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

doi:10.3877/cma.j.issn.2095-655X.2025.01.006

Abstract

Abstract:

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

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]. Chinese Journal of Diagnostics(Electronic Edition), 2025, 13(01): 38-44.

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Figures/Tables 5

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, $\overset{ˉ}{x}$ ±s)	10.68±3.09	10.01±3.22	10.55±3.29	F=2.015	0.135
骨龄(岁, $\overset{ˉ}{x}$ ±s 岁)	9.00±3.17	9.09±3.60	9.58±3.36	F=0.375	0.688
身高(cm, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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

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, $\overset{ˉ}{x}$ ±s)	10.68±3.09	10.01±3.22	10.55±3.29	F=2.015	0.135
骨龄(岁, $\overset{ˉ}{x}$ ±s 岁)	9.00±3.17	9.09±3.60	9.58±3.36	F=0.375	0.688
身高(cm, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±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

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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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

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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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, $\overset{ˉ}{x}$ ±s)	FT3(pmol/L, $\overset{ˉ}{x}$ ±s)	FT4(pmol/L, $\overset{ˉ}{x}$ ±s)	TSH(mU/L, $\overset{ˉ}{x}$ ±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

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
指标	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
指标	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	-	-	-	-

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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