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中华诊断学电子杂志 ›› 2025, Vol. 13 ›› Issue (01) : 38 -44. doi: 10.3877/cma.j.issn.2095-655X.2025.01.006

内分泌代谢性疾病诊治

矮小症儿童脂质运载蛋白2 水平及重组人生长激素治疗后脂质运载蛋白2、胰岛素样生长因子1 的变化
朱昱颖1, 赵倩倩2, 李艳英2, 潘珂鑫1, 马兆慧1, 张梅2,†()   
  1. 1. 272067 济宁医学院临床医学院
    2. 272029 济宁医学院附属医院内分泌遗传代谢科
  • 收稿日期:2024-12-16 出版日期:2025-02-26
  • 通信作者: 张梅
  • 基金资助:
    济宁市重点研发计划项目(2023YXNS029)

The level of LCN2 in children with short stature and the changes of LCN2 and IGF-1 after treatment with recombinant human growth hormone

Yuying Zhu1, Qianqian Zhao2, Yanying Li2, Kexin Pan1, Zhaohui Ma1, Mei Zhang2,†()   

  1. 1. College of Clinical Medicine, Jining Medical University, Jining 272067,China
    2. Department of Endocrinology, Genetics and Metabolism, the Affiliated Hospital of Jining Medical University, Jining 272029,China
  • Received:2024-12-16 Published:2025-02-26
  • Corresponding author: Mei Zhang
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引用本文：

朱昱颖, 赵倩倩, 李艳英, 潘珂鑫, 马兆慧, 张梅. 矮小症儿童脂质运载蛋白2 水平及重组人生长激素治疗后脂质运载蛋白2、胰岛素样生长因子1 的变化[J/OL]. 中华诊断学电子杂志, 2025, 13(01): 38-44.

Yuying Zhu, Qianqian Zhao, Yanying Li, Kexin Pan, Zhaohui Ma, Mei Zhang. The level of LCN2 in children with short stature and the changes of LCN2 and IGF-1 after treatment with recombinant human growth hormone[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2025, 13(01): 38-44.

目的

探讨脂质运载蛋白2(LCN2)在矮小症儿童血清中的水平以及应用重组人生长激素(rhGH)治疗后血清LCN2、胰岛素样生长因子1(IGF-1)的变化。

方法

选择2020 年1 月至2023年10 月就诊于济宁医学院附属医院内分泌遗传代谢科的440 例矮小症患者,根据病因不同将其分为生长激素缺乏症(GHD)组(n=334)和特发性矮小症(ISS)组(n=106),其中GHD 组根据生长激素峰值不同进一步分为完全性GHD(n=161)和部分性GHD(n=173)。 收集3 组患者在应用rhGH 治疗前的临床特征及血清学参数,分析LCN2 在区分完全性GHD、部分GHD、ISS 患者中的诊断效能。 对其中2023 年1~10 月就诊的82 例患者随访治疗6 个月以及12 个月,观察血清LCN2、IGF-1 等指标的变化情况及临床治疗效果;并对治疗前后不同时期血清LCN2 水平与临床特征及血清学参数进行相关性分析。

结果

治疗前ISS 组血清LCN2 水平[337.69(276.35,449.28)μg/L]显著高于完全性GHD组[238.81(188.70,350.62)μg/L]和部分性GHD 组[278.95(211.45,393.29)μg/L],差异具有统计学意义(H=10.464,P<0.01)。 rhGH 治疗12 个月后,3 组患儿身高标准差积分(SDS)均较治疗前、治疗6 个月后呈明显增长趋势(H=66.167,41.040,19.142;均P<0.01)。 3 组患者血清LCN2 的表达水平均随着治疗时间的延长呈显著下降趋势(H=60.500,44.720,38.095),IGF-1 水平(H=55.056,40.106,35.524)、IGF-1 SDS(H=43.167,38.480,33.429)均较治疗前逐渐增加,均差异具有统计学意义(均P<0.01)。 完全性GHD、部分GHD、ISS 患者治疗前、治疗6 个月时LCN2 与IGF-1 呈明显负相关(r=-0.219,-0.461,-0.443,-0.575,-0.443,-0.457;均P<0.05)。 LCN2 在区分ISS 与完全性GHD 的受试者操作特征(ROC)曲线下面积(AUC)为0.709,特异度为63.98%,敏感度为75.47%;区分ISS 与部分性GHD 的ROC 曲线AUC 为0.628,特异度为38.73%,敏感度为85.85%;区分完全性与部分性GHD 的ROC 曲线AUC 为0.588,特异度为48.45%,敏感度为69.36%。

结论

GHD 和ISS儿童在应用rhGH 治疗后临床疗效确切,血清LCN2 水平可作为身材矮小儿童诊断及治疗后的一项疗效监测与评估的指标。

关键词: 生长激素缺乏症, 特发性矮小症, 重组人生长激素, 胰岛素样生长因子-1, 脂质运载蛋白2

Objective

To study the expression of serum lipocalin-2 (LCN2) in children with short stature and the application of recombinant human growth hormone (rhGH) in children with short stature, as well as the changes of LCN2 and insulin-like growth factor 1 (IGF-1) serum level after rhGH treatment.

Methods

A total of 440 patients with short stature admitted to the Department of Endocrinology, Genetics andMetabolism of the Affiliated Hospital of Jining Medical University from January 2020 to October 2023 were analyzed. Patients were divided into growth hormone deficiency (GHD) group (n=334) and idiopathic short stature (ISS) group (n=106). GHD group was further divided into complete GHD group (n=161)and partial GHD group (n=173) according to the peak value of growth hormone. The clinical characteristics and serological parameters of the three groups before rhGH treatment were collected. The diagnostic efficacy of LCN2 in differentiating patients with complete GHD, partial GHD and ISS was analyzed. A subgroup of 82 patients (treated January-October 2023) underwent 6 month and 12 month follow-up to monitor therapeutic responses and changes of indicators (LCN2 and IGF-1 serum levels). The correlation between LCN2 serum levels and clinical features and serological parameters at different periods before and after treatment was analyzed.

Results

Before treatment, the LCN2 serum levels in the ISS group [337.69(276.35, 449.28)μg/L]were significantly higher than those in the complete GHD group [238.81(188.70, 350.62)μg/L] and the partial GHD group [278.95(211.45, 393.29)μg/L], with the differences being statistically significant(H=10.464, P<0.01). After 12 months of rhGH treatment, the height standard deviation score (SDS) of children in all three groups showed a significant upward trend compared to baseline and six months treatment(H=66.167, 41.040, 19.142, all P<0.01). The expression level of LCN2 decreased significantly with the extension of treatment time (H=60.500, 44.720, 38.095), while IGF-1 level (H=55.056, 40.106,35.524) and IGF-1 SDS (H=43.167, 38.480, 33.429) gradually increased compared with those before treatment, with statistically significant differences (all P<0.05). LCN2 and IGF-1 levels showed a significant negative correlation in patients with complete GHD, partial GHD, and ISS both before treatment and at 6 months of treatment (r=-0.219, -0.461, -0.443, -0.575, -0.443, -0.457, all P<0.05). The area under the curve (AUC) of LCN2 in distinguishing ISS children from complete GHD was 0.709, with a specificity of 63.98% and a sensitivity of 75.47%. The AUC of LCN2 in distinguishing ISS children from partial GHD was 0.628, with a specificity 38.73% and a sensitivity of 85.85%. The AUC for distinguishing complete GHD from partial GHD was 0.588, with a specificity of 48.45% and a sensitivity of 69.36%.

Conclusions

rhGH treatment is effective in children with GHD and ISS. The serum level of LCN2 can be used as an indicator for the diagnosis and treatment of children with short stature.

Key words: Growth hormone deficiency, Idiopathic short stature, Recombinant human growth hormone, Insulin-like growth factor-1, Lipocalin-2
表1 治疗前完全性GHD 组、部分性GHD 组和ISS 组临床特征及血清学指标比较
指标 完全性GHD(n=161) 部分性GHD(n=173) ISS(n=106) 统计量 P值
性别[例(%)] χ 2=0.087 0.916
男性 103(63.98) 114(65.90) 70(66.04)
女性 58(36.02) 59(34.10) 36(33.96)
年龄(岁,xˉ±s) 10.68±3.09 10.01±3.22 10.55±3.29 F=2.015 0.135
骨龄(岁,xˉ±s 岁) 9.00±3.17 9.09±3.60 9.58±3.36 F=0.375 0.688
身高(cm,xˉ±s) 127.24±16.42 125.28±16.63 127.49±16.71 F=0.815 0.443
身高SDS[M(Q1,Q3)] -2.57(-2.91,-2.28) -2.57(-2.88,-2.34) -2.67(-2.97,-2.32) H=0.426 0.654
体重(kg,xˉ±s) 28.03±10.67 26.46±10.26 26.71±9.52 F=1.074 0.343
体重SDS[M(Q1,Q3)] -1.81(-2.25,-1.01) -1.46(-1.84,-1.08) -1.59(-2.21,-1.25) H=2.095 0.064
BMI(kg/m2,xˉ±s) 17.10±6.31 16.41±3.86 16.01±3.19 F=1.832 0.161
BMI SDS[M(Q1,Q3)] -0.29(-1.06,0.38) -0.46(-1.28,0.21) -0.71(-1.38,0.04) H=1.895 0.152
GH峰值(μg/L,xˉ±s) 3.07±1.27 6.99±1.47 13.74±4.63 F=552.000 0.000
IGF-1[μg/L,M(Q1,Q3)] 165.00(111.50,215.75)ab 156.00(104.00,209.50) 169.00(102.08,258.75)c H=0.920 0.492
IGF-1 SDS[M(Q1,Q3)] -1.07(-1.73,-0.47) -1.25(-1.96,-0.51) -1.45(-2.06,-0.81) H=2.256 0.106
IGFBP3(μg/L,xˉ±s) 4.64±1.22 4.44±1.29 4.65±1.12 F=1.311 0.271
LCN2[μg/L,M(Q1,Q3)] 238.81(188.70,350.62)ab 278.95(211.45,393.29) 337.69(276.35,449.28)c H=10.464 0.000
表2 3 组随访患者生长激素治疗前后临床特征及血清学指标变化
组别 身高SDS[M(Q1,Q3)] BMISDS[M(Q1,Q3)] LCN2[μg/L,M(Q1,Q3)] IGF-1[μg/L,M(Q1,Q3)] IGF-1SDS[μg/L,M(Q1,Q3)] 空腹血糖(mmol/L,xˉ±s) FT3(pmol/L,xˉ±s) FT4(pmol/L,xˉ±s) TSH(mU/L,xˉ±s)
完全性GHD(n=36)
治疗前 -2.33(-2.54,-2.07)ab -0.11(-0.88,1.46) 254.62(210.08,366.43)ab 159.00(111.00,193.00)ab -1.33(-2.13,-0.88)ab 5.29±0.50 6.86±0.68 17.38±2.28 2.42±1.13
治疗6个月 -1.99(-2.23,1.87) -0.12(-0.67,1.14) 189.53(156.72,216.70) 276.00(224.50,304.50) -0.01(-0.54,0.77) 5.16±0.40 6.96±0.66 17.29±2.64 2.19±0.99
治疗12个月 -1.63(-1.87,-1.27)c -0.57(-1.25,1.02) 104.89(79.69,140.52)c 303.00(236.00,363.50)c 0.13(-0.39,0.99)c 5.08±0.55 6.81±0.79 17.07±2.30 2.06±0.88
统计量 H=66.167 H=5.156 H=60.500 H=55.056 H=43.167 F=1.665 F=0.578 F=0.424 F=1.898
P值 0.000 0.051 0.000 0.000 0.000 0.206 0.563 0.656 0.158
组别 身高SDS[M(Q1,Q3)] BMISDS[M(Q1,Q3))] LCN2[μg/L,M(Q1,Q3)] IGF-1[μg/L,M(Q1,Q3)] IGF-1SDS[μg/L,M(Q1,Q3)] 空腹血糖(mmol/L,xˉ±s) FT3(pmol/L,xˉ±s) FT4(pmol/L,xˉ±s) TSH(mU/L,xˉ±s)
部分性GHD(n=25)
治疗前 -2.35(-2.72,-2.05)ab -0.69(-1.75,0.21) 292.95(248.84,380.69)ab 144.00(90.92,185.00)ab -1.70(-1.98,-1.11)ab 5.11±0.33 7.07±0.72 17.97±2.28 2.73±1.23
治疗6个月 -2.00(-2.31,-1.70) -0.66(-1.01,0.29) 249.60(185.16,290.96) 228.00(147.75,323.25) -0.34(-0.82,0.36) 5.05±0.66 7.06±0.94 17.95±2.57 2.73±1.48
治疗12个月 -1.43(-1.91,-1.12)c -0.84(-1.76,-0.09) 99.86(68.50,132.16)c 266.00(199.25,393.50)c 0.44(-0.31,1.00)c 5.08±0.31 6.86±1.07 17.81±2.66 2.27±0.81
统计量 H=41.040 H=1.234 H=44.720 H=40.106 H=38.480 F=0.253 F=0.744 F=0.047 F=2.094
P值 0.000 0.020 0.000 0.000 0.000 0.779 0.481 0.954 0.124
组别 身高SDS[M(Q1,Q3)] BMISDS[M(Q1,Q3)] LCN2[μg/L,M(Q1,Q3)] IGF-1[μg/L,M(Q1,Q3)] IGF-1SDS[μg/L,M(Q1,Q3)] 空腹血糖(mmol/L,xˉ±s) FT3(pmol/L,xˉ±s) FT4(pmol/L,xˉ±s) TSH(mU/L,xˉ±s)
ISS(n=21)
治疗前 -2.30(-2.54,-2.16)b -1.01(-1.32,-0.35) 308.73(246.13,547.73)ab 164.00(76.83,258.25)ab -1.36(-1.84,-0.67)ab 5.00±0.40 7.01±0.70 18.00±3.51 2.39±1.29
治疗6个月 -2.06(-2.44,-1.85) -0.49(-1.37,-0.06) 213.82(146.61,317.19) 234.00(181.75,327.00) -0.41(-0.92,0.58) 4.95±0.28 7.29±1.05 17.15±3.24 1.96±0.98
治疗12个月 -1.70(-2.02,-1.16)c -1.13(-1.58,-0.35) 81.30(49.93,125.96)c 299.50(233.25,366.25)c 0.10(-0.17,1.29)c 5.11±0.27 7.16±1.03 16.94±2.20 1.88±0.76
统计量 H=19.142 H=5.081 H=38.095 H=35.524 H=33.429 F=1.995 F=0.700 F=1.370 F=1.393
P值 0.000 0.055 0.000 0.000 0.000 0.149 0.470 0.266 0.272
表3 3 组随访患者治疗前后LCN2 水平与生长指标和血清学指标相关性分析
指标 完全性GHD治疗前 完全性GHD治疗6个月 完全性GHD治疗12个月 部分性GHD治疗前 部分性GHD治疗6个月 部分性GHD治疗12个月
r P值 r P值 r P值 r P值 r P值 r P值
身高(cm) -0.164 ＜0.05 -0.617 ＜0.01 -0.457 ＜0.05 -0.330 ＜0.01 -0.677 ＜0.05 -0.489 ＜0.05
身高 SDS -0.134 0.091 -0.034 0.091 0.069 0.687 -0.060 0.435 -0.001 1.000 -0.232 0.263
体重 SDS -0.137 0.083 -0.154 0.475 0.021 0.902 -0.250 ＜0.05 -0.294 0.153 0.038 0.857
BMI SDS -0.005 0.952 -0.048 0.739 0.069 0.691 -0.004 0.954 -0.116 0.579 0.239 0.250
生长速率(cm/年) - - -0.042 0.536 0.111 0.518 - - -0.161 0.441 -0.311 0.131
生长激素峰值(μg/L) -0.024 0.764 0.183 0.060 0.242 0.154 0.051 0.509 -0.312 0.128 -0.119 0.571
IGF-1(μg/L) -0.219 ＜0.05 -0.461 ＜0.05 -0.220 0.197 -0.443 ＜0.01 -0.575 ＜0.05 -0.167 0.423
IGFBP3(μg/L) -0.001 0.998 - - - - 0.052 0.518 - - - -
指标 ISS治疗前 ISS治疗6个月 ISS治疗12个月
r P值 r P值 r P值
身高(cm) -0.525 ＜0.05 -0.429 0.052 -0.588 ＜0.05
身高 SDS -0.157 0.495 0.146 0.527 0.187 0.415
体重 SDS -0.140 0.543 -0.078 0.738 0.058 0.802
BMI SDS 0.096 0.678 0.114 0.624 0.071 0.767
生长速率(cm/年) - - 0.220 0.339 0.199 0.388
生长激素峰值(μg/L) 0.359 0.110 0.169 0.463 0.083 0.718
IGF-1 -0.443 ＜0.05 -0.457 ＜0.05 -0.473 ＜0.05
IGFBP3(μg/L) -0.316 0.163 - - - -
图1 血清LCN2 水平诊断完全性GHD、部分性GHD 与ISS 患者的ROC 曲线分析 注:a 图为LCN2 区分ISS 与完全性GHD 的ROC 曲线;b 图为 LCN2 区分ISS 与部分性GHD 的ROC 曲线;c 图为LCN2 区分部分性GHD 与完全性GHD 的ROC 曲线。 LCN2 为脂质运载蛋白2;GHD 为生长激素缺乏症;ISS 为特发性矮小;ROC 为受试者操作特征
表4 血清LCN2 水平在区分完全性GHD、部分GHD、ISS 患者中的诊断效能
组别 AUC 95%CI P值 截断值(μg/L) 敏感度(%) 特异度(%)
ISS与完全性GHD 0.709 0.646~0.771 0.001 275.49 75.47 63.98
ISS与部分性GHD 0.628 0.562~0.694 0.005 231.41 85.85 38.73
完全性与部分性GHD 0.588 0.527~0.650 0.001 231.41 69.36 48.45
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