Risk Scores for Prediction of Major Cardiovascular Events in Non-Alcoholic Fatty Liver Disease: A No Man’s Land?

**Background:** Cardiovascular disease (CVD) is the leading cause of mortality globally, and non-alcoholic fatty liver disease (NAFLD) affects an estimated 32.4% of the world's population. Patients with NAFLD have a twofold increased risk of cardiovascular events, and this risk is doubled in those with liver fibrosis. Despite this, no validated CVD risk score specific to NAFLD patients exists, and traditional risk scores tend to underestimate CV risk in this population. This narrative review aims to assess current risk scores and their utility for predicting cardiovascular events among patients with NAFLD.

**Methods:** The authors performed a literature search between January 2012 and January 2023 on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org, and ClinicalTrials.gov for English-language articles. Search terms included 'NAFLD', 'non-alcoholic fatty liver disease', 'risk scores', 'cardiovascular risk scores', 'cardiovascular risk factors', 'mortality prediction scores', 'cardiovascular risk assessment', and 'prediction models'. Articles were selected based on relevance to the review objective.

**Key Results:** The review synthesizes evidence from multiple studies and meta-analyses. A meta-analysis by Targher et al. found that NAFLD patients had a 64% higher likelihood of fatal or nonfatal cardiovascular events compared to those without NAFLD. NAFLD prevalence in type 2 diabetes (T2DM) patients ranges from 70% to 95%, and in severe obesity can reach up to 98%. Hepatic fibrosis is a significant predictor of all-cause mortality, CV mortality, cirrhosis, and hepatocellular carcinoma. The Framingham risk score underestimates CV risk in NAFLD patients due to overlapping features with metabolic syndrome. The NAFLD fibrosis score (>0.68) increased the probability of death by four times. The fatty liver index shows strong correlation with incident CVD. The APRI (AST-to-Platelet Ratio Index) significantly correlates with CV risk, particularly in younger premenopausal women. Hs-CRP levels below 0.5 mg/dL were identified as an independent risk factor for all-cause and cardiovascular mortality in MAFLD patients (median follow-up 22.3 years). A meta-analysis by Tang et al. found that among 7,951 NAFLD patients, more than one-third had carotid atherosclerosis (OR 3.20), with stroke prevalence of 5.04% (ischemic stroke 6.05%, hemorrhagic stroke 2.22%). Lean NAFLD patients showed higher ASCVD scores than obese NAFLD patients, and lean subjects with significant liver fibrosis had a higher probability of ASCVD.

**Clinical Implications:** The review highlights that current guidelines do not recognize NAFLD as an independent risk factor for CVD, despite mounting evidence of its involvement in incident CVD. The authors emphasize that traditional CV risk scores are inadequate for NAFLD patients and that new risk scores incorporating liver fibrosis severity and metabolic factors are urgently needed. Non-invasive fibrosis scores (NAFLD fibrosis score, FIB-4, APRI, fatty liver index) may serve dual purposes for assessing both liver disease severity and CV risk. Early clinical intervention in at-risk patients could alter disease course. Emerging therapies targeting both NAFLD and cardiometabolic risk factors (GLP1 agonists, SGLT2 inhibitors, farnesoid X receptor agonists) show promise. The authors call for prospective long-term studies with homogeneous diagnostic criteria to test whether NAFLD diagnosis can improve CVD risk stratification.