噬血性淋巴组织细胞增生症患儿血清生长分化因子15水平检测及意义

Measurement of serum growth differentiation factor 15 concentration in children with hemophagocytic lympohistiocytosis and implications in the development of hyperferritinemia

目的检测噬血性淋巴组织细胞增生症（HLH）患儿血清生长分化因子15（GDF15）水平，探讨GDF15与HLH高铁蛋白血症发生的关系。方法采集28例HLH患儿（诊断时）（HLH组）和20例健康对照儿童（健康对照组）血液标本，采用美国R＆D公司Quantikine ELISA试剂盒测定血清GDF15水平。血常规和血清铁蛋白等血液生化指标由本院检验科按常规方法检测。比较2组研究对象血清GDF15水平，统计分析GDF15与Hb、血清铁蛋白、肝肾功能等多项指标的相关性。结果HLH组血清GDF15水平（中位水平1710ng／L，范围190～2400ng／L）显著高于健康对照组（中位水平260ng／L，范围104～649ng／L）（P〈0．001）。HLH组GDF15与初诊时以及化疗前最低Hb水平无相关性（P〉0．05），但与诊断时总胆红素和病程中最高三酰甘油水平呈正相关（χ2=0．475、0．465，P=0．011、0．019），与病程中最低纤维蛋白原和诊断时血清清蛋白水平呈负相关（χ2=-0．423、-0．399，P=0．031、0．039）。血清GDF15与HLH的病因和病死率无相关关系。结论GDF15为铁调节激素hepcidin上游抑制分子，巨噬细胞活化时以自分泌方式产生大量GDF15，抑制巨噬细胞进-步活化。HLH患儿血清GDF15水平显著升高，提示与HLH铁稳态调控及高铁蛋白血症的发生密切相关。

Objective To measure the serum growth differentiation factor （GDF15） levels in children with hemophagocytic lympohistiocytosis （HLH）, and to explore its possible implications in the development of hyperferritinemia in HLH. Methods Twenty-eight children with newly-diagnosed HLH and 20 age-and-sex matched healthy chil- dren were enrolled in this study as research subjects and controls respectively. Serum GDF15 levels were measured by Quantikine ELISA assay （product of R＆D Company, USA） according to manufacturer＇s instructions. Serum ferritin con- centration and other biochemical parameters were determined by conventional methods. Comparison of serum GDF15 levels between HLH group and healthy control group were made by nonparametric Mann-Whitney test. Correlations between serum GDF15 concentration and hemobiochemical parameters （ Hb, serum ferritin, fibrinogen, blood lipids, and liver and renal function tests） were made via Spearman correlation analysis. Results Serum GDF15 concentration was significantly higher in HLH group than that in healthy control group, with median concentrations and ranges of 1710 ng/L, 190 - 2400 ng/L,and 260 ng/L, 104 - 649 ng/L, respectively （ P 〈 0. 001 ）. Serum GDF15 concentration was correlated neither to Hb concentration at diagnosis nor to lowest Hb concentration before HLH-directed chemotherapy. Nevertheless it was positively correlated to serum level of total bilirubin at diagnosis and highest concentration of triglycerates during disease course （χ2 = 0. 475,0.465 ; P = 0.011,0.019, respectively ） , and negatively correlated to lowest levels of fibrinogen and albumin at diagnosis （χ2 = - 0. 423, - 0.399 ; P = O. 031,0. 039, respectively）. Serum GDF15 level was not correlated to underlying etiology and mortality rate of children with HLH. Conclusions GDF15 has been documented as an upstream negative regulator of hepcidin, the central iron regulatory hormone produced primarily by hepatocytes, and is massively produced by activated maerophages in an autoerine fashion to suppress further activation of macrophages. This research finding that serum GDF15 level is significantly elevated in children with HLH suggests that GDF 15 is intimately implicated in the modulation of iron homeostasis and the development of byperferritinemia in HLH.