IGF-1在兒童矮小癥診治中的應(yīng)用(初稿)

1、IGF-1在兒童矮小癥診治中應(yīng)用的過去、現(xiàn)在與未來安科生物 袁牧2014.9.9編輯課件主要內(nèi)容IGF-1的歷史與簡介IGF-1在矮小癥診斷中應(yīng)用的研究現(xiàn)狀I(lǐng)GF-1在矮小癥GH治療監(jiān)測中應(yīng)用的研究現(xiàn)狀I(lǐng)GF-1作為藥物治療矮小癥的研究現(xiàn)狀I(lǐng)GF-1臨床應(yīng)用的未來編輯課件歷史年份事件1957IGF-1 and IGF-2 were identified by Salmon and Daughadayand designated “sulphation factor” by their ability to stimulate 35-sulphate incorporation into rat

2、 cartilage. 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. 21976Ri

3、nderknecht 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). 31988The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with

4、LS.1.J Lab Clin Med 1957;49:82536 2.J Clin Invest 1963;42:1816343. Proc Natl Acad Sci U S A 1976;73:23659.編輯課件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-lik

5、e growth factor 1; IGFBPs, IGF binding proteins; +, stimulation; , inhibition.Figure 1編輯課件IGF-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, includ

6、ing two leader exons, and has two promoters.Figure 2編輯課件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 c

7、arried 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. 編輯課件IGF-1受體Resemblance bet

8、ween the insulin and insulin-like growth factor 1 (IGF-1) receptorsFigure 3編輯課件GH刺激試驗的局限性藥物刺激試驗不是生理過程,不能反映生理狀態(tài)下的GH分泌情況GH刺激試驗的重復(fù)性差GH刺激試驗準(zhǔn)確性差影響GH刺激試驗的因素較多,患者的年齡、性發(fā)狀態(tài)以及刺激藥物、GH檢測方法等會影響試驗的結(jié)果不能根據(jù)GH刺激試驗預(yù)測患者對rhGH治療的反應(yīng)部分藥物刺激試驗有一定的副作用編輯課件IGF-I和IGFBP-3測定由于藥物刺激試驗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

9、顯脈沖式分泌和晝夜節(jié)律變化,因此能較好地反映內(nèi)源性生長激素分泌狀態(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,應(yīng)選擇血清IGF-1 和IGFBP-3的測定作為篩查1 :IGF-1和IGFBP-3水平在正常范圍的第5百分位上,可排除GHD,不需要作進一步試驗IGF-1低于第1百分位, IGFBP-3低于第5百分位,除進行GH-IGF軸檢查外,還需進行全面系統(tǒng)檢查IGF-1水平低于第10百分位, IGFBP-3

10、水平低于第20百分位,則不能排除GH2IGF軸功能異常。對所有IGF-1和IGFBP-3低水平者,則必須進行GH刺激試驗,如GH有正常響應(yīng)時,應(yīng)疑為GH不敏感綜合征(GH insensitivity syndrom, GHIS) ,需進行IGF 生成試驗1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2003.12.中國實用兒科雜志,1999,14:89-91. 3.中華內(nèi)分泌代謝雜志,1999,15:125-126.4.實用醫(yī)學(xué)雜志,2002,18:1100-1101編輯

11、課件不同年齡組健康人血清IGF-1水平(g/L)1.Ranke MB.Diagnostics of Endocrine function in children andadolescents.Basel:Karger,2003.1編輯課件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編輯課件IGF- I 生成試驗GH 抵抗時，基礎(chǔ)血漿GH 水平升高或正常，IGF-I、IGFBP3 和GHBP 降低；GH 釋

12、放刺激試驗中，GH 濃度增高、IGF-I 水平降低指征： 疑存在GH抵抗，測定GH受體功能，如Laron 綜合征方法:空腹6小時后，于第一天上午采血一次，測定IGF-1及 IGFBP-3的基礎(chǔ)值當(dāng)日、第2、3、4日下午4-7時，皮下注射 0.1 g/kg于第5日晨8-10時，再次采血測上述指標(biāo)結(jié)果分析：正常人IGF-I 增幅20%，Laron 綜合征矮身材的IGF-I 濃度仍為低水平編輯課件生長激素缺乏癥生化檢測綜合分析方法：放免方法檢測84例可疑GHD患者及63例非GHD患者GH峰值、IGF-I及IGFBP-3，運ROC曲線方法選定各生化檢測的最佳截定值，并計算各最佳截定值的敏感性(sens

13、itivity，S)、特異(specificity，Sp)及診斷有效率(diagnosticeficiency，Def)結(jié)論：GH激發(fā)試驗如選取一個好的截定值(本研究為GH峰值7.65 g/L)，則該試驗對GHD具有較高診斷價值；單個IGF-I檢測則遜于GH激發(fā)試驗；IGFBP-3單獨診斷GHD價值不大。三者聯(lián)合使用診斷率及準(zhǔn)確率皆很高，最具診斷價值。結(jié)果：ROC曲線顯示GH激發(fā)試驗GH峰值7.65 g/L為最佳截定值，DEf達84.4 ，S為75.9 ，Sp達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

14、截定值為-1.55，比傳統(tǒng)-2SD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)，評估生長激素激發(fā)試驗、胰島素樣生長因子I(IGF-I)及IGF結(jié)合蛋白3(IGFBP-3)對GHD的診斷價值。中華內(nèi)分泌代謝雜志,2005,8(21):341-343編輯課件矮小兒童血清生長激素IGF-1及尿生長激素檢測GHD 組患兒血清IGF-1、尿GH 水平與正常兒相比明顯降低( P 0.01)。pGHD和GHND組患兒血IGF-1水平波動較大, 無統(tǒng)計學(xué)差

15、異。GHND組患兒尿GH 水平按ng /g 肌酐( C r)計量顯著低于正常對照相( P 0.05) 。pGHD組患兒尿GH 水平按兩種方法計量值均介于正常和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)中國實用兒科雜志 ,2006, 7(21):511-514編輯課件矮小兒童血清生長激素IGF-1及尿生長激素檢測cGHD和pGHD 組患兒尿GH 的ng /g Cr計量值與其血GH 峰值呈顯著性正相關(guān)( rcGHD= 0.556, P 0.05; rpGHD = 0.423, P 0.05) 結(jié)論：血清IGF-1的檢測只需抽血1 次, 尿GH 測定采集標(biāo)本方便,

16、無創(chuàng)傷性, 樣本不需特殊處理, 運用ELISA 方法操作簡便, 重復(fù)性好, 尿Cr的校正進一步減少了干擾因素, 家長和兒童易于接受。血清IGF-1、尿GH 的測定與藥物刺激試驗相互彌補各自的不足, 加強診斷的準(zhǔn)確性和可靠性, 與常規(guī)藥物激發(fā)試驗聯(lián)合應(yīng)用, 對于矮小兒童的臨床診療具有一定的指導(dǎo)意義。編輯課件矮身材兒童的診斷流程圖編輯課件基于IGF一1水平生長激素缺乏癥診斷預(yù)測模型的建立目的：探討矮小癥患兒的病因及胰島素樣生長因子(IGF)一1與生長激素(growth hormone，GH)水平之間的關(guān)系，建立基于IGF1水平的簡易GH缺乏(GHD)診斷預(yù)測模型。方法：矮小癥住院患兒1496例，采

17、用胰島素低血糖法和精氨酸法測定GH分泌狀態(tài)，根據(jù)體格檢查及實驗室檢查分析病因；Logistic逐步多元回歸模型建立基于IGF-1的GHD診斷預(yù)測模型。不同預(yù)測GHD的ROC曲線生長激素缺乏的多因素Logictic逐步回歸分析及參數(shù)最大似然法估計5個參數(shù)預(yù)測概率臨床兒科雜志,2012,12:1110-15編輯課件基于IGF一1水平生長激素缺乏癥診斷預(yù)測模型的建立相對較準(zhǔn)確識別GHD和非GHD因上述參數(shù)的測定均簡單易行，且模型中與IGF-1體內(nèi)水平有關(guān)的因素如年齡、BMI、ALT也進入了模型，故可作為門診GHD篩查的簡易工具，其臨床效用如何則仍需更多研究數(shù)據(jù)檢驗和完善。編輯課件中國兒童青少年血清I

18、GF-1與IGFBP-3正常參考值研究男孩IGF-1值在13歲達到高峰值；女孩IGF-1值在11歲達到高峰值同年齡組比較，男孩IGF-1值高于女孩化學(xué)熒光法測定編輯課件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歲達到高峰值；女孩IGFBP-3值在11歲達到高峰值同年齡組比較，女孩IGFBP-3值高于男孩編輯課件中國兒童青少年血清IGF-1與IGFBP-3正常參考值研究618歲兒童青少年血清IGF-1的正常參考值618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編輯課件中國兒童青少年血清IGF-1與IGFBP-3

19、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，但進入Tanner 期后， IGF-1和IGFBP-3的水平較期明顯升高編輯課件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)系。不同的發(fā)育階段對IGFBP-3的影響不大。生長發(fā)育階段決定作用對IGF-1的決定作用遠大于IGFBP-3的影響。BMI對IGF-1和IGFBP-3的水平無影響。編輯課件rhGH Therapy Based on Target IGF-I LevelsRelationship between GH-induced IGF-I levels or

20、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

21、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

22、 remain to be determined.J Clin Endocrinol Metab, July 2007, 92(7):24802486編輯課件IGF-1用于GH治療的療效評價和安全性監(jiān)測編輯課件IGF-1用于GH治療的療效評價和安全性監(jiān)測編輯課件IGF-1用于GH治療的療效評價和安全性監(jiān)測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 h

23、igh IGF-I and low IGFBP-3 was shown to be related to an increased colon cancer risk.編輯課件rhGH治療過程中的監(jiān)測指標(biāo)及監(jiān)測頻率編輯課件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 circ

24、le) and during first year of therapy (closed circles) for each child is displayed relative to pretreatment height.n=76J Clin Endocrinol Metab, March 2007, 92(3):902910B, The dose dependency of first-year growth rate is shown. Each point represents a single subject. The equation for the regression li

25、ne shown is: height velocity (centimeters per year)-6.2+7.2 log10 rhIGF-I dose (microgram per kilogram, BID).編輯課件Treatment with IGF-1 in Children with Severe IGF-IDeficiency due to GH InsensitivityHeight Velovity (cm/yr)P 0.0001C, Average growth rates before and during rhIGF-I for first and subseque

26、nt 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

27、lower during subsequent years but remained above baseline for up to8 yr.人數(shù)編輯課件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 heigh

28、ts, 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.編輯課件Trea

29、tment with IGF-1 in Children 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, 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 m