Department of Medicine, Duke University, Durham, NC; Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC.
Hepatology. 2014 Feb;59(2):471-82. doi: 10.1002/hep.26661. Epub 2013 Dec 13.
Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer.
By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.
临床医生依赖于肝纤维化的严重程度，将代偿良好的非酒精性脂肪性肝病 (NAFLD) 患者分为高风险和低风险亚组，以预测其发生与肝脏相关的发病率和死亡率的风险。我们比较了高风险和低风险 NAFLD 患者的肝基因表达谱，以确定区分这两组的过程，这些过程可能是新的生物标志物或治疗靶点。使用微阵列分析方法对低风险、“轻度”NAFLD 患者（纤维化分期 0-1；n=40）和高风险、“重度”NAFLD 患者（纤维化分期 3-4；n=32）的经皮肝活检组织中的基因表达进行了特征描述。在第二个独立队列中对研究结果进行了验证，并通过实时聚合酶链反应和免疫组织化学（IHC）进行了确认。作为一个整体，有不良 NAFLD 结局风险的患者的肝损伤和更严重的纤维化（重度 NAFLD）明显比具有良好预后的临床无法区分的 NAFLD 患者（轻度 NAFLD）更严重。一个 64 基因谱能够重复区分重度 NAFLD 和轻度 NAFLD，并且该谱内的一个 20 基因亚组与 NAFLD 严重程度相关，与其他已知影响 NAFLD 进展的因素无关。在重度 NAFLD 中，多个涉及组织修复/再生和某些代谢相关的基因被诱导。通路分析和 IHC 证实，在重度 NAFLD 中代谢和再生途径失调，并揭示了重度 NAFLD、心血管疾病和癌症的基因表达模式之间的重叠。
通过证明在严重 NAFLD 肝脏中差异激活的特定代谢和修复途径，基因谱分析确定了可用于改善风险最大的 NAFLD 患者的诊断和治疗的新靶点。
