肝细胞来源的生物标志物可预测 Child-Pugh 分级 A 酒精性肝硬化患者 2 年内的肝脏相关事件。
Hepatocyte-derived biomarkers predict liver-related events at 2 years in Child-Pugh class A alcohol-related cirrhosis.
机构信息
Université Paris-Cité, Inserm, Centre de Recherche sur l'inflammation, UMR 1149, Paris, France; Service d'hépato-gastroentérologie, Hôpital Trousseau, CHRU de Tours and Faculté de médecine de Tours, France.
AP-HP, Service d'Hépatologie, Hôpital Avicenne, Bobigny, France; Sorbonne Paris Nord, UFR SMBH, Bobigny, France; INSERM UMR 1138, Centre des Cordeliers, Université Paris-Cité, Paris, France.
出版信息
J Hepatol. 2023 Oct;79(4):910-923. doi: 10.1016/j.jhep.2023.05.025. Epub 2023 Jun 9.
BACKGROUND & AIMS: In patients with compensated alcohol-related cirrhosis, reliable prognostic biomarkers are lacking. Keratin-18 and hepatocyte-derived large extracellular vesicle (lEV) concentrations reflect disease activity, but their ability to predict liver-related events is unknown.
METHODS
We measured plasma keratin-18 and hepatocyte lEV concentrations in 500 patients with Child-Pugh class A alcohol-related cirrhosis. The ability of these hepatocyte-derived biomarkers, alone or combined with model for end-stage liver disease (MELD) and FibroTest scores, to predict liver-related events at 2 years was analyzed, taking into account the alcohol consumption at inclusion and during follow-up.
RESULTS
Keratin-18 and hepatocyte lEV concentrations increased with alcohol consumption. In patients without active alcohol consumption at enrollment (n = 419), keratin-18 concentration predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both keratin-18 concentrations >285 U/L and FibroTest >0.74 had a 24% cumulative incidence of liver-related events at 2 years, vs. 5% to 14% in other groups of patients. Similar results were obtained when combining keratin-18 concentrations >285 U/L with MELD >10. In patients with active alcohol consumption at enrollment (n = 81), hepatocyte lEVs predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both hepatocyte lEV concentrations >50 U/L and FibroTest >0.74 had a 62% cumulative incidence of liver-related events at 2 years, vs. 8% to 13% in other groups of patients. Combining hepatocyte lEV concentrations >50 U/L with MELD >10 had a lower discriminative ability. Similar results were obtained when using decompensation of cirrhosis, defined according to Baveno VII criteria, as an endpoint.
CONCLUSION
In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers with FibroTest or MELD scores identifies patients at high risk of liver-related events, and could be used for risk stratification and patient selection in clinical trials.
IMPACT AND IMPLICATIONS
In patients with compensated alcohol-related cirrhosis, reliable predictors of outcome are lacking. In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers (keratin-18 and hepatocyte-large extracellular vesicles) with FibroTest or MELD scores identifies those at high risk of liver-related events at 2 years. The identified patients at high risk of liver-related events are the target-of-choice population for intensive surveillance (e.g., referral to tertiary care centers; intensive control of risk factors) and inclusion in clinical trials.
背景与目的
在代偿期酒精性肝硬化患者中，缺乏可靠的预后生物标志物。角蛋白 18 和肝细胞来源的大细胞外囊泡（lEV）浓度反映疾病活动度，但它们预测肝相关事件的能力尚不清楚。
方法
我们测量了 500 例 Child-Pugh 分级为 A 的酒精性肝硬化患者的血浆角蛋白 18 和肝细胞 lEV 浓度。分析了这些肝细胞衍生生物标志物单独或与终末期肝病模型（MELD）和 FibroTest 评分联合预测 2 年内肝相关事件的能力，同时考虑了纳入时和随访期间的饮酒量。
结果
角蛋白 18 和肝细胞 lEV 浓度随酒精摄入量的增加而增加。在纳入时无活动性饮酒的患者（n=419）中，角蛋白 18 浓度可独立于 FibroTest 和 MELD 预测 2 年内的肝相关事件。角蛋白 18 浓度>285 U/L 且 FibroTest>0.74 的患者 2 年内肝相关事件的累积发生率为 24%，而其他组患者为 5%至 14%。当将角蛋白 18 浓度>285 U/L 与 MELD>10 联合时，也得到了类似的结果。在纳入时具有活动性饮酒的患者（n=81）中，肝细胞 lEV 可独立于 FibroTest 和 MELD 预测 2 年内的肝相关事件。肝细胞 lEV 浓度>50 U/L 且 FibroTest>0.74 的患者 2 年内肝相关事件的累积发生率为 62%，而其他组患者为 8%至 13%。将肝细胞 lEV 浓度>50 U/L 与 MELD>10 联合具有较低的鉴别能力。当使用 Baveno VII 标准定义的肝硬化失代偿作为终点时，也得到了类似的结果。
结论
在 Child-Pugh 分级为 A 的酒精性肝硬化患者中，将肝细胞衍生生物标志物与 FibroTest 或 MELD 评分联合使用可识别出发生肝相关事件风险较高的患者，并可用于临床试验中的风险分层和患者选择。
影响和意义
在代偿期酒精性肝硬化患者中，缺乏可靠的预后预测指标。在 Child-Pugh 分级为 A 的酒精性肝硬化患者中，将肝细胞衍生生物标志物（角蛋白 18 和肝细胞大细胞外囊泡）与 FibroTest 或 MELD 评分联合使用，可识别出 2 年内发生肝相关事件风险较高的患者。识别出的肝相关事件风险较高的患者是强化监测（例如，转至三级护理中心；强化控制危险因素）和纳入临床试验的目标人群。
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