Departments of Research, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India.
Hepatology. 2015 Apr;61(4):1306-20. doi: 10.1002/hep.27636. Epub 2015 Mar 10.
Acute-on-chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron-regulating proteins are associated with development of MOF and can predict 15- or 30-day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF-MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF-MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF-MOF, compared to other groups (P < 0.01). Whereas expression of iron-regulatory genes was markedly down-regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up-regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former.
Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients.
慢加急性肝衰竭（ACLF）是一种多器官衰竭（MOF）发生率高、死亡率高的疾病。铁稳态失调和巨噬细胞功能障碍与 MOF 发生率增加有关。我们研究了循环铁调节蛋白是否与 MOF 的发生有关，并能预测 ACLF 患者 15 天或 30 天的死亡率。
研究了 120 例 ACLF 患者、20 例代偿性肝硬化患者和 20 例健康对照者。在衍生队列中进行相对蛋白表达谱分析，并在验证队列中进行验证。确定了一组铁调节因子和指标。采用多参数流动细胞术测定不稳定铁池（LIP）。
在 ACLF 和 ACLF-MOF 患者中，血清转铁蛋白（Tf）和铜蓝蛋白水平明显低于肝硬化和对照组患者（P<0.01）。血清铁和铁蛋白水平显著升高（P<0.001；P<0.05），肝铁调素水平降低（P<0.001），且 MOF 患者的这些指标与无 MOF 患者和其他组患者相比差异均有统计学意义（P<0.001）。ACLF-MOF 患者的转铁蛋白饱和度（%SAT）较高（39.2%；P<0.001），且与不良预后相关（危险比：6.970；P<0.01）。与其他组相比，ACLF-MOF 患者循环巨噬细胞亚群的细胞内 LIP 指数显著升高（P<0.01）。与肝硬化患者相比，ACLF 患者的铁调节基因表达明显下调，内质网应激、凋亡和炎症相关基因上调。在前者中还观察到自噬机制的严重失调。
ACLF 患者的铁代谢和转运严重紊乱，MOF 患者更为严重。%SAT、循环肝铁调素和巨噬细胞中的 LIP 与疾病严重程度相关，%SAT 可用于 ACLF 患者的早期预后判断。
