Research Haematology Department, Cancer Institute, University College London, UK
University College London Hospitals and.
Haematologica. 2017 Oct;102(10):1640-1649. doi: 10.3324/haematol.2017.170605. Epub 2017 Jun 22.
Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21 mg/kg/day (odds ratio 48). Labile plasma iron was >3-fold higher when this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. The risk of cardiosiderosis was decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modeling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially when iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake and decreased both intracellular reactive oxygen species and labile plasma iron under conditions favoring monoferric species. In conclusion, high transferrin iron utilization, relative to the transfusion-iron load rate, decreases the risk of cardiosiderosis. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species.
血色病是输血依赖型地中海贫血患者死亡的主要原因。血浆中非转铁蛋白结合铁及其具有氧化还原活性的成分，即不稳定血浆铁，是血色病铁过载的主要来源。在 73 名有或无血色病的患者中确定了危险因素。患有血色病的患者可溶性转铁蛋白受体 1 水平显著降低（比值比 21）。当输血铁负荷率超过红细胞转铁蛋白摄取率（由可溶性转铁蛋白受体 1 推导得出）超过 0.21mg/kg/天时（比值比 48），这种风险会增加。当超过此摄取率阈值时，不稳定血浆铁增加了 3 倍以上，但非转铁蛋白结合铁和转铁蛋白饱和度相当。当这种摄取率阈值升高时，患者的血色病风险降低，且肝铁、铁蛋白和不稳定血浆铁水平较低，或胆红素、网织红细胞计数或铁调素水平较高。我们假设高红细胞转铁蛋白摄取率通过增加脱铁转铁蛋白的红细胞再生来降低血色病的风险。为了验证这一点，在模拟转铁蛋白对柠檬酸铁中非转铁蛋白结合铁形态影响的条件下，在 HL-1 心肌细胞中检查了铁摄取和细胞内活性氧。当铁与柠檬酸的比值特别超过 1:100 时，即有利于动力学不稳定的单高铁而不是低聚物的条件下，细胞内铁和活性氧随着柠檬酸铁浓度的增加而增加。当有利于单高铁物种时，脱铁转铁蛋白的过量铁结合当量抑制铁摄取并降低细胞内活性氧和不稳定血浆铁。总之，相对于输血铁负荷率，高转铁蛋白铁利用率降低了血色病的风险。一个假定的机制是活跃的红细胞短暂地再生脱铁转铁蛋白，迅速结合可检测的不稳定血浆铁-柠檬酸单铁物种。
