ORIGINAL ARTICLE http://dx.doi.org/10.15263/jlmqa.2014.36.1.48 Usefulness of Serum IGF-I and IGFBP-3 Levels in Children with Short Stature Young Su Je 1, Woo Ri Jang 1, Chung Hyun Nahm 1, Jong Won Choi 1, Jin Ju Kim 1, Soon Ki Kim 2, Ji Eun Lee 2, In Young Hyun 3, and Yeonsook Moon 1 Departments of 1 Laboratory Medicine, 2 Pediatrics, and 3 Nuclear Medicine, Medical School of Inha University, Incheon, Korea Corresponding author: Yeonsook Moon Department of Laboratory Medicine, Inha University Hospital, Inha University School of Medicine, 27 Inhang-ro, Junggu, Incheon 400-711, Korea Tel: +82-32-890-2523 Fax: +82-32-890-2529 E-mail: moonys@inha.ac.kr Background: Serum insulin-like growth factor-i (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels are known markers of growth hormone (GH) secretion. The clinical utility of serum IGF-I and IGFBP-3 testing, however, remains controversial. The aims of this study were to evaluate the usefulness of IGF-I and IGFBP-3 as indicators of GH secretion through the GH stimulation test and to investigate whether a decrease in serum IGF-I levels in children with short stature, regardless of the cause, can be used as a screening test for short stature. Methods: A total of 262 children presented with short stature, precocious puberty, or premature thelarche and were grouped into 7 tiers based on the 2007 growth chart. Serum IGF-I and IGFBP-3 levels and GH stimulation were analyzed using an immunoradiometric assay, and the data from 68 children who were below the 3rd percentile for height were used to evaluate the usefulness of IGF-I and IGFBP-3 as markers of GH status. Results: GH deficiency was confirmed by the GH stimulation test in 25 of the 68 children, and 15 (15/25, 60%) and 4 (4/25, 16%) of them showed a decrease in IGF-I and IGFBP-3 levels, respectively. The sensitivity and specificity for predicting GH secretion were 60% and 16%, respectively, for IGF-1 and 41.9% and 97.7%, respectively, for IGFBP-3. Decreased serum IGF-I levels were more frequently observed in children below the 25th percentile than in those in the 25th to 95th percentiles. Conclusions: IGF-I and IGFBP-3 levels have been used as a screening tool for GH secretion in children with short stature, but based on the results of the GH stimulation test in the current study, the levels of IGF-I and IGFBP-3 might not be useful as markers of GH secretion. Evaluating serum IGF-I levels alone is not a sufficient screening test for children with a short stature. (J Lab Med Qual Assur 2014;36:48-53) Key Words: Insulin-like growth factor I, Insulin-like growth factor binding protein 3, Short stature, Growth hormone pissn: 1225-097X eissn: 2288-7261 Received October 10, 2013, Revision received December 6, 2013, Accepted January 12, 2014 서론 저신장은하나의질환이기보다는다양한원인으로발생하는현상으로신장이같은연령, 같은성별의평균신장보다 3백분위수미만일경우또는 -2.0 SD ( 표준편차 ) 보다작은경우를말한다 [1,2]. 임상에서는저신장증의원인을찾기위해가족력, 성장환경, 영양상태, 선천성대사이상질환유무등을알아보고, 성장호르몬관련검사, 갑상샘호르몬검사, 유전자검사등의진단적검사를시행한다. 그중성장호르몬은뇌하수체에서박동성으로분비되기때문에한번측정한검사결과는 의미가없으며 24시간동안일정간격으로채혈하여그농도를검사하거나 2가지이상의약물을통한유발검사를시행한다 [3,4]. 그러나성장호르몬자극검사의번거로운과정과자연적인생체내의성장호르몬분비를반영하지못한다는점등으로인하여, 일중변동이거의없고내인성성장호르몬분비상태를잘반영하는인슐린양성장인자 I (insuline like growth factor-i, IGF-I) 과인슐린양성장인자결합단백 -3 (insulin like growth factor binding protein-3, IGFBP-3) 이성장호르몬결핍증의진단에유용한선별검사로이용되고있다 [5,6]. 하지만이두검사에대한민감도와특이도가보고자마다달라 48 Copyright 2014 The Korean Association of Quality Assurance for Clinical Laboratory
서성장평가로서의의의에논란이있어왔고 [7-9] 각각단독으 로검사를시행하거나병합으로측정하여도성장호르몬결핍 의효과적인선별검사가되지못한다는보고도있다 [10]. 이에 저자들은한국소아표준발육표 2007 의분류표상 3 백분위수미 만의저신장증을주소로내원한 16 세미만의소아들중성장 호르몬자극검사를시행한소아들을대상으로혈중성장호르 몬농도지표로써의혈중 IGF-I, IGFBP-3 농도의임상적유 용성을알아보았다. 또한 IGF-I 농도가성장호르몬결핍과연관되지않은특발 성저신장증에서도의미있게낮다는보고 [11] 가있어, 원인에 관계없이저신장증을주소로내원한소아들에서 IGF-I 의농도 를측정하여저신장증지표로써의이용가능성을알아보기위 해한국소아표준발육표 2007 의분류표상 7 개의각군별감소 빈도를비교하였다. 대상및방법 1. 대상환자 2009 년 1 월부터 2012 년 12 월까지저신장으로내원한소아 중한국소아표준발육표 2007 에의거하여 3 백분위수미만의 환자 68 명 ( 남아 33 명, 여아 35 명, 연령분포 1 16 세 ) 을대상 으로 IGF-I, IGFBP-3, 성장호르몬자극검사를시행하였다. 저 신장증으로내원한소아 180 명과성조숙증, 유방조기발육등 저신장증이외의원인으로성장발달에관한평가를받기위해 내원한소아 82 명을포함한총 262 명 ( 남아 70 명, 여아 192 명, 연령분포 1 16 세 ) 을대상으로혈청 IGF-I 농도를측정하였 다. 소아들은한국소아표준발육표 2007 에의거하여일곱개의 군으로나누었고 (Table 1), 각군별남아의수가충분치않아 Table 1. Study participants stratified by height Height* (percentile) Male Female Total Cumulative total 0 3 56 89 145 145 3 5 2 17 19 164 5 10 4 4 8 172 10 25 1 9 10 182 25 50 3 17 20 202 50 75 1 25 26 228 75 95 3 31 34 262 Total 70 192 262 *Height groups were based on the 2007 Korean National Growth Charts. 남녀구별없이각군별감소빈도를조사하였다. 2. 방법신장의계측은일어설수없는소아의경우에는신생아 / 유아용신장체중자동측정기를이용하여측정하였고, 일어설수있는소아의경우에는일반신장체중측정기를이용하여측정하였다. 대상소아들에서채취한전혈은즉시원심분리하여검사를시행할때까지 -70 o C 이하에서냉동보관하였다. 혈청 IGF-I 농도와 IGFBP-3 농도는면역방사측정 (IRMA) 키트 (Immunotech; Beckman Coulter, Marseille, France) 을이용하여측정하였다. 두검사모두각소아의연령별참고치가달라서동일한기준치를적용할수없으므로시약회사에서제공하는연령별참고치에비교하여증가혹은감소여부를판정하였고성장호르몬자극검사를시행한소아에서증가, 감소의빈도를조사하였다. 성장호르몬자극검사는성장호르몬분비를자극하는자극제를투여하지않은상태에서측정을하고자극제인 levodopa 투여후 60, 90, 120 분에, 인슐린투여후 30, 60, 90분에, 글루카곤투여후 90, 120, 180 분에성장호르몬을측정 (HGH-CTK IRMA kit; DiaSorin SpA, Vercelli, Italy) 하였다. 성장호르몬결핍기준은각자극제투여후측정한성장호르몬수치가한번도 10 mu/l 이상으로측정된적이없을때로하였다. 저신장증과정상신장을갖는다른성장관련증상 ( 성조숙증, 조기유방발육등 ) 을주소로내원한소아들을대상으로 IGF-I 을측정하여 7개군간의감소빈도를비교하였다. 3. 통계분석성장호르몬자극검사결과와 IGF-I, IGFBP-3 감소빈도의통계학적유의성을확인하고, 7개의각군별소아들간혈중 IGF-I 농도의감소빈도차이를분석하기위해 Pearson 카이제곱검정을시행하였다. 자료의분석은 SAS ver. 8.2 (SAS Institute Inc., Cary, NC, USA) 프로그램을사용하였다. 통계학적유의성은 P<0.05 로정의하였다. 결과 1. 성장호르몬자극검사결과와 IGF-I, IGFBP-3 혈중농도성장호르몬자극검사를시행한 68명중 25명은자극제에대해반응하지않아성장호르몬결핍으로진단하였으며이들중 15명 (60%) 에서 IGF-I 이감소되어있었다. 43명은정상반응을보였고이중 25명 (58.1%) 에서 IGF-I 이감소되어있었다. 성장호르몬자극검사결과성장호르몬결핍증을진단받은군과 www.jlmqa.org J Lab Med Qual Assur 2014;36:48-53 49
Table 2. Incidence of decreased serum IGF-1 levels by growth hormone secretion levels in children below the 3rd percentile for height Growth hormone secretion levels Growth hormone deficiency (n=25) Normal growth hormone (n=43) Normal IGF-I Decreased IGF-I P-value 10 15 0.881* 18 25 Abbreviation: IGF-I, insuline like growth factor-i. *By chi-square test. Table 3. Incidence of decreased serum IGFBP-3 levels by growth hormone secretion levels in children below the 3rd percentile for height Growth hormone secretion levels Growth hormone deficiency (n=25) Normal growth hormone (n=43) Normal IGFBP-3 Decreased IGFBP-3 P-value 21 4 0.037* 42 1 Abbreviation: IGFBP-3, insuline like growth factor binding protein-3. *By chi-square test. Table 4. Frequency of decreased serum IGF-1 levels in 262 children Height (percentile) Normal IGF-I levels Decreased IGF-I levels Incidence (%) Cumulative incidence (n, %) 0 3 74 71 49.0 71/145 (49.0) 3 5 12 7 36.8 78/164 (47.6) 5 10 3 5 62.5 83/172 (48.3) 10 25 5 5 50.0 88/182 (48.4) 25 50 19 1 5.0 89/202 (44.1) 50 75 23 3 11.5 92/228 (40.4) 75 95 31 3 8.8 95/262 (36.3) Total 167 95 36.3 Abbreviation: IGF-I, insuline like growth factor-i. 정상반응을보인군에서 IGF-I 감소빈도의차이는통계적으로유의하지않았다 (P=0.881) (Table 2). IGFBP-3 는성장호르몬자극검사에서성장호르몬결핍을보인환아 25명중 4명 (16%) 에서, 정상반응을보인 43 명중 1명 (2.3%) 에서감소되어있었고, 성장호르몬결핍증을진단받은군과정상반응을보인군에서 IGFBP-3 의감소빈도차이는통계적으로유의하였다 (P=0.037) (Table 3). IGF-I 과 IGFBP-3 의민감도는각각 60%, 16% 이었고특이도는 41.9%, 97.7% 이었다. 2. 한국소아표준발육표 2007에따른각군간혈청 IGF-I값의감소빈도혈중 IGF-I 농도는총소아 262 명중 95명에서감소하였다. 신장 0 3 백분위수군의 49% (71/145), 0 10 백분위수군의 48.3% (83/172), 0 25 백분위수군의 48.4% (88/182) 에서혈청 IGF-I 값이감소하였다. 25백분위수미만군에서는각그룹별로감소된빈도에뚜렷한차이는관찰할수없었다. 25백분위수이상군에서는 80명중 7명 (8.8%) 에서혈청 IGF-I 값이감소해있었다신장 3백분위수를포함하는 25백분위수미만인소아군에서혈중 IGF-I 의값이감소된소아의비율은신장 25백분위수이상인소아군에비해의미있게높았다 (P<0.05) (Table 4). 고찰 혈중 IGF-I 과 IGFBP-3 농도는성장호르몬혈중농도에영향을받으면서체내에서일정한농도를유지하고측정이비교적용이하여, 내인성성장호르몬분비평가에유용한진단적지표로알려져있다 [12]. 하지만연구자들간의주장이달라아직까지도논란이계속되고있는데 Ranke 등 [13] 은 IGF-I 과 IGFBP-3 의민감도가 75%, 67% 이고특이도가 50%, 32% 이지만반복적인측정에서변화의폭이좁기때문에인체계측, 영상정보와함께시행하면성장호르몬결핍과특발성저신장증을감별하는데필요한검사법이라고하였고, Hasegawa 등 [14] 은성장호르몬결핍환자중부분성장호르몬결핍환자보다는고전적인성장호르몬결핍환자들에서 IGF-I 과 IGFBP-3 의민감도가 80%, 93% 로선별검사로좋은지표라고하였다. 그러나성장호르몬결핍증의진단에 IGF-I 과 IGFBP-3 모두민감도와특이도가좋지않으며, 50 J Lab Med Qual Assur 2014;36:48-53 www.jlmqa.org
특히 IGFBP-3 의경우성장호르몬결핍소아에서도정상값을보이는경우가많아민감도가떨어진다는보고도있다 [15]. 본연구의결과도이와유사하게 IGF-I 의민감도와특이도가 Ranke 등 [13] 의결과보다도낮은 60%, 41.9% 로성장호르몬결핍환자감별의선별검사로이용하기에만족할만한수준을보여주지못하였고, IGFBP-3 의민감도와특이도각각 16%, 97.7% 로특이도는높았으나민감도가너무낮아이또한선별검사로이용하기는어려울것으로판단하였다. 이는 Mitchell 등 [10] 이 IGF-I 과 IGFBP-3 중어느것도성장호르몬결핍의지표가아니며, 두가지검사를병행하여도효과적인선별검사로이용할수없다고주장한내용과도일치한다. 이러한제한점을갖는이유는 IGF-I, IGFBP-3 의혈중농도가성장호르몬분비외에간기능, 신기능, 영양상태, 갑상선기능저하증, 비만, 당뇨, 사춘기의상태, 체질량지수등에도영향을받기때문으로보인다 [3,16,17]. 이와같이다양한원인이 IGF-I 과 IGFBP-3 의혈중농도에영향을미친다는사실에근거하여성장호르몬결핍에의한저신장증이아닌특발성저신장증소아를대상으로한연구에서, IGF-I, IGFBP-3 농도가정상대조군에비해특발성저신장증소아군에서의미있게낮았다고하였다 [11]. 이에저자들은성장호르몬결핍에의한저신장증, 특발성저신장증을포함하는다양한원인에의해발생한저신장증소아들을대상으로 IGF-I 혈중농도를측정하고저신장증지표로써의이용가능성을알아보기위해저신장증이없는소아들에서의측정값과비교하였다. IGF-I 의연령별성별참고치가달라서절대값의비교보다는참고치를기준으로감소, 정상, 증가로구분하였고한국소아표준발육표 2007 에따른 7개의군별감소빈도를살펴본결과 25백분위수미만소아군에서 25백분위수이상소아군에비해감소빈도가뚜렷하게높았다. 25백분위수미만소아에 3백분위수미만의소아가다수를차지하고있어 25백분위수까지의 IGF-I 감소빈도에미치는영향을배제할수는없으나비록숫자가작기는하여도각군별로구별하여감소빈도를비교했을때 25백분위수이상군과는뚜렷한차이를보이고있어의미있는차이를보인다고보았으며 3 25 백분위수소아의수를늘려서확인을해보면더확실한결과를얻을수있을것으로보인다. 저신장의원인을구별하지않고나눈 3백분위수미만의 IGF-I 감소빈도 (49%) 가 3백분위수미만의성장호르몬결핍환자에서의감소빈도 (60%) 와큰차이를보이지않는다는것을감안하면 IGF-I 의혈중농도는성장호르몬뿐아니라다양한원인에의해발생하는저신장증과도연관이있음을확인할수있었다. 하지만양성률이 50% 에도미치지못하고있어 IGF-I 을저신장증의선별검사로사용하기는충분치 않은것으로판단하였다. 본연구에서저자들은성장호르몬결핍에의한저신장의선별검사로이용되는 IGF-I, IGFBP-3 의임상적유용성을알아보기위해 IGF-I, IGFBP-3, 성장호르몬자극검사를시행하였으나성장호르몬결핍의지표로써는효과적인검사가아니라고판단하였다. 또한저신장을주소로내원한소아들의혈중 IGF-I 농도를측정한후저신장증이아닌소아들과비교하였는데 3백분위수미만의소아 49% (71/145) 에서감소되어있어 IGF-I 이다양한원인의저신장증과도연관성이있음을알수있었으나저신장증의선별검사로이용하기는어려울것으로보인다. REFERENCES 1. Lee KH. Growth assessment and diagnosis of growth disorders in childhood. J Korean Pediatr Soc 2003;46: 1171-7. 2. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008;93:4210-7. 3. Juul A, Skakkebaek NE. Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3. J Pediatr 1997;130:197-204. 4. Rosenfeld RG. Biochemical diagnostic strategies in the evaluation of short stature: the diagnosis of insulin-like growth factor deficiency. Horm Res 1996;46:170-3. 5. Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, et al. Serum levels of insulin-like growth factor (IGF)- binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 1995;80:2534-42. 6. Jorgensen JO, Blum WF, Moller N, Ranke MB, Christiansen JS. Circadian patterns of serum insulin-like growth factor (IGF) II and IGF binding protein 3 in growth hormone-deficient patients and age- and sex-matched www.jlmqa.org J Lab Med Qual Assur 2014;36:48-53 51
normal subjects. Acta Endocrinol (Copenh) 1990;123: 257-62. 7. Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB. Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 1993;76:1610-6. 8. Smith WJ, Nam TJ, Underwood LE, Busby WH, Celnicker A, Clemmons DR. Use of insulin-like growth factor-binding protein-2 (IGFBP-2), IGFBP-3, and IGF-I for assessing growth hormone status in short children. J Clin Endocrinol Metab 1993;77:1294-9. 9. Bereket A. Diagnosis of growth hormone deficiency: the role of growth hormone (GH), insulin-like growth factor (IGF-I) and IGF-binding protein (IGFBP-3). J Clin Res Ped Endo 2009;1(Suppl 1):23-35. 10. Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA, Brook CG. Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency. Arch Dis Child 1999;80:443-7. 11. Bae WJ, Jung JM, Chung WY. Serum levels of insulin-like growth factor-i and insulin-like growth factor binding protein-3 in children with idiopathic short stature. J Korean Soc Pediatr Endocrinol 2008;13:143-9. 12. Kim SY. Growth and sex differentiation of children born small for gestational age. Korean J Pediatr 2009;52:142-51. 13. Ranke MB, Schweizer R, Elmlinger MW, Weber K, Binder G, Schwarze CP, et al. Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm Res 2000;54:60-8. 14. Hasegawa Y, Hasegawa T, Aso T, Kotoh S, Tsuchiya Y, Nose O, et al. Comparison between insulin-like growth factor-i (IGF-I) and IGF binding protein-3 (IGFBP-3) measurement in the diagnosis of growth hormone deficiency. Endocr J 1993;40:185-90. 15. Tillmann V, Buckler JM, Kibirige MS, Price DA, Shalet SM, Wales JK, et al. Biochemical tests in the diagnosis of childhood growth hormone deficiency. J Clin Endocrinol Metab 1997;82:531-5. 16. Yuksel B, Ozbek MN, Mungan NO, Darendeliler F, Budan B, Bideci A, et al. Serum IGF-1 and IGFBP-3 levels in healthy children between 0 and 6 years of age. J Clin Res Pediatr Endocrinol 2011;3:84-8. 17. Wilson DM, Stene MA, Killen JD, Hammer LD, Litt IF, Hayward C, et al. Insulin-like growth factor binding protein-3 in normal pubertal girls. Acta Endocrinol (Copenh) 1992;126:381-6. 52 J Lab Med Qual Assur 2014;36:48-53 www.jlmqa.org
저신장소아에서인슐린양성장인자 -I 와인슐린양성장인자결합단백 -3 혈중농도의유용성제영수 1 장우리 1 남정현 1 최종원 1 김진주 1 김순기 2 이지은 2 현인영 3 문연숙 1 인하대학교의학전문대학원 1 진단검사의학교실, 2 소아청소년과학교실, 3 핵의학교실 배경 : 혈청인슐린양성장인자 I (insuline like growth factor-i, IGF-I) 과인슐린양성장인자결합단백 -3 (insulin like growth factor binding protein-3, IGFBP-3) 은성장호르몬농도에대한지표로유용하다고알려져있다. 하지만 IGF-I 과 IGFBP-3 의임상적유용성에대해서는아직논란의여지가있다. 이에저자들은성장호르몬자극검사를통하여성장호르몬상태지표로써의 IGF-I 과 IGFBP-3 의유용성을평가하고, 원인에관계없이저신장을주소로내원한소아를대상으로혈청 IGF-I 의감소빈도를측정하여저신장증선별검사로써의이용가능성을알아보았다. 방법 : 한국소아표준발육표 2007 을기준으로신장 3 백분위수미만인소아 68 명에서혈청 IGF-I, IGFBP-3, 성장호르몬자극검사를하여 IGF-I 과 IGFBP-3 의성장호르몬의상태반영에대한유용성을평가하였다. 저신장이나성조숙증, 유방조기발육등이의심되어내원한 262 명의소아를대상으로한국소아표준발육표 2007 에따라일곱개의군으로나누어 IGF-I 값을측정한후각군별감소빈도를비교하였다. IGF-I, IGFBP-3, 성장호르몬혈중농도는면역방사측정 (IRMA) 키트를이용하여측정하였다. 결과 : 성장호르몬자극검사를시행한 68 명의소아중 25 명이성장호르몬결핍증으로진단되었고이중 15 명 (15/25, 60%) 에서 IGF-I 이감소되었고, 4 명 (4/25, 16%) 에서 IGFBP-3 가감소되어있었다. IGF-I 과 IGFBP-3 의민감도는각각 60%, 16% 이었고, 특이도는 41.9%, 97.7% 이었다. 결론 : IGF-I 과 IGFBP-3 의혈중농도는저신장증소아의성장호르몬결핍증에대한선별검사로사용되고있지만, 성장호르몬자극검사로확인한결과성장호르몬혈중농도에대한지표로써의유용성이있다고할수없었다. IGF-I 의감소빈도는원인에관계없이신장 25 백분위수미만인소아에서 25-95 백분위수소아에비해의미있게높았으나저신장증의선별검사로써의이용하기는어렵다고판단하였다. (J Lab Med Qual Assur 2014;36:48-53) 교신저자 : 문연숙우 )400-711 인천시중구인항로 27, 인하대병원진단검사의학과 Tel: 032)890-2523 Fax: 032)890-2529 E-mail: moonys@inha.ac.kr www.jlmqa.org J Lab Med Qual Assur 2014;36:48-53 53