Cardiovascular-Kidney-Metabolic Progression Associated with Major Adverse Liver Outcomes: Mediating Roles of Plasma Metabolites

Jingjing Liang¹Yongqi Liang^2,3Liwen Chen¹Mengyi Cai¹Shuxian Li⁴Lige He¹Yining Xu¹Yilan Tan²Linna Li^1*Xian-Bo Wu^2,5*Mengchen Zou^1*

• ¹Southern Medical University Nanfang Hospital Department of Endocrinology and Metabolism, Guangzhou, China
• ²Southern Medical University School of Public Health, Guangzhou, China
• ³JIangmen Maternity and Child Health Care Hospital, Jiangmen, China
• ⁴Southern Medical University Nanfang Hospital Department of Respiratory Medicine, Guangzhou, China
• ⁵Southern Medical University Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou, China

Objectives Previous research has not yet established whether and how cardiovascular-kidney-metabolic (CKM) syndrome progression affects liver outcomes. Methods This prospective study utilized data from UK Biobank cohort, including 415,713 individuals without prevalent liver diseases or substance use disorder. CKM syndrome stages were defined according to the Presidential Advisory from the American Heart Association. Outcomes were major adverse liver outcomes (MALOs), including hospitalization for metabolic dysfunction-associated steatotic liver disease (MASLD), severe liver disease (SLD) and liver-specific mortality. Cox proportional hazards models examined the association between CKM stages and MALOs. The CMAverse R package was employed to investigate potential mediating effects of plasma metabolomic data. Results After multivariable adjustment, a higher CKM stage was associated with elevated risks of incident MASLD hospitalization (hazard ratios (HRs) = 7.38, 95% confidence intervals (CIs): 4.34, 12.55), SLD hospitalization (HR = 3.46, 95% CI:1.94, 6.16), and liver-specific mortality (HR = 4.35; 95% CI: 1.38, 13.69). CKM components were respectively and cumulatively associated with MALOs (all p < 0.05). Mediation analyses indicated that tyrosine partially mediated the associations of CKM stage with MASLD-related hospitalization (7.62%), SLD-related hospitalization (9.46%) and liver-related death (11.19%); while linoleic acid-to-total fatty acids ratio partially mediated MASLD hospitalization (41.18%), SLD hospitalization (34.30%) and liver-related death (45.17%) (all q < 0.001). Conclusions CKM progression elevates MALOs risk, partially mediated by amino acids and fatty acids. These findings identify high-risk patients who may benefit from targeted liver surveillance for secondary prevention of CKM syndrome.