IGF-1在儿童矮小症诊治中的应用课件.ppt

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,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.,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,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 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-1,受体,Resemblance between the insulin and insulin-like growth factor 1(IGF-1)receptors,Figure 3,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,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,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,IGFBP-3,正常值,(mg/L),1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2019.1,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,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,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。,?,GHND,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),而按,ng/12h,尿量计算值虽低于正常组,但无统计学意义,(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),?,GHND,组患儿尿,GH,的,ng/g Cr,计量值与其血中,GH,峰值无相关性,(P 0.05),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：,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,IGF,1,水平的简易,GH,缺乏,(GHD),诊,断预测模型。,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,GHD,的,ROC,曲线,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,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-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,IGF-1,的正常参考值,618,岁儿童青少年血清,IGFBP-3,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,IGFBP-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 Levels,Relationship between GH-induced IGF-I levels or cumulative 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 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,determined.,J Clin Endocrinol Metab,July 2019,92(7):2480,2486,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,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 2000,10:297-305,GF-I was not found to be statistically associated with cancer risk,however,the combination of high IGF-I and low IGFBP-3 was 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-I,Deficiency due to GH Insensitivity,Linear growth in response to rhIGF-I treatment,A,Height velocity(centimeters per year),before(,open circle)and during first,year of,therapy(,closed circles)for each child is,displayed relative to,pretreatment height.,n=76,J Clin Endocrinol Metab,March 2019,92(3):902,910,B,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)-6.2+7.2 log,10,rhIGF-I dose(microgram per,kilogram,BID).,Treatment with IGF-1 in Children with Severe IGF-I,Deficiency due to GH Insensitivity,2.8,1.3,8,.7,1.,7,6.1,1.,6,0,1,2,3,4,5,6,7,8,9,10,baceline,first-yr,second-yr,H,e,i,g,h,t,V,e,l,o,v,i,t,y,(,c,m,/,y,r,),P 0.0001,C,Average growth rates before and during,rhIGF-I for first and subsequent years 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,during subsequent years but remained above,baseline for up to8 yr.,人数,Treatment with IGF-1 in Children with Severe IGF-I,Deficiency due to GH Insensitivity,The 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 absence 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 Children with Severe IGF-I,Deficiency due to GH Insensitivity,Triglyceride 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,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 homeostasis 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-I,Deficiency due to GH Insensitivity,The 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,