1、IGF-1在儿童矮小症诊治中应用的过去、现在与未来安科生物 袁牧2019.9.9主要内容IGF-1的历史与简介IGF-1在矮小症诊断中应用的研究现状IGF-1在矮小症GH治疗监测中应用的研究现状IGF-1作为药物治疗矮小症的研究现状IGF-1临床应用的未来历史年份年份事件事件1957IGF-1 and IGF-2 were identified by Salmon and Daughadayand designated“sulphation factor”by their ability to stimulate 35-sulphate incorporation into rat carti
2、lage.11963Froesch et al described the non-suppressible insulin-like activity(NSILA)of two soluble serum components(NSILA I and II)21972The labels sulphation factor and NSILA were replaced by the term“somatomedin”,denoting a substance under control and mediating the effects of GH.21976Rinderknecht an
3、d Humbel isolated two active substances from human serum,which owing to their structural resemblance to proinsulin were renamed“insulin-like growth factor 1 and 2”(IGF-1 and 2).31988The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS.1.J Lab Clin M
4、ed 1957;49:82536 2.J Clin Invest 1963;42:1816343.Proc Natl Acad Sci U S A 1976;73:23659.The cascade of the growth hormone axisThe cascade of the growth hormone axis.CNS,central nervous system;GH,growth hormone;GHBP,GH binding protein;GH-S,GH secretagogues;IGF-1,insulin-like growth factor 1;IGFBPs,IG
5、F binding proteins;+,stimulation;,inhibition.Figure 1IGF-1基因Type 1 insulin-like growth factor receptor gene and mRNA.Reproduced with permission from WernerThe IGF-1 gene is on the long arm of chromosome 12q2323.The human IGF-1 gene consists of six exons,including two leader exons,and has two promote
6、rs.Figure 2IGF binding proteins(IGFBPs)In the plasma,99%of IGFs are complexed to a family of binding proteins,which modulate the availability of free IGF-1 to the tissues.There are six binding proteins.In humans,almost 80%of circulating IGF-1 is carried by IGFBP-3,a ternary complex consisting of one
7、 molecule of IGF-1,one molecule of IGFBP-3,and one molecule of an 88 kDa protein named acid labile subunit.IGFBP-1 is regulated by insulin and IGF-1;IGFBP-3 is regulated mainly by GH but also to some degree by IGF-1.IGF-1受体Resemblance between the insulin and insulin-like growth factor 1(IGF-1)recept
8、orsFigure 3GH刺激试验的局限性 药物刺激试验不是生理过程,不能反映生理状态下的GH分泌情况 GH刺激试验的重复性差 GH刺激试验准确性差 影响GH刺激试验的因素较多,患者的年龄、性发状态以及刺激药物、GH检测方法等会影响试验的结果 不能根据GH刺激试验预测患者对rhGH治疗的反应 部分药物刺激试验有一定的副作用IGF-I和IGFBP-3测定 由于药物刺激试验存在较高的假阳性率,不能很好地反映GH分泌情况,而血中IGF-1和IGFBP-3水平相当稳定,无明显脉冲式分泌和昼夜节律变化,因此能较好地反映内源性生长激素分泌状态。临床研究显示1-4：IGF-1和IGFBP-3浓度与GH峰值相
9、关,但离散度较大;而IGFBP-3水平在两组中差异无统计学意义,仅IGF-1浓度与GHD组呈显著相关 如矮身材儿童的病史,临床症状和体格检查等数据不能排除GH 分泌不足时,应选择血清IGF-1 和IGFBP-3的测定作为筛查1:IGF-1和IGFBP-3水平在正常范围的第5百分位上,可排除GHD,不需要作进一步试验IGF-1低于第1百分位,IGFBP-3低于第5百分位,除进行GH-IGF轴检查外,还需进行全面系统检查IGF-1水平低于第10百分位,IGFBP-3水平低于第20百分位,则不能排除GH2IGF轴功能异常。对所有IGF-1和IGFBP-3低水平者,则必须进行GH刺激试验,如GH有正常
10、响应时,应疑为GH不敏感综合征(GH insensitivity syndrom,GHIS),需进行IGF 生成试验1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2019.12.中国实用儿科杂志,2019,14:89-91.3.中华内分泌代谢杂志,2019,15:125-126.4.实用医学杂志,2019,18:1100-1101不同年龄组健康人血清IGF-1水平(g/L)1.Ranke MB.Diagnostics of Endocrine function in ch
11、ildren andadolescents.Basel:Karger,2019.1不同年龄组健康人血清IGFBP-3正常值(mg/L)1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2019.1IGF-I 生成试验GH 抵抗时，基础血浆GH 水平升高或正常，IGF-I、IGFBP3 和GHBP 降低；GH 释放刺激试验中，GH 浓度增高、IGF-I 水平降低 指征：疑存在GH抵抗，测定GH受体功能，如Laron 综合征 方法:空腹6小时后，于第一天上午采血一次，测定IGF-
12、1及 IGFBP-3的基础值当日、第2、3、4日下午4-7时，皮下注射 0.1 g/kg于第5日晨8-10时，再次采血测上述指标 结果分析：正常人IGF-I 增幅20%，Laron 综合征矮身材的IGF-I 浓度仍为低水平生长激素缺乏症生化检测综合分析方法：方法：放免方法检测84例可疑GHD患者及63例非GHD患者GH峰值、IGF-I及IGFBP-3，运ROC曲线方法选定各生化检测的最佳截定值，并计算各最佳截定值的敏感性(sensitivity，S)、特异(specificity，Sp)及诊断有效率(diagnosticeficiency，Def)结论：结论：uGH激发试验如选取一个好的截定值
13、激发试验如选取一个好的截定值(本研究为本研究为GH峰值峰值7.65 g/L)，则该，则该试验对试验对GHD具有较高诊断价值；具有较高诊断价值；u单个单个IGF-I检测则逊于检测则逊于GH激发试验；激发试验；IGFBP-3单独诊断单独诊断GHD价值不大。价值不大。u三者联合使用诊断率及准确率皆很高，最具诊断价值。三者联合使用诊断率及准确率皆很高，最具诊断价值。结果：结果：ROC曲线显示GH激发试验GH峰值7.65 g/L为最佳截定值，DEf达84.4，S为75.9，Sp达94.9；IGF-I SDS最佳截定值为-1.85，S为70.2、Sp为83.1、DEf为70.2；IGFBP-3 SDS最佳
14、截定值为-1.55，比传统-2SD高，DEf为64.3，Sp较高(89.8)，但S仅为45.8。联合使用上述3种测定有较佳的DEf(91.2)，S(89.3)和sp(93.7)。目的：目的：以临床诊断作为矮小症患儿(可疑GHD)诊断标准，评估生长激素激发试验、胰岛素样生长因子I(IGF-I)及IGF结合蛋白3(IGFBP-3)对GHD的诊断价值。中华内分泌代谢杂志,2019,8(21):341-343矮小儿童血清生长激素IGF-1及尿生长激素检测GHD 组患儿血清IGF-1、尿GH 水平与正常儿相比明显降低(P 0.01)。pGHD和GHND组患儿血IGF-1水平波动较大,无统计学差异。GHN
15、D组患儿尿GH 水平按ng/g 肌酐(C r)计量显著低于正常对照相(P 0.05)。pGHD组患儿尿GH 水平按两种方法计量值均介于正常和GHD患者之间,与正常及GHD患者比较均有显著性差异(P 均 0.05)中国实用儿科杂志,2019,7(21):511-514矮小儿童血清生长激素IGF-1及尿生长激素检测cGHD和pGHD 组患儿尿GH 的ng/g Cr计量值与其血GH 峰值呈显著性正相关(rcGHD=0.556,P 0.05;rpGHD=0.423,P 0.05)结论：结论：血清IGF-1的检测只需抽血1 次,尿GH 测定采集标本方便,无创伤性,样本不需特殊处理,运用ELISA 方法操
16、作简便,重复性好,尿Cr的校正进一步减少了干扰因素,家长和儿童易于接受。血清IGF-1、尿GH 的测定与药物刺激试验相互弥补各自的不足,加强诊断的准确性和可靠性,与常规药物激发试验联合应用,对于矮小儿童的临床诊疗具有一定的指导意义。矮身材儿童的诊断流程图基于IGF一1水平生长激素缺乏症诊断预测模型的建立目的：目的：探讨矮小症患儿的病因及胰岛素样生长因子(IGF)一1与生长激素(growth hormone，GH)水平之间的关系，建立基于IGF1水平的简易GH缺乏(GHD)诊断预测模型。方法：方法：矮小症住院患儿1496例，采用胰岛素低血糖法和精氨酸法测定GH分泌状态，根据体格检查及实验室检查分
17、析病因；Logistic逐步多元回归模型建立基于IGF-1的GHD诊断预测模型。不同预测不同预测GHD的的ROC曲线曲线生长激素缺乏的多因素生长激素缺乏的多因素Logictic逐步回归分析及参数最大似然法估计逐步回归分析及参数最大似然法估计5个参数预测概率临床儿科杂志,2019,12:1110-15基于IGF一1水平生长激素缺乏症诊断预测模型的建立相对较准确识别GHD和非GHD因上述参数的测定均简单易行，且模型中与IGF-1体内水平有关的因素如年龄、BMI、ALT也进入了模型，故可作为门诊GHD筛查的简易工具，其临床效用如何则仍需更多研究数据检验和完善。中国儿童青少年血清IGF-1与IGFBP
18、-3正常参考值研究男孩IGF-1值在13岁达到高峰值；女孩IGF-1值在11岁达到高峰值同年龄组比较，男孩IGF-1值高于女孩化学荧光法测定中国儿童青少年血清IGF-1与IGFBP-3正常参考值研究男孩IGFBP-3值在14岁达到高峰值；女孩IGFBP-3值在11岁达到高峰值同年龄组比较，女孩IGFBP-3值高于男孩中国儿童青少年血清IGF-1与IGFBP-3正常参考值研究618岁儿童青少年血清岁儿童青少年血清IGF-1的正常参考值的正常参考值618岁儿童青少年血清岁儿童青少年血清IGFBP-3的正常参考值的正常参考值5条曲线分别代表：平均值、1SD、2SD中国儿童青少年血清IGF-1与IGF
19、BP-3正常参考值研究发育前期儿童的IGF-1和IGFBP-3的水平比较低，但进入Tanner 期后，IGF-1和IGFBP-3的水平较期明显升高中国儿童青少年血清IGF-1与IGFBP-3正常参考值研究IGD-1水平与年龄、性别和发育阶段有密切关系。不同的发育阶段对IGFBP-3的影响不大。生长发育阶段决定作用对IGF-1的决定作用远大于IGFBP-3的影响。BMI对IGF-1和IGFBP-3的水平无影响。rhGH Therapy Based on Target IGF-I LevelsRelationship between GH-induced IGF-I levels or cumul
20、ative GH dose and HT-SDS change from baseline.Correlation between HT-SDS and IGF-I SDS is presented in the left panel(combined three groups).Correlation between HT-SDS and cumulative GH dose(grams per kilogram)is presented in the right panel.LOCF method was used.Combined n=170.IGF-based GH dosing is
21、 clinically feasible,leads to the attainment of desired preselected IGF-I levels and allows maintaining serum IGF-I concentrations within the desired target and avoids IGF-I levels substantially outside the normal range.The longterm growth outcome and safety of IGF-based dosing regimens remain to be
22、 determined.J Clin Endocrinol Metab,July 2019,92(7):24802486IGF-1用于GH治疗的疗效评价和安全性监测IGF-1用于GH治疗的疗效评价和安全性监测IGF-1用于GH治疗的疗效评价和安全性监测Cohen P,et al.Growth Horm IGF Res 2000,10:297-305GF-I was not found to be statistically associated with cancer risk,however,the combination of high IGF-I and low IGFBP-3 was
23、shown to be related to an increased colon cancer risk.rhGH治疗过程中的监测指标及监测频率Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH InsensitivityLinear growth in response to rhIGF-I treatmentA,Height velocity(centimeters per year)before(open circle)and during first year of therapy(closed
24、 circles)for each child is displayed relative to pretreatment height.n=76J Clin Endocrinol Metab,March 2019,92(3):902910B,The dose dependency of first-year growth rate is shown.Each point represents a single subject.The equation for the regression line shown is:height velocity(centimeters per year)-
25、6.2+7.2 log10 rhIGF-I dose(microgram per kilogram,BID).Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH Insensitivity2.81.38.71.76.11.60123456789bacelinefirst-yrsecond-yrHeight Velovity(cm/yr)P 0.0001C,Average growth rates before and during rhIGF-I for first and subsequent year
26、s are shown.Error bar shows upper limit of 95%confidence interval.Number of subjects at each year is indicated.Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment and was dependent on the dose administered.Height velocities were lower durin
27、g subsequent years but remained above baseline for up to8 yr.人数Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH InsensitivityThe putative effect of the therapy on adult height was assessed in the few subjects who attained near final adult height.Their adult heights,in the absen
28、ce of treatment,were predicted using the growth charts developed by Laron et al.,assuming that each subject would have grown at the average rate reported by Laron et al.if untreated.Accordingly,five of the six appeared to have gained more than 10 cm from rhIGF-I treatment.Treatment with IGF-1 in Chi
29、ldren with Severe IGF-IDeficiency due to GH InsensitivityTriglyceride concentrations were normal during the first 4 yr of treatment but on average higher in the small number of subjects assessed at 8 yr.These changes occurred in the context of relatively small alterations in BMI and percent body fat
30、,which was estimated by DEXA in 22 subjects.Body fat percentage averaged 26.2%at baseline.During the next 2 yr,there was a mean decrease of 2.5%(P 0.05),but after 2 yr,the mean returned to the baseline level of 26.2%.Furthermore,there was no apparent effect of insulin sensitivity as estimated by hom
31、eostasis model assessment during the first year of treatment,and glycated hemoglobin concentrations were normal and unchanged throughout.Plasma cholesterol was in the normal range for the majority and appeared to increase modestly over time.Treatment with IGF-1 in Children with Severe IGF-IDeficienc
32、y due to GH InsensitivityThe most common adverse event was hypoglycemia,which was observed both before and during therapy.It was reported by 49%of treated subjects.The next most common adverse events were injection site lipohypertrophy(32%)and tonsillar/adenoidal hypertrophy(22%).Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.IGF-1临床应用的未来 随着对IGF-1研究的深入，将可能会出现基于IGF-1的各种新的诊断方法，更加便捷、准确的诊断矮身材儿童 IGF-1各种新的药理作用被发现，rhIGF-1将可能会用于更多的新的疾病的治疗 经修饰的新系列的IGF-1被设计出来，具有更强的生物选择性，副作用更小，将能更好的应用于临床THE END
