Risk-associated and clinically informative biomarkers for cardiovascular risk stratification in metabolic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with atherosclerotic cardiovascular disease (ASCVD), yet the magnitude of cardiovascular risk across various disease labels and the clinical utility of readily available risk-associated markers remains unclear.

We searched PubMed, Embase, Web of Science, and the Cochrane Library from 1 January 2000 to 30 September 2025. Observational studies, as well as randomized trials contributing baseline cross-sectional observational data, were included. We pooled relative effects for (i) 10-year ASCVD high-risk classification as defined by established risk engines and (ii) incident major adverse cardiovascular events (MACE). Heterogeneity (I² and τ²), small-study effects (funnel plots and Egger's tests), and leave-one-out sensitivity analyses were assessed. Risk of bias was evaluated using customized Newcastle-Ottawa Scales.

Fifty-two studies were included. Compared with non-steatotic comparators, steatotic liver disease was associated with a higher overall cardiovascular burden (pooled relative effect 2.02, 95 % CI 1.90-2.14). When stratified by outcome, pooled effects were 1.91 (95 % CI 1.60-2.29) for predicted 10-year ASCVD high-risk classification and 1.74 (95 % CI 1.43-2.12) for incident MACE. Associations were consistent across disease labels, including nonalcoholic fatty liver disease (NAFLD; 1.98, 95 % CI 1.81-2.16), with higher but less precise estimates observed for nonalcoholic steatohepatitis (NASH; 3.60, 95 % CI 1.16-6.04). Readily available biomarkers may help complement established ASCVD risk scores by refining cardiovascular risk stratification in individuals with MASLD. Several readily available markers were informative for cardiovascular risk: Fatty Liver Index (FLI) ≥60 (hazard ratio [HR] 1.61, 95 % CI 1.12-2.11) and ≥30 (HR 1.39, 95 % CI 1.11-1.66); Fibrosis-4 index (FIB-4) ≥1.30 (HR 2.25, 95 % CI 1.84-2.65); blood pressure ≥130/85 mmHg (HR 2.16, 95 % CI 1.81-2.51); triglyceride-glucose index (TyG) >8.716 (HR 1.40, 95 % CI 1.26-1.54); and type IV collagen 7S ≥5 ng/mL (HR 2.37, 95 % CI 1.45-4.29). Compared with controls, MASLD was also associated with an adverse biomarker profile, including higher high-sensitivity C-reactive protein (hs-CRP) (+1.06 mg/L), homeostasis model assessment of insulin resistance (HOMA-IR) (+1.65), alanine aminotransferase (ALT) (+8.89 U/L), aspartate aminotransferase (AST) (+6.10 U/L), gamma-glutamyl transferase (GGT) (+13.23 U/L), total cholesterol (TC) (+9.05 mg/dL), triglycerides (TG) (+48.33 mg/dL), low-density lipoprotein cholesterol (LDL-C) (+8.46 mg/dL), glycated hemoglobin (HbA1c) (+0.43 %), and lower high-density lipoprotein cholesterol (HDL-C) (-8.41 mg/dL).

MASLD is associated with an approximate twofold increased risk of cardiovascular events, but this association varies based on population and clinical context. A concise and pragmatic panel-FIB-4, FLI, blood pressure, and triglyceride-glucose index, with type IV collagen 7S where available (and NAFLD-LFS in selected settings)-may complement established ASCVD risk assessment and support earlier, risk-guided prevention in routine MASLD care.