及儿童Graves甲亢一直列为131I治疗的适应证[1],但国内对于青少年及儿童Graves甲亢是否采用131I治疗仍然存有诸多顾虑。为了探讨131I治疗青少年及儿童Graves甲亢的疗效及安全性,笔者收集了1995年1月1日至1999年12月31日ATD治疗无效或效果差的青少年及儿童Graves甲亢行131I治疗,对此进行前瞻性随访研究,现报道如下。

1.   资料与方法

    1.1.   临床资料

  • 从1995年1月1日至1999年12月31日,陆续对来西南医科大学附属医院(原泸州医学院附属医院)行ATD治疗且无效或效果差的89例青少年及儿童Graves甲亢患者行131I治疗并每年1次定期随访。本研究在治疗前均将131I治疗的优缺点以及可能发生的不良反应如实告之,患者及其家属均表示理解并签字同意。本研究获得了川北医学院附属医院伦理委员会的批准。

    入选标准:(1)有Graves甲亢病史;(2)青少年(13~19岁)、儿童(6~12岁);(3)内科ATD治疗无效或效果差(≥2年);(4)内科ATD过敏、WBC降低(<3.0×109个/L)。排除标准:(1)妊娠和哺乳患者;(2)急性心肌梗死患者;(3)严重肾功能障碍患者。

    Graves甲亢的诊断标准:(1)临床高代谢的症状和体征;(2)总3,5,3′,5′-四碘甲状腺原氨酸(total thyroxine,TT4)、游离T4(free T4,FT4)、总3,5,3′-三碘甲状腺原氨酸(total triiodothyronine,TT3)、游离T3(free T3,FT3)增高,TSH降低;(3)甲状腺肿和(或)甲状腺结节(少数病例无此体征)。诊断辅助条件:(1)眼球突出或其他浸润性眼征;(2)胫前黏液性水肿;(3)甲状腺TSH受体抗体增高。

  • 1.2.   131I治疗方法与随访

  • 治疗前准备:(1)停服ATD 2周;(2)禁食含碘丰富食物;(3)测甲状腺激素、血常规、心电图、肝肾功能、甲状腺摄碘功能,行甲状腺显像;(4)15~19岁女性患者加测人绒毛膜促性腺激素;(5)患者及家属知情同意并签署知情同意书。给药剂量采用公式法计算,131I活度为2.59~4.44 MBq/g,参考病程及年龄、甲状腺质量、最高摄碘率进行修正。甲状腺质量由我科两位专科医师共同触诊而定。所有患者131I治疗均采用一次性空腹口服,有合并症的给予相应处理。治疗后3、6、12个月随访,以后每年随访1次。详细记录随访患者的治疗经过、甲状腺激素水平变化情况、甲状腺良恶性肿瘤发生情况、患者生育情况及后代健康情况。

  • 1.3.   疗效评估参考标准

  • (1)痊愈:随访半年以上,患者的甲亢症状和体征完全消失,血清FT3、FT4及TSH恢复到正常水平;(2)好转:患者的甲亢症状减轻,体征未完全消失,血清FT3、FT4未降到正常范围;(3)无效:患者的甲亢症状和体征无变化或反而加重,血清FT3、FT4一直高于正常水平;(4)复发:131I治疗后的患者已达治愈标准,再次出现甲亢的症状和体征,血清甲状腺激素水平再次升高;(5)甲状腺功能减退症(以下简称甲减):患者出现甲减症状,血清FT3、FT4低于正常水平,TSH高于正常水平。痊愈、好转和甲减为131I治疗Graves甲亢有效。

2.   结果
  • 89例青少年及儿童Graves甲亢患者中,行131I治疗并随访至今的患者80例,其中,男性30例、女性50例,年龄6~19岁,平均年龄(12.2±2.3)岁,失访9例(10.1%)。随访142~221个月,平均(183±23)个月,到2013年12月31日统计截止。患者服用131I治疗次数为:服1次者71例(88.75%),服2次者8例(10%),服3次者1例(1.25%)。第1次131I治疗的剂量范围为177.6~555.0 MBq,平均剂量为203.5 MBq,以后再次服131I间隔时间均大于3个月。患者初次行131I治疗时,有6例患者在3 d内出现轻度头晕、食欲下降、颈部不适等症状,未经特殊处理后好转。

    治疗后3个月随访时,57例痊愈,痊愈率为71.25%(57/80);18例好转,好转率为22.50%(18/80);2例无效(2.50%);3例甲减(3.75%),有效率为97.50%(78/80)。2例无效患者及18例好转患者中6例再次行131I治疗,其余好转患者给予ATD治疗,3例甲减患者给予甲状腺激素替代治疗。治疗后6个月随访时65例痊愈,痊愈率为81.25%(65/80),15例好转,好转率为18.75%(15/80),无无效及甲减患者,有效率达100%(80/80)。15例好转患者采用ATD治疗。随访至第12个月,有1例患者Graves甲亢治疗无效(因未按医嘱服药),5例患者Graves甲亢好转,66例患者痊愈,8例患者发生甲减,甲减发生率为10.00%(8/80),131I治疗Graves甲亢有效率为98.75%(79/80),1例无效患者再次行131I治疗。随访至5年,12例发生甲减,5年甲减累计发生率为15.00%(12/80)。随访至10年,19例患者发生甲减,10年甲减累计发生率为23.75%(19/80)。随访至15年,28例患者发生甲减,15年甲减累计发生率为35.00%(28/80)(表 1)。所有甲减患者均给予甲状腺激素替代治疗,无不良反应发生。治愈病例中无复发病例,未见不良反应发生,生长发育均正常。有1例女性患者患甲状腺右叶结节(手术后病理证实),随访病例中无甲状腺癌、白血病等疾病发生。

    随访时间 痊愈 好转 无效 甲减 有效率
    3个月 57(71.25%) 18(22.50%) 2(2.50%) 3(3.75%) 97.50%
    6个月 65(81.25%) 15(18.75%) 0 0 100%
    12个月 66(82.50%) 5(6.25%) 1(1.25%) 8(10.00%) 98.75%
    5年 68(85.00%) 0 0 12(15.00%) 100%
    10年 61(76.25%) 0 0 19(23.75%) 100%
    15年 52(65.00%) 0 0 28(35.00%) 100%
    注:表中,痊愈率+好转率+甲减率=有效率。

    Table 1.  The follow-up results of 80 adolescents and children with Graves hyperthyroidism after 131I treatment(case)

    截至2013年12月31日,所有治疗患者均育有后代,共计生育92个小孩,其中,男性52人、女性40人,年龄1~17岁,平均年龄(12±3.2)岁,智力及发育未见确切异常,无死婴。有2例甲减女性患者分别有1次自然流产史,流产期前患者未按时服用甲状腺激素处于甲减状态。随访后代中甲状腺功能暂未发现异常,亦无甲状腺癌、白血病等疾病发生。

3.   讨论
  • Graves甲亢是一种以免疫紊乱为主导的自身免疫性甲状腺疾病,此外还与遗传因素、精神因素和碘摄入量的异常等有关[2]。青少年及儿童Graves甲亢症状、体征典型,结合实验室检查指标(血清甲状腺激素水平升高、TSH水平降低),不难诊断。近年来,青少年及儿童Graves甲亢有明显上升趋势,其中青少年Graves甲亢年发病率为3/10万,儿童年发病率为0.1/10万[3];不同地区和国家青少年及儿童Graves甲亢的发病率又有区别,美国的年发病率为1/10 000,英国和爱尔兰的年发病率为1/10万[4]。据统计,青少年及儿童Graves甲亢ATD治疗的复发率为30%左右,高于成人Graves甲亢复发率,同时有14%~25%的青少年及儿童Graves甲亢患者ATD治疗时会出现药物不良反应,如皮疹、白细胞减少症、中毒性肝病、血管炎等[5],这就为青少年及儿童Graves甲亢的治疗带来了困扰。

    本研究对80例ATD治疗无效或效果差的青少年及儿童Graves甲亢患者近20年的131I治疗实践及随访观察表明,131I治疗青少年及儿童Graves甲亢后3个月随访时,痊愈率为71.25%,好转率为22.50%,有效率为97.50%;6个月随访时痊愈率为81.25%,好转率为18.75%;1年后有效率为98.75%,这与国际水平相当(95%)[6]。随着时间的推移,行131I治疗的青少年及儿童Graves甲亢患者的甲减发生率逐渐升高也不可否认,15年甲减累计发生率高达35.00%。大量研究表明,任何治疗Graves甲亢的方法都会不可避免地导致甲减发生[7],陈丹云与陈棠华[8]的研究结果也显示,131I与ATD治疗儿童Graves甲亢后总甲减及永久性甲减的发生率差异无统计学意义。甲减是一种好诊断好治疗的疾病,一旦出现甲减只要及时进行生理性替代治疗,不会带来严重的后果。所以,甲减不应成为131I治疗青少年及儿童Graves甲亢的顾虑。

    131I治疗Graves甲亢已有60多年的历史,据不完全统计有超过1200例儿童及青少年Graves甲亢患者选择131I治疗,其缓解率高达95%以上[6]。1990年至2008年,11~19岁的Graves甲亢患者选择131I治疗的例数上涨了7.5倍[9]。国内131I治疗儿童及青少年Graves甲亢备受争议,最主要的原因是顾虑其短期及远期的并发症。短期不良反应有恶心、颈部不适等症状,能自行缓解,可不予特殊处理,情况严重者可加用非甾体类抗炎药。131I治疗后Graves甲亢危险主要发生于严重的甲亢和巨大甲状腺,在131I治疗前可辅以ATD治疗,以减小其发生的风险。长期研究表明,131I治疗青少年及儿童Graves甲亢是安全有效的[9],这在本研究中亦得到证实。尽管在大自然或者医源性诊断中接受的低剂量辐射曝光(0.1~25.0 Gy/g)与甲状腺癌发生的增加有相关性,但是131I治疗Graves甲亢时接受的相对高剂量的辐射能消融甲状腺组织,可使甲状腺癌的发生率相对降低。美国甲状腺协会与临床内分泌医师协会(ATA)2011年版甲亢指南指出,青少年及儿童Graves甲亢的治疗方法可选择ATD治疗、131I治疗或者手术。5~10岁患者131I治疗剂量应小于370 MBq,大于10岁者单位质量甲状腺131I治疗剂量可以大于5.55 MBq/g[1]。郑艳等[10]在关于儿童和青少年Graves甲亢患者行131I治疗剂量的分析研究中,建议所给予的131I应为成年人相应甲状腺质量所给131I总剂量的63%左右或每克剂量的74%左右。Read等[11]随访了116例接受131I治疗的青少年及儿童Graves甲亢患者(3.7~19.9岁)26~36年不等,随访病例中无白血病及甲状腺癌的发生,其中有2例患者患有单侧的甲状腺结节病,术后病理证实为良性。该研究表明131I治疗青少年及儿童Graves甲亢没有其他遗传性损伤或者甲状腺问题,这与本研究随访结果一致,甲状腺良恶性肿瘤的发生率不高于普通人群,且暂未见该治疗对患者的生长发育和对其后代有相关负面影响。没有证据表明青少年及儿童Graves甲亢患者接受131I治疗后其后代发生先天性畸形的风险会增加,而关于非甲状腺的癌症发生风险评估的远期并发症还未见报道[12]

    综上所述,通过国内外131I治疗Graves甲亢的实践证明,131I治疗青少年及儿童Graves甲亢是可行的,安全有效且不良反应少,值得临床推广应用。

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