Abstract

Background & aims: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) was shown to predict outcomes of primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study.

Methods: We performed an international, multicentre, retrospective follow-up study of 3985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least one reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n=2740) 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 confidence intervals (CIs) were determined using a time-dependent multivariable Cox regression analysis.

Results: LSM was independently associated with poor clinical outcomes in the derivation (5324 LSMs, mean follow-up 5.0 ± 3.1 yrs.) and validation (1470 LSMs, mean follow-up 5.0 ± 2.8 yrs.) 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.

Conclusions: 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.

Lay summary: Serum levels of bilirubin and alkaline phosphatase are the only surrogate markers approved by regulatory authorities to assess patients with PBC in therapy trials. Liver histology has been shown to improve prediction of survival beyond these markers but liver biopsy is a potentially harmful, invasive procedure and a serious obstacle to clinical trial recruitment. In the present large, international retrospective cohort study, liver stiffness assessed by vibration-controlled transient elastography was validated as one of the strongest predictive factors of poor clinical outcome in PBC and was shown to improve the prognostic ability of established biochemical markers of treatment response. Studies to evaluate the prognostic impact of LSM changes over time are needed to determine whether LSM can be used as a new surrogate end point for PBC.