Laboratory investigations in the diagnosis and follow-up of GH-related disorders

ABSTRACT In addition to auxiological, clinical and metabolic features measurements of growth hormone (GH) and insulin-like growth factor I (IGF-I) complement our tools in diagnosis and follow-up of GH-related disorders. While comparably robust during the pre-analytical phase, measurement and interpretation of concentrations of both hormones can be challenging due to analytical issues and biological confounders. Assay methods differ in terms of antibody specificity, interference from binding proteins, reference preparations and sensitivity. GH assays have different specificity towards different GH-isoforms (e.g. 20 kDa GH, placental GH) and interference from the GH antagonist Pegvisomant. The efficacy to prevent binding protein interference is most important in IGF-I assays. Methodological differences between assays require that reference intervals and diagnostic cut-offs are assay-specific. Among biological variables, pubertal development and age are most relevant for IGF-I, making detailed reference intervals mandatory for interpretation. GH has pulsatile secretion and short half-life. Its concentration is modified by acute factors such as stress, exercise and sleep, but also by intake of oral estrogens and anthropometric factors (e.g. BMI). Other GH dependent biomarkers such as free IGF-I, IGF binding protein 3 (IGFBP 3) and acid labile subunit (ALS) have been proposed. Their concentrations largely mirror the information obtained through measurement of IGF-I, but their measurement can be helpful in particular situations. In this review, we describe the evolution of analytical methods to measure biomarkers of GH action, the impact of the methodological changes on laboratory results and the need to include biological variables in their interpretation. Arch Endocrinol Metab. 2019;63(6):618-29摘要 除生长学、临床与代谢特征外，生长激素（growth hormone, GH）与胰岛素样生长因子I（insulin-like growth factor I, IGF-I）的检测可完善生长激素相关疾病的诊断与随访手段。尽管两种激素的检测在分析前阶段均具备较好的稳定性，但受分析相关问题与生物学混杂因素影响，二者的浓度检测与结果解读仍存在挑战。不同检测方法在抗体特异性、结合蛋白干扰、参考品与灵敏度等方面存在差异。生长激素检测对不同生长激素亚型（如20 kDa GH、胎盘生长激素）具有不同的特异性，且会受到生长激素拮抗剂培维索孟（Pegvisomant）的干扰。在胰岛素样生长因子I的检测中，阻断结合蛋白干扰的效能最为关键。不同检测方法间的方法学差异，要求参考区间与诊断临界值需针对特定检测方法制定。在生物学变量中，青春期发育状态与年龄对胰岛素样生长因子I的影响最为显著，因此解读检测结果时必须使用针对性的详细参考区间。生长激素呈脉冲式分泌且半衰期较短，其浓度会受应激、运动与睡眠等急性因素影响，同时也会受口服雌激素摄入以及人体测量学因素（如身体质量指数BMI）的调控。此外，已有研究提出其他生长激素依赖性生物标志物，如游离胰岛素样生长因子I、胰岛素样生长因子结合蛋白3（IGFBP-3）与酸不稳定亚基（ALS）。这些标志物的浓度大体可反映通过胰岛素样生长因子I检测获取的信息，但在特定临床场景中，其检测仍具备辅助诊断价值。本综述将介绍生长激素作用相关生物标志物检测方法的发展历程、方法学变更对实验室检测结果的影响，以及解读检测结果时纳入生物学变量的必要性。《内分泌代谢学档案》（Arch Endocrinol Metab），2019年；63(6):618-29