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Summary: Background and Aims: The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first‐step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met‐ALD and ALD) and various age classes. Methods: We analysed a total of 3372 individuals at risk of SLD from the 2017–2018 National Health and Nutrition Examination Survey (NHANES17‐18), projected to 152.3 million U.S. adults, 300,329 from the UK Biobank (UKBB) and 57,644 from the Biobank Japan (BBJ). We assessed liver stiffness measurement (LSM) ≥8 kPa and liver‐related events occurring within 3 and 10 years (3/10 year‐LREs) as outcomes. We defined MASLD, MetALD, and ALD according to recent international recommendations. Results: FIB4 sensitivity for LSM ≥ 8 kPa was low (27.7%), but it ranged approximately 80%‐90% for 3‐year LREs. Using FIB4, 22%–57% of subjects across the three cohorts were identified as candidates for vibration‐controlled transient elastography (VCTE), which was mostly avoidable (positive predictive value of FIB4 ≥ 1.3 for LSM ≥ 8 kPa ranging 9.5%–13% across different SLD categories). Sensitivity for LSM ≥ 8 kPa and LREs increased with increasing alcohol intake (ALD>MetALD>MASLD) and age classes. For individuals aged ≥65 years, using the recommended age‐adjusted FIB4 cut‐off (≥2) substantially reduced sensitivity for LSM ≥ 8 kPa and LREs. Conclusions: The first‐step FIB4 EASL CP is poorly accurate and feasible for individuals at risk of SLD in the general population. It is crucial to enhance the screening strategy with a first‐step approach able to reduce unnecessary VCTEs and optimise their yield. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of liver‐related events (LREs). Here, we have assessed the ability of a composite score based on clinical features, metabolic comorbidities, and genetic variants to predict LREs. A total of 546 consecutive patients with NAFLD were recruited and stratified according to the fibrosis‐4 (FIB‐4) index. LREs were defined as occurrence of hepatocellular carcinoma or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LREs. The UK Biobank was used as the validation cohort, and severe liver disease (incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation) was used as the outcome. LREs were experienced by 58 patients, only one of whom was in the cohort of patients with a FIB‐4 score < 1.3. Multivariate Cox regression analysis of 229 patients with a FIB‐4 score ≥ 1.3 highlighted clinical variables independently associated with the development of LREs, including older age, low platelet count, low albumin, low high‐density lipoprotein cholesterol, certain genetic factors, and interactions between genetic factors and sex or diabetes. The area under the curve (AUC) for the model was 0.87 at 1, 3, and 5 years. Our novel Genetic and Metabolic Staging (GEMS) scoring system was derived from the Cox model linear predictor, ranked from 0 to 10, and categorized into five classes (0‐5, 5‐6, 6‐7, 7‐8, and 8‐10). The risk of LREs increased from 4% in patients in the best class (GEMS score 0‐5) to 91% in the worst (GEMS score 8‐10). GEMS score was associated with incident severe liver disease in the study population (hazard ratio, 1.56; 95% confidence interval, 1.48‐1.65; P < 0.001) as well as in the UK Biobank cohort where AUCs for prediction of severe liver disease at 1, 3, and 5 years were 0.70, 0.69, and 0.67, respectively. Conclusion: The novel GEMS scoring system has an adequate ability to predict the outcome of patients with NAFLD. [ABSTRACT FROM AUTHOR]