igf在兒童矮小癥診治中的應(yīng)用初稿

1、主要內(nèi)容,歷史,1.J Lab Clin Med 1957;49:825–36 2.J Clin Invest 1963;42:1816–343. 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 s

2、ystem; 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 fact

3、or 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.

4、,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 huma

5、ns, 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

6、regulated by insulin and IGF-1; IGFBP-3 is regulated mainly by GH but also to some degree by IGF-1.,IGF-1受體,Resemblance between the insulin and insulin-like growth factor 1 (IGF-1) receptors,Figure 3,GH刺激試驗(yàn)的局限性,藥物刺激試驗(yàn)不是生

7、理過程,不能反映生理狀態(tài)下的GH分泌情況GH刺激試驗(yàn)的重復(fù)性差GH刺激試驗(yàn)準(zhǔn)確性差影響GH刺激試驗(yàn)的因素較多,患者的年齡、性發(fā)狀態(tài)以及刺激藥物、GH檢測(cè)方法等會(huì)影響試驗(yàn)的結(jié)果不能根據(jù)GH刺激試驗(yàn)預(yù)測(cè)患者對(duì)rhGH治療的反應(yīng)部分藥物刺激試驗(yàn)有一定的副作用,IGF-I和IGFBP-3測(cè)定,由于藥物刺激試驗(yàn)存在較高的假陽性率,不能很好地反映GH分泌情況,而血中IGF-1和IGFBP-3水平相當(dāng)穩(wěn)定,無明顯脈沖式分泌和晝夜節(jié)律變化,因

8、此能較好地反映內(nèi)源性生長(zhǎng)激素分泌狀態(tài)。臨床研究顯示[1-4]：IGF-1和IGFBP-3濃度與GH峰值相關(guān),但離散度較大;而IGFBP-3水平在兩組中差異無統(tǒng)計(jì)學(xué)意義,僅IGF-1濃度與GHD組呈顯著相關(guān)如矮身材兒童的病史,臨床癥狀和體格檢查等數(shù)據(jù)不能排除GH 分泌不足時(shí),應(yīng)選擇血清IGF-1 和IGFBP-3的測(cè)定作為篩查[1] :IGF-1和IGFBP-3水平在正常范圍的第5百分位上,可排除GHD,不需要作進(jìn)一步試驗(yàn)IGF-

9、1低于第1百分位, IGFBP-3低于第5百分位,除進(jìn)行GH-IGF軸檢查外,還需進(jìn)行全面系統(tǒng)檢查IGF-1水平低于第10百分位, IGFBP-3水平低于第20百分位,則不能排除GH2IGF軸功能異常。對(duì)所有IGF-1和IGFBP-3低水平者,則必須進(jìn)行GH刺激試驗(yàn),如GH有正常響應(yīng)時(shí),應(yīng)疑為GH不敏感綜合征(GH insensitivity syndrom, GHIS) ,需進(jìn)行IGF 生成試驗(yàn),1.Ranke MB.Diagno

10、stics of Endocrine function in children andadolescents.Basel:Karger,2003.12.中國實(shí)用兒科雜志,1999,14:89-91. 3.中華內(nèi)分泌代謝雜志,1999,15:125-126.4.實(shí)用醫(yī)學(xué)雜志,2002,18:1100-1101,不同年齡組健康人血清IGF-1水平(μg/L),1.Ranke MB.Diagnostics of Endocri

11、ne function in children andadolescents.Basel:Karger,2003.1,不同年齡組健康人血清IGFBP-3正常值(mg/L),1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2003.1,IGF- I 生成試驗(yàn),GH 抵抗時(shí)，基礎(chǔ)血漿GH 水平升高或正常，IGF-I、IG

12、FBP3 和GHBP 降低；GH 釋放刺激試驗(yàn)中，GH 濃度增高、IGF-I 水平降低指征： 疑存在GH抵抗，測(cè)定GH受體功能，如Laron 綜合征方法:空腹6小時(shí)后，于第一天上午采血一次，測(cè)定IGF-1及 IGFBP-3的基礎(chǔ)值當(dāng)日、第2、3、4日下午4-7時(shí)，皮下注射 0.1 μg/kg于第5日晨8-10時(shí)，再次采血測(cè)上述指標(biāo)結(jié)果分析：正常人IGF-I 增幅>20%，Laron 綜合征矮身材的IGF-I 濃度仍

13、為低水平,生長(zhǎng)激素缺乏癥生化檢測(cè)綜合分析,方法：放免方法檢測(cè)84例可疑GHD患者及63例非GHD患者GH峰值、IGF-I及IGFBP-3，運(yùn)ROC曲線方法選定各生化檢測(cè)的最佳截定值，并計(jì)算各最佳截定值的敏感性(sensitivity，S)、特異(specificity，Sp)及診斷有效率(diagnosticeficiency，Def),結(jié)論：GH激發(fā)試驗(yàn)如選取一個(gè)好的截定值(本研究為GH峰值7.65 μg/L)，則該試驗(yàn)對(duì)GHD具有

14、較高診斷價(jià)值；單個(gè)IGF-I檢測(cè)則遜于GH激發(fā)試驗(yàn)；IGFBP-3單獨(dú)診斷GHD價(jià)值不大。三者聯(lián)合使用診斷率及準(zhǔn)確率皆很高，最具診斷價(jià)值。,結(jié)果：ROC曲線顯示GH激發(fā)試驗(yàn)GH峰值7.65 μg/L為最佳截定值，DEf達(dá)84.4％ ，S為75.9％ ，Sp達(dá)94.9％ ；IGF-I SDS最佳截定值為-1.85，S為70.2％ 、Sp為83.1％ 、DEf為70.2％ ；IGFBP-3 SDS最佳截定值為-1.55，比傳統(tǒng)-2

15、SD高，DEf為64.3％ ，Sp較高(89.8％)，但S僅為45.8％ 。聯(lián)合使用上述3種測(cè)定有較佳的DEf(91.2％)，S(89.3％)和sp(93.7％)。,目的：以臨床診斷作為矮小癥患兒(可疑GHD)診斷標(biāo)準(zhǔn)，評(píng)估生長(zhǎng)激素激發(fā)試驗(yàn)、胰島素樣生長(zhǎng)因子I(IGF-I)及IGF結(jié)合蛋白3(IGFBP-3)對(duì)GHD的診斷價(jià)值。,中華內(nèi)分泌代謝雜志,2005,8(21):341-343,矮小兒童血清生長(zhǎng)激素IGF-1及尿生長(zhǎng)激素檢測(cè),

16、GHD 組患兒血清IGF-1、尿GH 水平與正常兒相比明顯降低( P 0.05) 。pGHD組患兒尿GH 水平按兩種方法計(jì)量值均介于正常和GHD患者之間, 與正常及GHD患者比較均有顯著性差異( P 均< 0.05),中國實(shí)用兒科雜志 ,2006, 7(21):511-514,矮小兒童血清生長(zhǎng)激素IGF-1及尿生長(zhǎng)激素檢測(cè),cGHD和pGHD 組患兒尿GH 的ng /g Cr計(jì)量值與其血GH 峰值呈顯著性正相關(guān)( rcGHD=

17、 0.556, P 0.05),結(jié)論：血清IGF-1的檢測(cè)只需抽血1 次, 尿GH 測(cè)定采集標(biāo)本方便, 無創(chuàng)傷性, 樣本不需特殊處理, 運(yùn)用ELISA 方法操作簡(jiǎn)便, 重復(fù)性好, 尿Cr的校正進(jìn)一步減少了干擾因素, 家長(zhǎng)和兒童易于接受。血清IGF-1、尿GH 的測(cè)定與藥物刺激試驗(yàn)相互彌補(bǔ)各自的不足, 加強(qiáng)診斷的準(zhǔn)確性和可靠性, 與常規(guī)藥物激發(fā)試驗(yàn)聯(lián)合應(yīng)用, 對(duì)于矮小兒童的臨床診療具有一定的指導(dǎo)意義。,矮身材兒童的診斷流程圖,基于I

18、GF一1水平生長(zhǎng)激素缺乏癥診斷預(yù)測(cè)模型的建立,目的：探討矮小癥患兒的病因及胰島素樣生長(zhǎng)因子(IGF)一1與生長(zhǎng)激素(growth hormone，GH)水平之間的關(guān)系，建立基于IGF．1水平的簡(jiǎn)易GH缺乏(GHD)診斷預(yù)測(cè)模型。方法：矮小癥住院患兒1496例，采用胰島素低血糖法和精氨酸法測(cè)定GH分泌狀態(tài)，根據(jù)體格檢查及實(shí)驗(yàn)室檢查分析病因；Logistic逐步多元回歸模型建立基于IGF-1的GHD診斷預(yù)測(cè)模型。,不同預(yù)測(cè)GHD的ROC曲

19、線,生長(zhǎng)激素缺乏的多因素Logictic逐步回歸分析及參數(shù)最大似然法估計(jì),,5個(gè)參數(shù)預(yù)測(cè)概率,臨床兒科雜志,2012,12:1110-15,基于IGF一1水平生長(zhǎng)激素缺乏癥診斷預(yù)測(cè)模型的建立,,相對(duì)較準(zhǔn)確識(shí)別GHD和非GHD,因上述參數(shù)的測(cè)定均簡(jiǎn)單易行，且模型中與IGF-1體內(nèi)水平有關(guān)的因素如年齡、BMI、ALT也進(jìn)入了模型，故可作為門診GHD篩查的簡(jiǎn)易工具，其臨床效用如何則仍需更多研究數(shù)據(jù)檢驗(yàn)和完善。,中國兒童青少年血清IGF-1與I

20、GFBP-3正常參考值研究,,,男孩IGF-1值在13歲達(dá)到高峰值；女孩IGF-1值在11歲達(dá)到高峰值同年齡組比較，男孩IGF-1值高于女孩,化學(xué)熒光法測(cè)定,中國兒童青少年血清IGF-1與IGFBP-3正常參考值研究,,,男孩IGFBP-3值在14歲達(dá)到高峰值；女孩IGFBP-3值在11歲達(dá)到高峰值同年齡組比較，女孩IGFBP-3值高于男孩,中國兒童青少年血清IGF-1與IGFBP-3正常參考值研究,6~18歲兒童青少年血清IGF-

21、1的正常參考值,6~18歲兒童青少年血清IGFBP-3的正常參考值,5條曲線分別代表：平均值、 ±1SD、 ±2SD,中國兒童青少年血清IGF-1與IGFBP-3正常參考值研究,發(fā)育前期兒童的IGF-1和IGFBP-3的水平比較低，但進(jìn)入Tanner Ⅲ期后， IGF-1和IGFBP-3的水平較Ⅱ期明顯升高,中國兒童青少年血清IGF-1與IGFBP-3正常參考值研究,IGD-1水平與年齡、性別和發(fā)育階段有密切關(guān)

22、系。不同的發(fā)育階段對(duì)IGFBP-3的影響不大。生長(zhǎng)發(fā)育階段決定作用對(duì)IGF-1的決定作用遠(yuǎn)大于IGFBP-3的影響。BMI對(duì)IGF-1和IGFBP-3的水平無影響。,rhGH Therapy Based on Target IGF-I Levels,Relationship between GH-induced IGF-I levels or cumulative GH dose and HT-SDS change fr

23、om 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 m

24、ethod 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 avoi

25、ds 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 2007, 92(7):2480–2486,IGF-1用于GH治療的療效評(píng)價(jià)和安全

26、性監(jiān)測(cè),IGF-1用于GH治療的療效評(píng)價(jià)和安全性監(jiān)測(cè),IGF-1用于GH治療的療效評(píng)價(jià)和安全性監(jiān)測(cè),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 IGFB

27、P-3 was shown to be related to an increased colon cancer risk.,,,rhGH治療過程中的監(jiān)測(cè)指標(biāo)及監(jiān)測(cè)頻率,,Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH Insensitivity,Linear growth in response to rhIGF-I treatment,A

28、, 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 2007, 92(3)

29、: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 log10 rhIGF-I dose

30、 (microgram per kilogram, BID).,Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH Insensitivity,Height Velovity (cm/yr),P <0.0001,C, Average growth rates before and during rhIGF-I for first and s

31、ubsequent 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 fir

32、st 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.,人數(shù),Treatment with IGF-1 in Children with Severe IGF-IDefic

33、iency 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 usi

34、ng 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 f

35、rom rhIGF-I treatment.,Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH Insensitivity,Triglyceride concentrations were normal during the first 4 yr of treatment but on average higher in the small n

36、umber 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 bas

37、eline. 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

38、 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 t

39、o increase modestly over time.,Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH Insensitivity,,,,,The most common adverse event was hypoglycemia, which was observed both before and during therapy.

40、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 sufficien