Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France.
Public Health Unit, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Paris, France.
J Hepatol. 2022 Dec;77(6):1545-1553. doi: 10.1016/j.jhep.2022.06.017. Epub 2022 Jun 28.
BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study.
We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis.
LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM.
LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered.
Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.
振动控制瞬时弹性成像（VCTE）的肝硬度测量（LSM）已被证明可预测原发性胆汁性胆管炎（PBC）患者的结局，这在一些小型研究中已有报道。我们旨在通过一项大型队列研究来验证 LSM 的预后价值。
我们进行了一项国际性、多中心、回顾性随访研究，纳入了在 12 个国家的 23 个中心就诊的 3985 例 PBC 患者。入选标准包括至少有 1 次可靠的 VCTE 测量的 LSM 值和至少 1 年的随访。我们构建了独立的推导（n=2740）和验证（n=568）队列。主要终点是出现不良临床结局的时间，定义为与肝脏相关的并发症、肝移植或死亡。使用时间依赖性多变量 Cox 回归分析确定风险比（HR）及其 95%置信区间（CI）。
LSM 与推导（5324 次 LSM，平均随访 5.0±3.1 年）和验证（1470 次 LSM，平均随访 5.0±2.8 年）队列中的不良临床结局独立相关：每增加 1kPa 的调整 HR（95%CI）分别为 1.040（1.026-1.054）和 1.042（1.029-1.056）（均<0.0001）。基线时的调整 C 统计量（95%CI）分别为 0.83（0.79-0.87）和 0.92（0.89-0.95）。在 5~30kPa 之间，log-HR 随 LSM 的增加呈单调函数增加。LSM 的预测价值在时间上是稳定的。LSM 提高了生化应答标准、纤维化评分和预后评分的预后能力。8kPa 和 15kPa 的截断值可最佳地区分低、中、高危组。根据 LSM，40%的患者处于中高危。
VCTE 的 LSM 是 PBC 结局的主要、独立、验证过的预测因子。它作为 PBC 临床获益的替代终点的价值应予以考虑。
