Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, USA.
Aliment Pharmacol Ther. 2012 Mar;35(5):600-12. doi: 10.1111/j.1365-2036.2011.04982.x.
Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat.
To describe the global serum proteome of patients with DILI and controls.
A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples.
Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97).
This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.
特异质药物性肝损伤（DILI）是一种复杂的疾病，难以预测、诊断和治疗。
描述 DILI 患者和对照者的全球血清蛋白质组。
采用无标记、基于质谱的定量蛋白质组学方法，研究 74 例 DILI 患者（在 DILI 发病后 14 天内采集）和 40 例对照者的血清样本中的蛋白质表达。对 21 例有 6 个月随访血清样本的 DILI 患者进行亚组的纵向分析。
根据肝损伤模式、严重程度和因果关系评估，对 DILI 患者进行比较，发现各组之间有许多差异表达的优先级 1 蛋白。延胡索酰乙酰乙酸酶的表达与丙氨酸氨基转移酶（ALT；r = 0.237；P = 0.047）、天冬氨酸氨基转移酶（AST；r = 0.389；P = 0.001）和碱性磷酸酶（r = -0.240；P = 0.043）相关，这是比较肝细胞性与胆汁淤积性或混合性损伤患者时唯一具有显著差异表达的蛋白。在纵向分析中，从 DILI 发病到 6 个月随访时，53 个优先级 1 蛋白的表达显著变化，几乎所有蛋白的表达水平都恢复到与对照者相当的水平。当比较 DILI 组和对照组时，鉴定出 92 个具有显著差异表达的血清优先级 1 蛋白。模式分析显示，这些蛋白是炎症、免疫系统激活和几种肝毒性特异性途径的组成部分。载脂蛋白 E 的表达对区分 DILI 患者和对照者的能力最强（89%的正确分类；AUROC = 0.97）。
该蛋白质组学分析鉴定出差异表达的蛋白，这些蛋白是先前涉及特异质药物性肝损伤发病机制的途径的组成部分。
