Table 1_Alterations of lipoprotein subfractions in GH-deficient adults.docx

IntroductionDyslipidemia is a common complication of adult growth hormone deficiency (AGHD) and considered an important contributor to increased mortality. Previous studies mainly focused on quantitative assessment of lipoproteins, but lipoprotein subfractions and their relationship with insulin-like growth factor 1 (IGF-1) have not been explored.
PurposeTo perform a comprehensive evaluation of lipoprotein subfractions and measuring apolipoprotein L1 (apoL1), sphingosine 1-phosphate (S1P) and apolipoprotein M (apoM) in AGHD.
Materials and methods11 GH-substituted (GHS) patients, 9 GH-unsubstituted (GHU) patients and 37 controls were included in the study. Lipoprotein subfractions were separated by the Lipoprint system. ApoL1, apoM and S1P were determined by ELISA. In the GHS patients GH-replacement was discontinued for 2 months. Measurements were performed before GH-discontinuation, at the end of the 2-month GH-withdrawal, and 1 month after reinstituting GH-replacement.
ResultsStandard lipid parameters, apoM and apoL levels were not different between the groups. GHU patients demonstrated lower apolipoprotein A1 compared to controls (p=0.02) and higher apolipoprotein B100 compared to GHS (p=0.02). GHU and GHS showed higher S1P levels compared to controls (p=0.04 and p=0.01, respectively). Both GHU and GHS patients also presented higher percentage of intermediate-density lipoprotein (IDL) compared to controls (p=0.03 and p=0.01, respectively). Mean LDL size was lower in GHU compared to GHS (p=0.04). Percentage of intermediate HDL was lower in GHU and GHS compared to controls (p<0.001 and p<0.01, respectively). GHU demonstrated higher percentage of small HDL than controls (p<0.001). Overall, log10IGF-1 correlated positively with the percentage of large HDL (r=0.27; p=0.04) and intermediate HDL (r=0.38; p<0.01) and negatively with the percentage of small HDL (r=-0.46; p<0.01). Log10IGF-1 was the best predictor of small HDL (standardized β=-0.46; p<0.001) in overall subjects. In the GH-withdrawal study, the amount of HDL-6 increased with GH-withdrawal (p=0.03) and the percentage of IDL increased with reinstitution (p=0.05).
ConclusionDespite no changes in standard lipid parameters, considerable alterations of lipoprotein subfractions were revealed in GH-deficient adults indicating that lipoprotein subfraction analysis may allow for a more precise cardiovascular risk assessment in AGHD. Associations between HDL subfractions and Log10IGF-1 demonstrate a novel insight into the role of GH in lipid metabolism.

引言
血脂异常是成人生长激素缺乏症（adult growth hormone deficiency, AGHD）常见的并发症，被认为是死亡率升高的重要诱因。既往研究多聚焦于脂蛋白的定量评估，但脂蛋白亚组分及其与胰岛素样生长因子1（insulin-like growth factor 1, IGF-1）的关联尚未被探索。

研究目的
本研究旨在全面评估成人生长激素缺乏症患者的脂蛋白亚组分，并检测载脂蛋白L1（apolipoprotein L1, apoL1）、1-磷酸鞘氨醇（sphingosine 1-phosphate, S1P）及载脂蛋白M（apolipoprotein M, apoM）水平。

材料与方法
本研究共纳入11例接受生长激素替代治疗（GH-substituted, GHS）的患者、9例未接受生长激素替代治疗（GH-unsubstituted, GHU）的患者及37名健康对照者。脂蛋白亚组分采用Lipoprint系统进行分离。采用酶联免疫吸附试验（enzyme linked immunosorbent assay, ELISA）检测apoL1、apoM及S1P水平。对于GHS患者，暂停生长激素替代治疗2个月。分别于暂停生长激素治疗前、暂停2个月结束时、重新开始生长激素替代治疗后1个月进行指标检测。

结果
各组间的标准血脂参数、apoM及apoL水平无显著差异。与对照组相比，GHU患者的载脂蛋白A1水平更低（p=0.02），而载脂蛋白B100水平高于GHS患者（p=0.02）。GHU及GHS患者的S1P水平均高于对照组（分别为p=0.04及p=0.01）。与对照组相比，GHU及GHS患者的中间密度脂蛋白（intermediate-density lipoprotein, IDL）占比均更高（分别为p=0.03及p=0.01）。GHU患者的平均低密度脂蛋白（low-density lipoprotein, LDL）粒径小于GHS患者（p=0.04）。GHU及GHS患者的中间高密度脂蛋白（intermediate HDL）占比均低于对照组（分别为p<0.001及p<0.01）。GHU患者的小密度高密度脂蛋白（small HDL）占比高于对照组（p<0.001）。总体而言，log₁₀IGF-1水平与大密度高密度脂蛋白（large HDL）占比呈正相关（r=0.27；p=0.04），与中间高密度脂蛋白占比亦呈正相关（r=0.38；p<0.01），而与小密度高密度脂蛋白占比呈负相关（r=-0.46；p<0.01）。在所有受试者中，log₁₀IGF-1是小密度高密度脂蛋白水平的最佳预测因子（标准化β=-0.46；p<0.001）。在暂停生长激素治疗的亚组分析中，HDL-6的含量随暂停治疗时间延长而升高（p=0.03），而中间密度脂蛋白占比随重新启动治疗而升高（p=0.05）。

结论
尽管标准血脂参数未发生明显变化，但生长激素缺乏的成人患者存在显著的脂蛋白亚组分异常，这表明脂蛋白亚组分分析可实现对成人生长激素缺乏症患者更精准的心血管风险评估。高密度脂蛋白亚组分与log₁₀IGF-1的关联为生长激素在脂质代谢中的作用提供了新的研究视角。