Hypercholesterolemia is associated with dysregulation of lipid metabolism and poor prognosis in primary biliary cholangitis

Background and aims Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the lipid metabolism. Methods Of note, 531 patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation (LT) and cirrhosis-related complications. Untargeted lipidomics was performed in 89 patients and 28 healthy controls (HC). Results Baseline TC was independently associated with poor clinical outcomes and adjusted C-statistics were 0.8035 (95% confidence interval [CI]: 0.7372–0.8470) and 0.8754 (95% CI: 0.7777–0.9067) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over the years and comparable to the Globe score. The 5.2 mmol/L cut-off optimally divided patients into low- and high-risk groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Untargeted lipidomics indicated an upregulation of lipid families in high-risk patients. Pathway analysis of 66 upregulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-risk patients, which were associated with poor clinical outcomes. Conclusions Our results indicate that patients with PBC having baseline TC levels above 5.2 mmol/L have unique lipidome characteristics and are at a higher risk of poor clinical outcomes.