编者按:关注儿童生长发育,促进儿童健康成长,不仅是每位家长和儿童领域工作者的愿望,也是健康中国战略的关键要素之一。同时,这也是国家经济、社会发展与文明进步的重要保障。国务院印发的《中国儿童发展纲要(2021—2030年)》明确指出,5岁以下儿童生长迟缓率应控制在5%以下。最新报告显示我国儿童矮小症的发病率约为3%,中国矮小症儿童约有760万人,但得到规范化诊疗的比例不到5%。这些生长发育问题已经成为危害儿童健康的公共卫生问题。为帮助更多临床儿科医生,尤其是基层儿科医生进一步规范儿童矮身材的诊断及治疗,本刊特别推出系列讲座——儿童矮身材的规范诊疗。本栏目将邀请国内儿科领域著名专家围绕儿童矮身材的流行病学、诊断、治疗、监测管理等方面进行阐述。该系列讲座主题包括:儿童矮身材的临床诊断现状、青春期前矮小患儿的早期诊断及干预、生长激素激发试验和胰岛素样生长因子1水平检测对生长激素缺乏症的诊断意义和思考、改善中枢性性早熟患儿身高获益的思考、关注青春晚期矮身材儿童的身高管理、生长激素缺乏症全生命周期管理-过渡期的生长激素缺乏症、矮身材儿童的心理健康、重组人生长激素临床应用的安全性等。
本栏目后续将根据实际需求,围绕儿童矮身材发表相关综述和临床病例等文章。我们期待这个系列讲座能加深儿科医生,尤其是基层儿科医生对儿童矮身材的认识,并对矮身材患儿的规范诊疗起到积极的推动作用,也希望这个栏目能够成为儿童矮小症领域的学术交流平台,为临床医生提供更多的知识与技术,以促进该领域的发展。
摘要
生长激素(growth hormone, GH)/胰岛素样生长因子1(insulin growth factor-1, IGF-1)轴是下丘脑/垂体生长激素轴的重要组成部分,对儿童生长发育具有关键性作用。GH/IGF-1轴信号通路及其旁路的紊乱和异常通常在儿童时期表现为身材矮小。身材矮小的儿童通常需进行GH激发试验及IGF-1水平检测,以鉴别生长激素缺乏症(growth hormone deficiency, GHD)和其他导致生长迟缓的原因。该文对GH激发试验和IGF-1检测值进行分析与阐述,以期为临床儿童GHD的诊断提供参考。
关键词:生长激素缺乏症;生长激素;胰岛素样生长因子1;生长激素激发试验;儿童
正文
1 多种GH激发试验联合使用帮助诊断GHD
然而,值得注意的是,GH激发试验仍存在特异性不佳的问题,即使进行两种激发试验,其特异性也仅为14.9%~49%[11]。鉴于GH激发试验存在假阳性率高和特异性不佳等局限性,许多医生在临床实践中存在是否有必要对患儿进行复测的争议。一方面,由于GH激发试验需要采血,属于有创检查方法,且费用相对较高,重复检测往往会增加患儿痛苦以及家长的经济负担。国外学者Oron等[12]发现精氨酸-可乐定联合激发试验(n=362)检测儿童晚期和青春期GHD可减少对第2次GH激发试验的需求。生长激素研究学会针对GH激发试验的复测争议,也认为既往基于不同激发试验被诊断为GHD的儿童不应被要求重新检测[13]。而另一方面,应当明确GH激发试验是目前临床确诊GHD的必要手段,但不是唯一标准。GHD的诊断应结合生长速率和骨龄等综合判断,具体应满足以下7个要点[10]:(1)身高落后于同年龄、同性别正常健康儿童身高的第3百分位数或低于2个标准差;(2)年生长速率低于以下水平,即3岁以下儿童<7 cm/年,3岁至青春期前儿童<5 cm/年,青春期儿童<6 cm/年;(3)匀称性矮小、面容幼稚;(4)智力发育正常;(5)骨龄落后于实际年龄;(6)2项GH药物激发试验GH峰值均<10 μg/L;(7)IGF-1水平低于正常。
2 多种因素可影响GH激发试验结果,设定个体化GH峰值切点优化判读
目前不同国家、地区采用的GH激发试验的峰值切点略有不同,国际共识和我国采用的GH激发试验峰值为10 μg/L(峰值超过此值,可排除GHD),部分国家和地区峰值为7 μg/L或5 μg/L。笔者认为设定个体化GH峰值切点,有助于优化对GH激发试验结果的判读。多项研究已证实GH峰值受体重指数(body mass index, BMI)、青春期状态、年龄和性别等因素的影响[14]。
2.1 BMI标准差评分与GH峰值成显著负相关
2.2 青春期前性激素“引发”对GH激发试验结果的影响尚无定论
青春期前生理性GH分泌往往相对较低,对此类儿童行GH激发试验前,有专家建议用性激素进行“引发”以增强GH分泌,减少假阳性结果。2016年美国儿科内分泌学指南则建议对>11岁青春期前男性和>10岁青春期前女性进行GH激发试验前使用性激素“引发”[17]。目前最常见的“引发”年龄,男孩为10~13岁,女孩为8~12岁,所用性激素制剂多为口服17β-雌二醇或己烯雌酚。然而,“引发”时,GH分泌可能会以非生理性方式增强,可能出现假阴性结果,从而导致患儿未能及时接受治疗[18]。因此,临床对“引发”仍存在争议,上述研究对结果的影响并不确定,是否能有效减少假阳性结果,仍需进一步研究证实。在我国,临床中较少对青春期前儿童进行“引发”,且是否基于青春期调整GH峰值,目前鲜有研究结果支持。
2.3 不同年龄和性别儿童GH峰值存在差异,新生儿GH峰值有待考证
Chen等[19]进行的回顾性研究纳入18例身材矮小的GHD患儿,结果发现GH激发试验中男性患儿的GH峰值在>10岁组中最高,其次是7~10岁组,≤6岁组最低;对于女性患儿,7~10岁组和>10岁组的GH峰值相比≤6岁组更高。若临床怀疑新生儿患GHD,可通过单次GH检测证实,最好在出生后1周内低血糖发生期间进行检测。然而,值得注意的是,尚未确定诊断新生儿GHD的GH峰值。2000年儿童和青少年GHD诊断和治疗共识指出,GH<20 μg/L提示新生儿存在GHD[20];而2020年,有研究分析25例重度GHD新生儿和281例健康新生儿(胎龄34.0~37.9周)的GH水平,认为GH<7 μg/L在足月新生儿血液筛查中确认重度GHD具有较高的准确性[21]。而在合并其他垂体激素缺乏症或存在三联征(异位垂体后叶、垂体前叶发育不全及垂体柄异常)新生儿中,2016年美国儿科内分泌学指南建议GH峰值为5 μg/L[17]。在此问题上,我国学界并没有形成统一的有说服力的见解,适合我国新生儿的GH峰值还有待考证。
2.4 影响GH峰值的其他因素
3 IGF-1检测也可辅助诊断GHD,并监测GH治疗依从性
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