Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, Dallas, Texas; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Cliniques universitaires de Bruxelles Hôpital Erasme, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Clin Gastroenterol Hepatol. 2022 Mar;20(3):651-657. doi: 10.1016/j.cgh.2021.02.041. Epub 2021 Mar 2.
BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability.
All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients.
The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices.
The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.
严重酒精性肝炎（AH）是一种高度致命的疾病，预测其预后仍然是一个挑战。我们之前已经确定并验证了一种包含 123 个肝脏基因预后标志物的综合评分和终末期肝病模型（MELD）评分：基因标志物-MELD。然而，由于需要进行肝活检，这限制了其临床应用。因此，我们旨在确定一种基于血浆蛋白的基因标志物替代物，并对其独立验证其预后能力。
所有患者均在比利时布鲁塞尔大学附属医院（Erasme 医院）被诊断为严重 AH，并在入院前未接受任何治疗时采集血浆样本。主要结局为 90 天内死亡或肝移植。我们使用名为“组织表达转化为分泌组（TexSEC）”的计算流程，将基于肝脏转录组的预后标志物转化为基于血浆的分泌组标志物，通过比较其肝脏分子失调状态并结合 MELD 评分，在 50 例患者中对该标志物进行优化。在 57 例患者中独立验证了该综合评分。
TexSEC 和优化过程确定了一个由 6 个血浆蛋白组成的标志物面板，作为 123 个基因标志物的替代物。通过使用基因标志物-MELD 方程的系数，创建了包含 MELD 评分和血浆标志物（ps）-MELD 评分的复合评分。在验证队列中，高风险的 ps-MELD（n=23；40%）与 90 天内死亡或肝移植显著相关（调整后的危险比，4.57；95%可信区间，2.15-9.30；P<0.001）。ps-MELD 评分具有稳定的高预后相关性（时间依赖性受试者工作特征曲线下面积，>0.80），并且随时间校准良好；它通过各种模型性能指标一致地优于现有临床评分。
高风险的 ps-MELD 评分与严重 AH 患者的短期生存率相关。
