IGF-1在儿童矮小症诊治中的应用课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,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,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,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,主要内容IGF-1的历史与简介IGF-1在矮小症诊断中应用的,历史,年份,事件,1957,IGF-1 and IGF-2 were identified by,Salmon and Daughadayand,designated“sulphation,factor”by their ability to stimulate,35-,sulphate incorporation into rat cartilage.,1,1963,Froesch et al described the non-suppressible,insulin-like activity,(NSILA)of two soluble,serum components(NSILA I and II),2,1972,The labels sulphation factor and NSILA,were replaced by the term,“somatomedin”,denoting a substance under control and mediating,the effects of GH.,2,1976,Rinderknecht,and 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).,3,1988,The availability of biosynthetic IGF-1 since 1988 has enabled it to be,administered to children with LS.,1.J Lab Clin Med 1957;49:825,36 2.J Clin Invest 1963;42:1816,34,3.Proc Natl Acad Sci U S A 1976;73:2365,9.,历史年份事件1957IGF-1 and IGF-2 were,The cascade of the growth hormone axis,The 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,IGF binding proteins;+,stimulation;,inhibition.,Figure 1,The cascade of the growth horm,IGF-1,基因,Type 1 insulin-like growth factor receptor gene and mRNA.,Reproduced with permission from Werner,The IGF-1 gene is on the long arm of chromosome 12q23,23.,The human IGF-1 gene consists of six exons,including two leader exons,and has two,promoters.,Figure 2,IGF-1基因Type 1 insulin-like gro,IGF 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 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 binding proteins(IGFBPs)I,IGF-1,受体,Resemblance between the insulin and insulin-like growth factor 1(IGF-1)receptors,Figure 3,IGF-1受体Resemblance between the,GH,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,GH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,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,2019.1,2.,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,IGF-I和IGFBP-3测定?由于药物刺激试验存在较高的假,不同年龄组健康人血清,IGF-1,水平,(g/L),1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2019.1,不同年龄组健康人血清IGF-1水平(g/L)1.Ranke,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,2019.1,不同年龄组健康人血清IGFBP-3正常值(mg/L)1.R,IGF-,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-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,IGF-I生成试验?GH抵抗时，基础血浆GH水平升高或正常，,生长激素缺乏症生化检测综合分析,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：,?,GH,激发试验如选取一个好的截定值,(,本研究为,GH,峰值,7.65,g/L),，则该,试验对,GHD,具有较高诊断价值；,?,单个,IGF-I,检测则逊于,GH,激发试验；,IGFBP-3,单独诊断,GHD,价值不大。,?,三者联合使用诊断率及准确率皆很高，最具诊断价值。,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：,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,生长激素缺乏症生化检测综合分析方法：放免方法检测84例可疑G,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