贫血患儿血清生长分化因子15水平及其鉴别重型β地中海贫血的临床意义

Measurement of serum GDF15 levels in various childhood anemias and its clinical application in the differential diagnosis of β-thalassemia major

目的研究不同类型贫血患儿血清生长分化因子15（GDF15）水平及其与贫血程度、红系造血、铁代谢的相关性,以及在重型β地中海贫血（SBT）鉴别中的临床价值。方法入选85例不同类型的贫血患儿,包括缺铁性贫血（IDA）19例,慢性病贫血（ACD）8例,再生障碍性贫血（AA）24例,重型β地中海贫血（SBT）17例,非SBT溶血性贫血（nonSBT HA）17例,另选21例健康体检儿童为对照组;采用ELISA方法测定血清GDF15水平,并分析其与血红蛋白（Hb）水平、网织红细胞参数和铁代谢指标的相关关系,ROC曲线分析血清GDF15水平对于儿童SBT的诊断价值。结果各贫血亚组和对照组之间血清GDF15水平的差异有统计学意义（H=56.75,P〈0.001）。除ACD外,其他贫血亚组的血清GDF15水平均高于对照组,SBT组GDF15水平均高于对照组和其他贫血亚组,差异有统计学意义（P’〈0.003）,其中SBT组患儿血清GDF15中位浓度为对照组的28倍。贫血患儿GDF15与Hb水平呈显著负相关（rs=–0.429,P〈0.01）。贫血患儿GDF15水平与网织红细胞比例、网织红细胞绝对计数、RI和RPI显著正相关（rs=0.264-0.375,P均〈0.05）。贫血患儿GDF15水平与SF、SI和TS均显著正相关（rs=0.473-0.717,P均〈0.01）;与Tf和TIBC呈负相关（rs=–0.345、–0.349,P均〈0.05）。血清GDF15水平诊断重型β地中海贫血的ROC曲线下面积（AUC）为0.969（95%CI：0.937-1.0;P〈0.01）,如以血清GDF15浓度5 000 pg/ml作为截断值,诊断SBT的特异度为98.5%。结论血清GDF15水平显著升高是SBT患儿极为显著的血液生化特征,可能与骨髓无效造血密切相关;血清GDF15水平检测有助于SBT与其他类型溶血性贫血的鉴别。

Objective To measure the serum GDF15 levels, to explore the possible correlations between serum GDF15 levels to anemia severity, hematopoietic activity and iron parameters in various types of childhood anemia, and to investigate its clinical application in the differential diagnosis of severe beta thalassemia（SBT）. Methods Eighty-five children with various types of anemia were enrolled into this study, including 19 cases of IDA, 8 cases of ACD, 24 cases of AA, 17 cases of severe β-thalassemia（SBT） and 17 cases of hemolytic anemia other than SBT（non-SBT HA）. In addition, 21 age- and sex- matched healthy children were recruited as controls. Serum GDF15 levels both in anemic and healthy control subjects were determined by GDF15 Quantikine DGD 150 ELISA assay. Correlations were made between GDF15 levels and Hb concentrations, reticulocyte indices and iron parameters. The diagnostic significance of serum GDF15 determination in the differential diagnosis of SBT was evaluated by ROC analysis. Results With the exception of ACD, serum GDF15 level was significantly higher in each anemic subgroup than that in control group（all P0.001）. Median and range of serum GDF15 concentrations in hemolytic group（HA） were 2299 pg/ml and 444-13368 pg/ml respectively, which were greatly higher than that in iron deficiency anemia（IDA） and aplastic anemia（AA）（both P0.001）. Notably, GDF15 levels were remarkably elevated in SBT, with median and maximal concentrations being 7480 pg/ml and 13368 pg/ml, up to 28-fold and 50-fold increase respectively as compared to median concentration in control group, and were also significantly higher than that in non-SBT HA group（P〈0.0001）. Serum GDF15 levels were negatively correlated to Hb concentrations both in overall anemia and HA groups（with rank correlation coefficients of-0.4286 and-0.4903, and P 〈0.0001 and 0.0032 respectively）. Similarly, serum GDF15 levels were positively correlated to all 4 types of reticulocyte indices in the overall anemia group. Nevertheless, no correlation could be documented in each anemia subgroup. As for the 48 cases of children with measurement of iron parameters, GDF15 levels were positively correlated to serum ferritin（SF）, serum iron（SI） and transferrin saturation（TS）, with P values of 0.0005, 〈0.0001 and 〈0.0001 respectively. While for 23 cases with hemolytic anemia who had iron investigation results, GDF15 was also positively correlated to SI and TS, with P values of 0.0009 and 0.0042 respectively. Finally, the precision of SBT diagnosis based on serum GDF15 determination was 93.7%-100%（95% confidence interval）. With serum GDF15 concentration of 5000 pg/ml as the cutoff point, the specificity of SBT diagnosis was 98.5%. Conclusions As expected, childhood β-thalassemia major in China is also characterized by remarkably elevated serum GDF15 levels, which might be intimately associated with marked bone marrow ineffective erythropoiesis. Determination of serum GDF15 is of great significance in the differential diagnosis of β-thalassemia major.