Service des Maladies de l'appareil digestif, Hôpital Huriez, Lille, France.
Unité INSERM 995, Faculté de médecine, Lille, France.
Hepatology. 2017 Nov;66(5):1464-1473. doi: 10.1002/hep.29240. Epub 2017 Sep 26.
Understanding the mechanisms of outcome according to the time frame can help optimize the therapeutic development in severe alcoholic hepatitis. We assessed short-term and long-term survival in severe alcoholic hepatitis based on baseline disease severity, extent of therapeutic improvement, long-term influence of alcohol relapse, and their interaction. Data and alcohol consumption were prospectively recorded in 398 patients treated with corticosteroids in the short term (from corticosteroid initiation to 6 months) and long term (from 6 months to maximum follow-up time). Cumulative incidence rate of first alcohol relapse was 25.2%, 33.7%, and 35.2% at 1, 3, and 5 years, respectively. Alcohol relapse (≥30 g/day) was not associated with mortality (P = 0.24) during the short-term period (1,606 patient-months at risk), but the Lille (P < 0.0001) and Model for End-Stage Liver Disease (P < 0.0001) scores were independent prognostic factors. In patients who were alive at 6 months (median follow-up, 42 months; interquartile range 11-88), corresponding to 10,413 patient-months at risk, alcohol consumption (≥30 g/day) was associated with mortality (hazard ratio, 3.9; P < 0.0001). Additional analysis with abstinent patients as a reference showed a dose effect of alcohol on the hazard ratio of death: 2.36 (P = 0.052) for 1-29 g/day, 3.2 (P = 0.003) for 30-49 g/day, 3.51 (P < 0.0001) for 50-99 g/day, and 5.61 (P < 0.0001) for ≥ 100 g/day. The baseline Model for End-Stage Liver Disease score was not predictive of long-term outcome, while Lille score (P = 0.02) and alcohol relapse (P < 0.0001) were independent prognostic factors.
This study shows that new therapeutic development for severe alcoholic hepatitis must target liver injury in the short term and alcohol consumption in the long term; thus, health agencies can endorse future study designs adapted to the time frame of factors influencing mortality; with this in mind, drug-targeting mechanisms involved in liver injury should only be tested for the short-term period. (Hepatology 2017;66:1464-1473).
了解根据时间框架的结局机制有助于优化重症酒精性肝炎的治疗开发。我们根据基线疾病严重程度、治疗改善程度、酒精复发的长期影响及其相互作用，评估了重症酒精性肝炎的短期和长期生存率。
前瞻性地记录了 398 例接受短期（从皮质类固醇开始到 6 个月）和长期（从 6 个月到最大随访时间）皮质类固醇治疗的患者的数据和酒精摄入量。在第 1、3 和 5 年，首次酒精复发的累积发生率分别为 25.2%、33.7%和 35.2%。酒精复发（≥30g/天）与短期（1606 患者月风险）期间的死亡率无关（P=0.24），但 Lille 和终末期肝病模型（P<0.0001）评分是独立的预后因素。在 6 个月时存活的患者（中位随访时间 42 个月；四分位间距 11-88），相应的风险患者有 10413 例，酒精摄入（≥30g/天）与死亡率相关（危险比，3.9；P<0.0001）。对以戒酒患者为参照的额外分析显示，酒精对死亡风险比的剂量效应：1-29g/天为 2.36（P=0.052），30-49g/天为 3.2（P=0.003），50-99g/天为 3.51（P<0.0001），≥100g/天为 5.61（P<0.0001）。基线终末期肝病模型评分不能预测长期结局，而 Lille 评分（P=0.02）和酒精复发（P<0.0001）是独立的预后因素。
本研究表明，重症酒精性肝炎的新治疗开发必须针对短期的肝损伤和长期的酒精摄入；因此，卫生机构可以支持未来针对影响死亡率的因素的时间框架的研究设计；考虑到这一点，仅应在短期内测试涉及肝损伤的药物靶向机制。
