Background & Aims

Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables.

Methods

We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2).

Results

We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature–MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73–0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71–0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001).

Conclusions

We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.

中文翻译：

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基因表达特征与终末期肝病评分模型的结合可预测严重酒精性肝炎患者的生存

背景与目标

重度酒精性肝炎 (AH) 患者在 90 天内死亡的风险很高。可引起严重不良事件的皮质类固醇是唯一可提高短期生存率的治疗方法。预测严重 AH 患者的预后是一项挑战。因此，我们开发了一个评分系统来预测患者的生存，整合基线分子和临床变量。

方法

我们从 2006 年 7 月至 2013 年 12 月在比利时布鲁塞尔（推导队列）诊断为严重 AH 并接受皮质类固醇治疗的 71 名连续患者中获取了固定的肝活检样本。通过微阵列分析基因表达模式，并收集了 180 天的临床数据。我们确定了在皮质类固醇治疗开始后 90 天和 180 天与未进行肝移植的生存相关的基因表达特征和临床数据。使用从 2010 年 3 月至 2015 年 2 月在比利时和瑞士的医院（验证队列 1）收集的 48 名连续接受皮质类固醇治疗的严重 AH 患者的肝活检以及来自 20 名患者（9 名接受皮质类固醇治疗）的肝活检对结果进行了验证，

结果

我们整合了 123 个基因的表达模式数据和终末期肝病 (MELD) 评分模型，将患者分为生存率低（29% 存活 90 天，26% 存活 180 天）和存活率高（76% 存活90 天和 65%在推导队列中存活 180 天）（ P < .001）。我们将此分配系统命名为基因特征-MELD (gs-MELD) 评分。在验证队列 1 中，gs-MELD 评分区分了存活率低的患者（43% 存活 90 天）和存活率高的患者（96% 存活 90 天）（P < .001）。gs-MELD 评分还可以区分 180 天时存活率低（34% 存活）和 180 天时存活率高（84% 存活）的患者（P<.001）。接受者操作员特征曲线下评分的时间依赖性面积对于 90 天的存活率是 0.86（95% 置信区间 0.73-0.99），对于 180 天的存活率是 0.83（95% 置信区间 0.71-0.96）。该评分优于其他临床模型来预测验证队列 1 中重度 AH 患者的生存率。在验证队列 2 中，gs-MELD 区分了 90 天生存率低（12% 生存）的患者与 90 天生存率高的患者天 (100%) ( P  < .001)。

结论

我们整合了基线肝脏基因表达模式和 MELD 评分的数据，以创建 gs-MELD 评分系统，该系统可识别患有严重 AH 的患者，无论是否接受皮质类固醇治疗，最有可能和最不可能存活 90 天和 180 天。