Complementary prognostic value of nonalcoholic fatty liver disease and cardiovascular-kidney-metabolic syndrome for major adverse cardiovascular and liver events: a prospective cohort study

Background Cardiovascular-kidney-metabolic (CKM) syndrome describes a progressive continuum of metabolic, cardiovascular, and renal dysfunction, yet the liver—both a driver and target of systemic metabolic injury—remains underrepresented. Overlooking liver risk may underestimate CKM-related disease burden. Unlike metabolic dysfunction-associated steatotic liver disease, nonalcoholic fatty liver disease (NAFLD) excludes overlapping metabolic components, making it more suitable for integration into the CKM framework. Purpose To investigate the interaction between NAFLD and CKM stages and evaluate their joint prognostic value for major adverse cardiovascular events (MACE) and major adverse liver events (MALE). Methods 313,970 participants in CKM stages 0–3 were included from the UK Biobank. NAFLD was defined as fatty liver index ≥60, excluding other liver diseases and excessive alcohol intake. CKM stages 0-2 were defined as non-advanced, and stage 3 as advanced. The primary endpoint was MACE (myocardial infarction, stroke, heart failure, coronary artery bypass grafting, or cardiovascular death), and the secondary endpoint was MALE (cirrhosis, hepatocellular carcinoma, or liver-related death). Results Over a median 15.70 years of follow-up, 32,110 MACE and 1,599 MALE events occurred. NAFLD prevalence increased progressively across CKM stages (<0.1%, 13%, 40%, and 73%). In fully adjusted Cox models, NAFLD (MACE: HR 1.53, 95% CI 1.49-1.56; MALE: HR 3.00, 95% CI 2.68-3.35) and advanced CKM stage (MACE: HR 1.79, 95% CI 1.69-1.88; MALE: HR 2.07, 95% CI 1.65-2.59) were independently associated with higher outcome risk. The co-occurrence of NAFLD and advanced CKM stages synergistically amplified MACE and MALE risk, with the highest hazard observed in participants with both conditions (MACE: HR 2.33, 95% CI 2.19-2.47; MALE: HR 5.09, 95% CI 3.97-6.54) compared with non-NAFLD and non-advanced CKM participants. A significant multiplicative interaction between NAFLD and CKM stage was observed for MACE (Pinteraction<0.001), with NAFLD showing a stronger association in early CKM stages (HR 1.51, 95% CI 1.48-1.55) but no significant association in stage 3 (HR 1.09, 95% CI 0.97-1.23). Mediation analysis indicated that NAFLD accounted for 41.12% of the positive association between CKM stage and MALE. Time-dependent ROC analyses demonstrated superior and stable discriminative performance for the combined NAFLD-CKM model compared with either factor alone throughout follow-up. Conclusions NAFLD and CKM stages synergistically increase cardiovascular and hepatic risk. NAFLD amplifies cardiovascular risk in early CKM stages and substantially mediates CKM-related liver risk, supporting its role as an early, clinically modifiable intermediate phenotype. Incorporating NAFLD into CKM assessment provides complementary prognostic information for more precise multi-organ risk stratification and earlier intervention.